Inhibition of dopamine conversion to norepinephrine by Clostridia metabolites appears to be a (the) major cause of autism, schizophrenia, and other neuropsychiatric disorders.
William Shaw, PhD
Concentrations of the dopamine metabolite homovanillic acid, or HVA, have been reported to be much higher in the urine of children with autism compared to controls. In the same study, severity of autism symptoms was directly related to the concentration of HVA. There was a relation between the urinary HVA concentration and increased agitation, stereotypical behaviors, and reduced spontaneous behavior. Furthermore, vitamin B6, which has been shown to decrease autistic symptoms, decreases urinary HVA concentrations. Excess dopamine has been implicated in the etiology of psychotic behavior and schizophrenia for over 40 years. Drugs that inhibit dopamine binding to dopaminergic receptors have been some of the most widely used pharmaceuticals used as antipsychotic drugs and have been widely used in the treatment of autism. Recent evidence reviewed below indicates that dopamine in high concentrations may be toxic to the brain.
Dopamine is a very reactive molecule compared with other neurotransmitters, and dopamine degradation naturally produces oxidative species (Figure 1). More than 90 percent of dopamine in dopaminergic neurons is stored in abundant terminal vesicles and is protected from degradation. However, a small fraction of dopamine is cytosolic, and it is the major source of dopamine metabolism and presumed toxicity. Cytosolic dopamine (Figure 1) undergoes degradation to form 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) via the monoamine oxidase pathway. Alternatively, dopamine undergoes oxidation in the presence of excess iron or copper (common in autism and schizophrenia) to form dopamine cyclized o-quinone, which is then converted to dopamine cyclized o-semiquinone, depleting NADPH in the process. Dopamine cyclized o-semiquinone then reacts with molecular oxygen to form oxygen superoxide free radical, an extremely toxic oxidizing agent. In the process, dopamine cyclized o-quinone is reformed, resulting in a vicious cycle extremely toxic to tissues producing dopamine, including the brain, peripheral nerves, and the adrenal gland.
It is estimated that each molecule of dopamine cyclized o-quinone produces thousands of molecules of oxygen superoxide free radical in addition to depleting NADPH. The o-quinone also reacts with cysteine residues on glutathione or proteins to form cysteinyl-dopamine conjugates (Figure 1). One of these dopamine conjugates is converted to N-acetylcysteinyl dopamine thioether, which causes apoptosis (programmed cell death) of dopaminergic cells. These biochemical abnormalities cause severe neurodegeneration in pathways that utilize dopamine as a neurotransmitter. Neurodegeneration is due to depletion of brain glutathione and NADPH as well as the overproduction of oxygen superoxide free radicals and neurotoxic N-acetylcysteinyl dopamine thioether. In addition, the depletion of NADPH also results in a diminished ability to convert oxidized glutathione back to its reduced form.
What is the likely cause of elevated dopamine in autism? A significant number of studies have documented increased incidence of stool cultures positive for certain species of Clostridia bacteria in the intestine in children with autism using culture and PCR techniques. All these studies have indicated a disproportionate increase in various Clostridia species in stool samples compared to normal controls. In addition, metabolic testing has identified the metabolites 3-(3-hydroxyphenl)-3-hydroxypropionic acid (HPHPA) and 4-cresol from Clostridia bacteria at significantly higher concentrations in the urine samples of children with autism and in schizophrenia.
Treatment with antibiotics against Clostridia species, such as metronidazole and vancomycin, eliminates these urinary metabolites with reported concomitant improvement in autistic symptoms. In addition, I had noticed a correlation between elevated HPHPA and elevated urine homovanillic acid (HVA). The probable mechanism for this correlation is that certain Clostridia metabolites have the ability to inactivate dopamine beta-hydroxylase, which is needed for the conversion of dopamine to norepinephrine (Figure 2).
Figure 2. Effect of Clostridia metabolites on human catecholamine metabolism. DHPPA, 4-cresol, HPHPA, HVA, and VMA are all measured in The Great Plains Laboratory organic acid test.
Such metabolites are not found at only trace levels. The concentration of the Clostridia metabolite HPHPA in children with autism may sometimes exceed the urinary concentration of the norepinephrine metabolite vanillylmandelic acid (VMA) by a thousand fold on a molar basis and may be the major organic acid in urine in those with severe gastrointestinal Clostridia overgrowth, and even exceed the concentration of all the other organic acids combined. Dopamine beta hydroxylase that converts dopamine to norepinephrine in serum of severely intellectually disabled children with autism was much lower than in those who were higher functioning. Decreased urine output of the major norepinephrine metabolite meta-hydroxyphenolglycol (MHPG) was decreased in urine samples of children with autism, consistent with inhibition of dopamine beta hydroxylase.
Many physicians treating children with autism have noted that the severity of autistic symptoms is related to the concentration of the Clostridia marker 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) in urine. These are probably the children with autism with severe and even psychotic behavior treated with Risperdal® and other anti-psychotic drugs, which block the activation of dopamine receptors by excess dopamine. I have identified a number of species of Clostridia species that produce HPHPA including C. sporogenes, C.botulinum, C. caloritolerans, C. mangenoti, C. ghoni, C.bifermentans, C. difficile, and C. sordellii. All species of Clostridia are spore formers and thus may persist for long periods of time in the gastrointestinal tracts even after antibiotic treatment with oral vancomycin and metronidazole.
How do the changes in brain neurotransmitters caused by Clostridia metabolites alter behavior? The increase in phenolic Clostridia metabolites common in autism significantly decreases brain dopamine beta hydroxylase activity. This leads to overproduction of brain dopamine and reduced concentrations of brain norepinephrine, and can cause obsessive, compulsive, stereotypical behaviors associated with brain dopamine excess and reduced exploratory behavior and learning in novel environments that are associated with brain norepinephrine deficiency. Such increases in dopamine in autism have been verified by finding marked increases in the major dopamine metabolite homovanillic acid (HVA) in urine. The increased concentrations of HVA in urine samples of children with autism are directly related to the degree of abnormal behavior. The concentrations of HVA in the urine of some children with autism are markedly abnormal.
In addition to alteration of brain neurotransmitters, the inhibition of the production of norepinephrine and epinephrine by Clostridia metabolites may have a prominent effect on the production of neurotransmitters by the sympathetic nervous system and the adrenal gland. The major neurotransmitter of the sympathetic nervous system that regulates the eyes, sweat glands, blood vessels, heart, lungs, stomach, and intestine is norepinephrine. An inadequate supply of norepinephrine or a substitution of dopamine for norepinephrine might result in profound systemic effects on physiology. The adrenal gland which produces both norepinephrine and epinephrine might also begin to release dopamine instead, causing profound alteration in all physiological functions. In addition to abnormal physiology caused by dopamine substitution for norepinephrine and dopamine, dopamine excess causes free radical damage to the tissues producing it, perhaps leading to permanent damage of the brain, adrenal glands, and sympathetic nervous system if the Clostridia metabolites persist for prolonged periods of time, if glutathione is severely depleted, and if there is apoptotic damage caused by the dopamine metabolite N-acetylcysteinyl dopamine thioether.
Depletion of glutathione can be monitored in The Great Plains Laboratory organic acid test by tracking the metabolite pyroglutamic acid, which is increased in both blood and urine when glutathione is depleted. In addition, The Great Plains Laboratory also tests the other molecules involved in this toxic pathway, the dopamine metabolite homovanillic acid (HVA), the epinephrine and norepinephrine metabolite VMA and the Clostridia metabolites HPHPA and 4-cresol.
In summary, gastrointestinal Clostridia bacteria have the ability to markedly alter behavior in autism and other neuropsychiatric diseases by production of phenolic compounds that dramatically alter the balance of both dopamine and norepinephrine. Excess dopamine not only causes abnormal behavior but also depletes the brain of glutathione and NADPH and causes a vicious cycle producing large quantities of oxygen superoxide that causes severe brain damage. Such alterations appear to be a (the) major factor in the causation of autism and schizophrenia. The organic acid test (see sample organic acid test report below) now has the ability to unravel a major mystery in the causation of autism, schizophrenia, and other neuropsychiatric diseases, namely the reason for dopamine excess in these disorders.
In the past, some physicians would order the organic acid test once a year or less. With the new knowledge of the mechanism of Clostridia toxicity via inhibition of dopamine beta-hydroxylase, it seems that the control of such toxic organisms needs to monitored much more frequently to prevent serious brain, adrenal gland, and sympathetic nervous system damage caused by excess dopamine and oxygen superoxide. Below is a test report of a child with autism tested with The Great Plains Laboratory Organic acid test.
DISCUSSION OF PATIENT RESULTS
In the graph above, the vertical bar is the upper limit of normal and the patient’s value is plotted inside a diamond (red for abnormal, black for normal). The above results were from a boy with severe autism. The HPHPA Clostridia marker was very high (979 mmol/mol creatinine), about 4.5 times the upper limit of normal. However, the metabolite due to Clostridium difficile was in the normal range, indicating that Clostridium difficile was unlikely to be the Clostridium bacteria producing the high HPHPA. In other words, a different Clostridia species was implicated. The major dopamine metabolite homovanillic acid (HVA) was extremely high (87 mmol/mol creatinine), almost 7 times the upper limit of normal. The major metabolite of epinephrine and norepinephrine, VMA was in the normal range. The HVA/VMA ratio was 15, more than five times higher than the upper limit of normal, indicating a severe imbalance in the production of epinephrine/norepinephrine and that of dopamine. The very high dopamine metabolite, HVA, indicates that the brain, adrenal glands, and sympathetic nervous system may be subject to severe oxidative stress due to superoxide free radicals and that brain damage due to severe oxidative stress might result if the Clostridia bacteria are left untreated. Below the same patient’s results are displayed in a form that is related to the metabolic pathways. This graphical result now appears on all organic acid results from The Great Plains Laboratory, Inc.
Reference:
Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010 Jun;13(3):135-43.
The Clinical Significance of Organic Acids Testing to Mental Health – How Fungal, Bacterial, Mitochondrial, and Other Test Markers Influence the Brain
Kurt Woeller, D.O.
Organic acids testing is diagnostic tool that every healthcare practitioner should know about. Whether you are a family practitioner, psychiatrist, a nutritionist, or other type of practitioner, the information provided by organic acids testing can help identify underlying causes of a variety of chronic illnesses, including the symptoms of autism, neuropsychiatric disorders like depression and anxiety, and neurodegenerative disorders like Alzheimer’s disease. Below is a review of some of the most clinically significant markers measured with organic acids testing to mental health and the health of the brain in general.
Many of the case studies reviewed in presentations about organic acids testing involve patients with autism. While autism may not typically be considered a mental health disorder, it is a neurodevelopmental disorder and many autistic individuals suffer with mental symptoms such as anxiety and depression, along with associated behavioral problems. Many patients with autism also have mitochondrial dysfunction and chronic infections (like Candida and clostridia), which are measured with organic acids testing. (1)
Mitochondria are linked to every organ system in the body, including the brain, and there markers for mitochondrial function in organic acids testing. Without adequate mitochondrial function, neurons cannot function appropriately to produce neurochemicals such as dopamine and serotonin. Mitochondria are damaged by various endogenous toxins produced by Candida (a fungus) such as tartaric acid and citramalic acid. Also, certain clostridia bacteria produce propionic acid which damages mitochondria. Candida and clostridia are both measured with organic acids testing. Mitochondria are also damaged by oxalate, which is produced by Candida and some molds, and is also measured with organic acids testing. Certain molds like Aspergillus produce mycotoxins which directly damage mitochondria. Organic acids testing specifically measures candida toxins, bacteria toxins, and mold toxins, along with mitochondria markers. (2, 3)
Clostridia bacteria can produce various compounds like HPHPA, 4-Hydroxyphenylacetic acid and 4-Cresol (all measured with organic acids testing), and are known to inhibit dopamine metabolism. These chemicals inhibit Dopamine-Beta Hydroxylase which causes neuronal dopamine levels to rise. This has been associated with paranoia and schizophrenia. Also, the breakdown products of dopamine are neurotoxic and cause brain receptor damage. Chronic infections and the compounds produced from them such as bacteria lipopolysaccharides (LPS), along with elevated cortisol (seen in hypothalamic-pituitary-adrenal dysfunction), viral infections, and beta-amyloid and niacin deficiency (seen in schizophrenia) can trigger tryptophan metabolism problems. Tryptophan is the amino acid precursor to serotonin. In the presence of these chronic stressors, tryptophan conversion to serotonin is reduced. This can lead to depression and anxiety. Elevated tryptophan metabolites can lead to increased quinolinic acid (QA). (4)
Quinolinic acid is neurotoxic and measured with organic acids testing. It is an NDMA receptor agonist, which is linked to various mental health disorders (anxiety, depression, suicidal ideation) and chronic neurodegenerative diseases (Alzheimer’s, Huntington’s). Quinolinic acid can also block acetylcholine production (linked to memory) and gamma-amino-butyric acid (which can trigger anxiety and panic). (5)
The aforementioned markers in organic acids testing are some of the most clinically significant to mental health and brain function, though there are many other examples. This information is critical for mental health professionals to help deepen their knowledge about sophisticated testing and advanced solutions for patient intervention.
References
Shaw, W., et. al. Increased Urinary Excretion of Analogs of Krebs Cycle Metabolites and Arabinose in Two Brothers with Autistic Features. Clin Chem 41:1094-1104, 1995.
Shaw, W., et. al. Assessment of antifungal drug therapy in autism by measurement of suspected microbial metabolites in urine with GC/MS. Clinical Practice of Alternative Medicine: 15-26.
Persico AM, et. al. Urinary p-cresol in autism spectrum disorders, Neurotoxicol Teratol. 2013 Mar-Apr;36:82-90, 2012 Sep 10.
Heyes MP, et. al. A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain. 1993 Dec;116 (pt 6):1425-50.
Ganiyu Oboh, et. al. Anticholinesterase and Antioxidative Properties of Aqueous Extract of Cola acuminata Seed In Vitro. Int J Alzheimers Dis. 2014; 2014: 498629.
Integrative Therapies for Obsessive Compulsive Disorder
James Greenblatt, MD
While it is human nature to occasionally ruminate or overanalyze important decisions, these thought patterns normally dissipate quickly freeing us of those fleeting moments of inner turmoil. However, for those suffering from Obsessive Compulsive Disorder (OCD), letting go of repetitive thoughts is not so effortless. Relentless ideas, impulses, or images inundate the brain leaving the individual mentally imprisoned to an existence of recurrent, irrational thought patterns. These senseless obsessions often drive the individual to perform ritualistic behaviors or compulsions, in an effort to temporarily relieve their anxiety. Sufferers stagger through life with a sense of pure powerlessness against their disorder; fully aware that the behavior is abnormal, yet unable to stop.
Psychotropic medications such as selective serotonin reuptake inhibitors (SSRI’s) and Anafranil and cognitive behavioral therapy are the conventional treatment options for Obsessive Compulsive Disorder. Sadly, the likelihood of complete recovery from OCD has not been shown to exceed 20% and relapse is quite common. Inadequate treatment and limited biomedical options contribute to the high relapse rate as conventional medicine does not address underlying nutritional deficiencies or the root cause. Though unlikely to be caused by deficiencies alone, addressing vital nutrient depletions is a critical aspect of treating OCD since certain vitamins, minerals, and amino acids significantly impact serotonin neurotransmission. Specifically, natural therapies including: 5-HTP, niacin (B3), pyridoxal-5-phosphate (B6), folate (5-MTHF), vitamin C, zinc, magnesium, inositol, and taurine are important to serotonin synthesis. Therefore, the combination of aforementioned nutrients taken in therapeutic dosages should be part of integrative treatment approach for Obsessive Compulsive Disorder.
The fourth most common psychiatric illness in the United States, Obsessive Compulsive Disorder or “OCD” onset typically occurs by adolescence usually between the ages of 10-24, with one third of all cases appearing by age 15. In fact, OCD is said to be more common than asthma and diabetes (Schwartz, 1997). Despite its prevalence, it is often under diagnosed and under treated with more than half of those suffering receiving no treatment at all for their condition. Gender does not affect susceptibility, as men and women are equally affected by this detrimental disorder.
To fully grasp the inner workings of OCD, consider Jeffrey Schwartz’s description of “Brain Lock” (Schwartz, 1997) where four key structures of the brain become locked together sending false messages that the individual cannot interpret as false. The brain is made up of two structures called the caudate nucleus and the putamen, which can be compared to a gearshift in a car. According to Schwartz, “The caudate nucleus works like an automatic transmission for the front, or thinking part, of the brain…the putamen is the automatic transmission for the part of the brain that controls body movements… the caudate nucleus allows for the extremely efficient coordination of thought and movement during everyday activities. In a person with OCD, however, the caudate nucleus is not shifting gears properly, and messages from the front part of the brain get stuck there. In other words, the brain’s automatic transmission has a glitch. The brain gets ‘stuck in gear’ and can’t shift to the next thought” (Schwartz, 1997).
It is clear that enhancing serotonin neurotransmission through psychotropic medications helps the brain “shift into gear” so to speak. But what exactly causes this glitch that leads to serotonin deficiency syndrome? A number of factors including genes, diet, stress, neurotoxins, and inflammation are responsible for inadequate serotonin synthesis. Amino acid availability for neurotransmitter synthesis is dependent upon certain digestive enzymes, and their activation is dependent on hydrochloric acid. Without sufficient amino acid availability, neurotransmitter synthesis will suffer. Specifically, availability of the essential amino acid L-tryptophan is required for serotonin production. Because serotonin synthesis depends on the availability of L-tryptophan and essential cofactors including vitamin B3, folate (5-MTHF), vitamin B6, and zinc, serotonin levels will be less than optimal if any of the required building blocks are deficient. The process of serotonin synthesis starts when L-tryptophan is converted into 5-hydroxytryptophan with the help of tryptophan hydroxylase (a vitamin B3 dependent enzyme), which requires 5-MTHF. 5-hydroxytryptophan (5-HTP) then converts to serotonin with the aid of decarboxylase, vitamin B6 dependent enzymes, and zinc.
Supplemental 5-hydoxytryptophan (5-HTP) can be beneficial for individuals as it essentially bypasses the need for L-tryptophan availability. Easily crossing the blood brain barrier, 5-HTP works like a targeted missile directly increasing brain serotonin levels. It does not require a transport molecule for crossing the blood brain barrier, and unlike L-tryptophan, it is shunted from incorporation into proteins and niacin conversion (Birdsall, 1998). What’s more, promising research indicates that the therapeutic effect of 5-HTP compared to fluoxetine (Prozac), is actually equal (Jangid et al., 2013). Antidepressant effects are experienced in as little as two weeks with 5-HTP; effectively treating individuals with varying degrees of depression (Jangid et al., 2013).There has been four research studies looking at 5-HTP supplements specifically for OCD. Clinicians around the globe, for more than twenty years, have had success with amino precursors including 5-HTP for the treatment of OCD. I recommend starting all patients with 50 mg of 5-HTP and titrate slowly every 2 weeks up to a maximum of 200 mg per day. Side effects of 5-HTP include nausea, irritability, and possible anxiety.
In addition to the influence of digestive health on serotonin synthesis, absorption of vital minerals specifically zinc and magnesium, are also impacted by Hydrochloric Acid (HCL) availability. Thus, if HCL and digestive enzyme production is low, mineral deficiencies will likely follow. This is worth noting because optimal levels of zinc and magnesium are imperative to maintaining healthy serotonin levels, while moderating the activity of glutamate receptors. As stated previously, zinc is an important coenzyme required for decarboxylase activation and the conversion of 5-HTP to serotonin. Magnesium also plays an essential role, aiding the conversion process of L-tryptophan to serotonin.
In addition to zinc and magnesium, folate plays a critical role in serotonin neurotransmission. Specifically, the enzyme responsible for converting L-tryptophan to 5-HTP, requires 5-MTHF, also known as “L-Methylfolate.” Without sufficient folate, L-tryptophan will struggle to convert to 5-HTP. Research on depression and folate is extensive; hundreds of studies support the relationship between folate and depression. Thus, it is imperative to consider folate status when treating OCD. Specifically, low folate levels are associated with increased incidence of depression, poor response to antidepressants, and higher relapse rates. Because dietary sources of folate are heat labile and easily oxidized (more than 50% is oxidized during food processing) folate malabsorption and deficiency is quite prevalent in our society. To make matters worse, individuals taking certain medications such as anticonvulsants, oral contraceptives, antacids, antibiotics, and Metaformin are at increased risk of deficiency.
Individuals that possess genetic polymorphisms in the gene coding for the methylenetetrahydrofolate reductase (MTHFR) gene are at high risk for low folate status due to reduced ability to convert folic acid to its active form. Folic acid requires a four step transformation process to be converted to L-methylfolate, where dietary folate requires three steps. MTHFR polymorphisms reduce efficiency of this transformation process; severely impacting conversion of folic acid to L-methylfolate. Since L-methylfolate is the active absorbable form of folate that crosses the blood brain barrier for use, inability to properly convert dietary or supplemental folic acid may cause folate deficiency (Lewis et al., 2006).
Inositol has proven particularly effective for SSRI resistant patients as well. Specifically, OCD patients experiencing lack of response to SSRI’s or clomipramine have been examined. There are research studies demonstrating dosages of 18/gms of inositol per day was effective in OCD treatment. Improvement in symptoms had been reported at 6 weeks of treatment with no reported side effects (Fux et al., 1996). A promising finding, inositol is an effective natural therapy for OCD treatment when taken on its own. It is particularly helpful to individuals who are unresponsive to conventional SSRI treatment. However, at this time use of inositol as an augmentation agent to improve SSRI function has not been proven effective (Fux et al., 1999).
Inositol’s effect on treatment resistant patients is likely due to its role in the neurotransmission process. Operating as a secondary messenger, it enhances the sensitivity of serotonin receptors on the postsynaptic neuron using signal transduction. Upon binding to its receptor, messages from serotonin are then translated into signals that are expressed through behaviors such as positive mood, relaxation, and reduced obsessions. Due to its role in serotonin signaling, patients resistant to SSRI treatment may not necessarily have an issue with serotonin synthesis but rather decreased receptor sensitivity.
Controlled trials of inositol have confirmed therapeutic effects in a wide spectrum of psychiatric illnesses generally treated with SSRI’s including: OCD, Major Depressive Disorder, Panic Disorder, and Bulimia. In particular, children exhibiting OCD symptoms have shown considerable life altering improvements with inositol treatment. For instance, “S.M.” a socially withdrawn, 11 year old child who obsessively feared fire and contamination, transformed into a “completely different child” with inositol treatment. Similarly, “P.J.”, treated with inositol and 5-HTP, showed significant improvement in OCD symptoms. A third clinical case, “C.K.” had suffered immensely with severe adverse side effects to Celexa and Prozac including aggressive thoughts of self-harm. Upon treatment with inositol, no side effects were reported and minimal improvement was even displayed. Even though research studies suggest 18 grams of Inositol per day, I start all patients with OCD on approximately 3 grams of Inositol per day (1/2 Tsp. 3 times per day).this minimizes GI side effects including bloating and nausea. If needed, Inositol dosages can be titrated up slowly with most patients responding below 12 grams per day.
Improving serotonin production and neurotransmission is integral to boosting serotonin levels and combating symptoms of OCD. However, preventing over-activity of neurotransmitters should also be considered. Taurine is an essential amino acid and precursor to GABA, an inhibitory neurotransmitter. A regulatory agent, GABA helps maintain healthy serotonin levels and reuptake. Widely known for its calming effect, taurine’s therapeutic use for anxiety and depression treatment has been explored. In one study, animals fed a high taurine diet for 4 weeks exhibited anti-depressive behavior (Caletti, 2015). Furthermore, a study on mice indicated a reduction in anxiety where taurine was administered 30 minutes before anxiety tests (Kong et al., 2006). Though taurine does not directly target serotonin production, it is still worth noting as its inhibitory effect may reduce racing thoughts associated with anxiety disorders such as OCD.
Based on extensive scientific evidence supporting the relationship of aforementioned nutrients to serotonin production, as well as decades of clinical experience, I developed SeroPlus (https://www.nbnus.net/). SeroPlus is a nutritional supplement to help patients with OCD and depression. The formula provides serotonin building blocks including therapeutic doses of 5-HTP (direct precursor to serotonin), Inositol, and Taurine in addition to vital cofactors magnesium, vitamin C, pyridoxal-5- phosphate (activated B6), and Metafolin® (activated folate). Inositol elevates sensitization of serotonin receptors while taurine maintains healthy sympathetic nervous system tone and moderates serotonin activity and reuptake. The formula also includes niacin and zinc picolinate which enhance availability of 5-HTP by reducing the amount of 5-HTP used for activation and absorption of these nutrients. Synergistically, these ingredients work effectively together to optimize serotonin production and restore healthy serum levels of common deficiencies contributing to abnormalities in serotonin neurotransmission.
As with any psychiatric illness, treating OCD is complex and requires a comprehensive multi-prong approach beyond basic SSRI prescriptions and behavioral therapy. Although directly enhancing serotonin production through natural therapies such as 5-HTP as well as correcting underlying B3, B6, zinc, magnesium, folate, and inositol deficiencies is at the heart of integrative treatment there are a number of alternative factors that may be contributing to the cause. Low levels of B12, DHA, and vitamin D must be addressed.
A prisoner to their own thoughts, OCD sufferers are frustrated and searching for alternative treatment options. The complex etiology of OCD includes genetics, inflammation, and the dysfunction of serotonin synthesis. While SSRI’s may enhance serotonin synthesis, a number of OCD patients do not experience long term results. Thus, identifying key nutrient depletions and replenishing them through dietary modification and supplementation is essential to increasing chances of long term recovery.
James M. Greenblatt, MD, is the author of Finally Focused: The Breakthrough Natural Treatment Plan for ADHD (Harmony Books, 2017). He currently serves as Chief Medical Officer and Vice-President of Medical Services at Walden Behavioral Care, and he is an Assistant Clinical Professor of Psychiatry at Tufts University School of Medicine and Dartmouth Geisel School of Medicine. An acknowledged expert in integrative medicine, Dr. Greenblatt has lectured throughout the United States on the scientific evidence for nutritional interventions in psychiatry and mental illness. For more information, visit www.JamesGreenblattMD.com
References
Birdsall. (1998). 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. Aug; 3(4): 271-80.
Caletti. (2015). Antidepressant dose of taurine increases mRNA expression of GABAA receptor α2 subunit and BDNF in the hippocampus of diabetic rats. Behav Brain Res. 2015 Apr 15; 283:11-5.
Fux et al. (1996). Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry, Vol 153(9) 1219-1221.
Fux et al. (1999). Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder: a double blind cross-over study. International Journal of Neuropsychopharmacology 2, 193-195.
Jangid et al. (2013) Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr. Feb;6(1):29-34
Kong. (2006). Effect of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav. Feb; 83(2):271-6.
Milner. (1963). Ascorbic acid in chronic psychiatric patients. Brit J Psychiatr 109; 294-299.
Schwartz, Jeffrey M. Brain Lock: Free Yourself from Obsessive-Compulsive Behavior . Harper Perennial; 1st edition, 1997.
Integrative Treatments for Behavioral Problems in Children
By: James Greenblatt, MD
Attention deficit/hyperactivity disorder (ADHD) is a multifactorial condition that is influenced by genetic, biological, environmental, and nutritional factors. While there are numerous integrative therapies available including vitamins, minerals, herbs, neurofeedback, exercise, and meditation, individuals are unique and thus require personalized treatments based on their own biological needs identified through laboratory testing. In this article, we will discuss commonly overlooked mineral deficiencies and imbalances in the gastrointestinal flora that can exacerbate behavioral symptoms and impede the therapeutic effect of pharmacological treatment.
In the early 1960s, researchers discovered that zinc was an essential trace mineral necessary for normal growth and development. Zinc is also critical for immune function, and the activity of over 300 enzymes is dependent on zinc bioavailability. Zinc is a vital component of the central nervous system, maintaining neurotransmitter activity. This mineral enhances GABA, one of our main inhibitory/relaxation neurotransmitters. Moreover, zinc is needed as a co-factor to produce melatonin which helps regulate dopamine function.
Multiple studies have confirmed that not only are zinc levels lower in children with ADHD, but the extent of the deficiency is proportionately correlated with the severity of ADHD symptoms including inattention, hyperactivity, impulsivity, and conduct problems:
Toren et al. (1996) found that almost one-third of 43 ADHD children aged 6-16 were severely deficient in serum zinc.
Another study involving 48 ADHD children aged 5-10 demonstrated that most of the participants had serum zinc levels in the lowest 30% of the reference range.
There is a highly significant inverse correlation between zinc level and parent and teacher ratings of inattention among children with ADHD (Arnold et al., 2005). A more recent study echoed the same findings, when researchers analyzed the zinc in the hair of 45 children with ADHD against 44 controls. They found that there was a relationship between hair zinc levels and worse overall ADHD symptoms (Shin et al., 2014).
In a recent study, 70% of the 20 ADHD cases examined were zinc deficient. Those with lower hair zinc levels reported significantly increased symptoms of inattention, hyperactivity, and impulsivity (Elbaz et al., 2016).
In a larger group of 118 children with ADHD, those with the lowest blood levels of zinc had the most severe conduct problems, anxiety, and hyperactivity as rated by their parents (Oner et al., 2010).
In children with ADHD, plasma zinc levels were shown to directly affect information processing via event related potentials which reflect brain activity. In ADHD children compared to controls, the amplitudes of P3 waves in frontal and parietal brain regions were significantly lower (worse working memory) and the latency of P3 in the parietal region was significantly longer (slower information processing). Unsurprisingly, plasma zinc levels were significantly lower in the ADHD children compared to the control children. When a low-zinc ADHD subgroup was compared to a nondeficient ADHD subgroup, the latencies of N2 in frontal and parietal brain regions were significantly shorter (worse information processing and inhibition) (Yorbik et al., 2008).
Supplementation with zinc is more effective at improving ADHD symptoms when compared to placebo, and can also be an effective adjuvant therapy to enhance the therapeutic effect of stimulant medication without increasing the dosage. When 400 ADHD children aged 6-14 were randomized to zinc sulfate 150 mg/day or placebo for 12 weeks, those taking zinc had significantly reduced symptoms of hyperactivity, impulsivity, and impaired socialization (Bilici et al., 2004). Similarly, when over 200 children were randomized to zinc 15 mg/day or to placebo for 10 weeks, those taking zinc saw significant improvement in attention, hyperactivity, oppositional behavior, and conduct disorder. And these children had normal zinc levels to begin with (Üçkardeş et al., 2009). In a small study of 18 boys with ADHD, higher baseline hair zinc levels predicted better behavioral response to amphetamine (Arnold et al., 1990). In a six-week double blind, placebo controlled trial, researchers assessed the effects of zinc in combination with methylphenidate (Ritalin). 44 children aged 5-11 were randomized to methylphenidate plus zinc sulfate 55 mg/day or methylphenidate plus placebo. At week 6, those taking zinc had significantly better scores on the Parent and Teacher ADHD Rating Scale (Akhondzadeh et al., 200452 children aged 6-14 with ADHD were randomized to zinc glycinate 15 mg/day or placebo for 13 weeks. For the first 8 weeks, they only took zinc then for the last 5 weeks they also took d-amphetamine. The optimal absolute mg/day amphetamine dose with zinc was 43% lower than with placebo (Arnold et al., 2011).
Copper is an essential trace mineral that plays an active role in the synthesis of dopamine and norepinephrine. However, excess copper can manifest as displays of aggression, hyperactivity, insomnia, and anxiety. Elevated copper levels can also cause low zinc levels and reduce the efficacy of medications commonly used to treat ADHD.
Copper may affect ADHD through its role in antioxidant status. Copper/Zinc superoxide dismutase (SOD-1) is a key enzyme in our antioxidant defense system. Both copper and zinc participate in SOD enzymatic activities that protect against free radical damage. In a study on 22 ADHD children and 20 controls, serum Copper/Zinc SOD levels of ADHD children were significantly lower in individuals with high serum copper when compared to controls. It is also hypothesized that excess copper can damage dopamine brain cells by destroying antioxidant defenses, such as lowering Copper/Zinc SOD levels (Russo, 2010).
In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement (Rucklidge et al., 2014). Unfortunately, even copper levels that are considered normal can negatively affect cognition. In a group of 600 adolescents with normal copper levels, blood copper was associated with decreased sustained attention and short-term memory (Kicinski et al., 2015).
Magnesium is part of 300 enzymes that utilize ATP (cellular energy) and is important for nerve transmission. It is involved in the function of the serotonin, noradrenaline, and dopamine receptors. Magnesium has been progressively declining in our food supply due to increased consumption of processed foods. The use of medications, presence of stress, and caffeine and soft drink consumption also deplete magnesium, and it is estimated that 50% of Americans are deficient in magnesium (Mosfegh et al., 2009).
Symptoms of magnesium deficiency include irritability, difficulty with concentration, insomnia, depression, and anxiety. A prospective population-based cohort of over 600 adolescents at the 14- and 17-year follow-ups found that higher dietary intake of magnesium was significantly associated with reduced externalizing behaviors (attention problems, aggressiveness, delinquency) (Black et al., 2015). Because up to 95% of those with ADHD are deficient in magnesium, almost all ADHD children can benefit from magnesium supplementation (Kozielec & Starobrat-Hermelin, 1997).
In a recent study on 25 patients with ADHD aged 6-16, 72% of children were deficient in magnesium and there was a significant correlation between hair magnesium, total IQ, and hyperactivity. The magnesium deficient children were randomized to magnesium supplementation 200 mg/day plus standard medical treatment or to standard medical therapy alone for 8 weeks. Those taking magnesium saw a significant improvement in hyperactivity, impulsivity, inattention, opposition, and conceptual level while those taking medication alone did not see these improvements (El Baza et al., 2015).
Supplements of magnesium plus vitamin B6, which increases magnesium absorption, have shown promise for reducing ADHD symptoms. One study on 52 children with ADHD found that 58% had low red blood cell magnesium levels. All the children were given preparations of magnesium plus vitamin B6 100 mg/day for a period of 1 to 6 months. In all patients, physical aggression, instability, attention at school, muscle rigidity, spasms, and twitching were improved. One of the treated children was a six-year old identified as “J”. Initially, J suffered from aggressiveness, anxiety, inattention, and lack of self-control. After taking magnesium supplements, he reported better sleep and concentration and no methylphenidate was needed (Mousain-Bosc et al., 2004). A later study by the same researchers also found that 40 children with ADHD had significantly lower red blood cell magnesium values than control children. Likewise, a magnesium-vitamin B6 regimen for at least 2 months significantly improved hyperactivity, aggressiveness, and school attention. The researchers concluded, “As chronic magnesium deficiency was shown to be associated to hyperactivity, irritability, sleep disturbances, and poor attention at school, magnesium supplementation as well as other traditional therapeutic treatments, could be required in children with ADHD” (Mousain-Bosc et al., 2006). In a larger study of 122 children with ADHD aged 6-11, 30 days of magnesium-vitamin B6 supplementation led to improved anxiety, attention, and hyperactivity. On a battery of tests, magnesium treatment increased attention, work productivity, task performance, and decreased the proportion of errors. The EEG of treated children showed positive changes as well, with brain waves significantly normalizing (Nogovitsina & Levitina, 2007).
There has also been a considerable amount of research illustrating the symbiotic, bidirectional relationship between the brain and the gut, and animal studies have demonstrated how certain strains of bacteria, or lack thereof, can alter cognitive and emotional processes. In the presence of dysbiosis, where “bad” bacteria outnumber the “good,” harmful strains of bacteria can proliferate and cause behavioral disturbances.
HPHPA is a harmful byproduct of some strains of the bacterium Clostridium that can disrupt the normal gut environment. Elevated urinary levels are commonly seen in ADHD children, especially those with poor response to stimulants. HPHPA inhibits the conversion of dopamine to norepinephrine. This causes dopamine to accumulate, resulting in decreased attention and focus. A patient should especially be tested for HPHPA if he or she experiences stimulant side effects such as irritability, agitation, or anxiety. ADHD medications work by increasing dopamine. But high HPHPA levels prevent the breakdown of dopamine, exacerbating symptoms. HPHPA must be cleared before medications will be helpful. Probiotics, good bacteria found in fermented food such as yogurt, or antibiotics can be used to lower HPHPA.
Intestinal overgrowth of Candida yeast is seen in some children with ADHD, mostly in those with a diet high in sugar that feed Candida, or in those who have received many rounds of antibiotics for recurrent ear infections. Antibiotics are effective at resolving infections by eradicating all bacteria, including the good bacteria. An early study found that children with the greatest history of ear infections (and presumably the greatest frequency of antibiotic use) had an increased chance for developing hyperactivity later (Hagerman & Falkenstein, 1987). Toxins produced by Candida can enter the bloodstream and then enter the brain where they can cause changes leading to hyperactivity and poor attention span. Fortunately, the presence of HPHPA and other yeast overgrowth can be easily detected with an organic acids test or with a stool sample. Candida can be treated with probiotics, antifungal foods (e.g. garlic, oregano, ginger), and a lower sugar diet. In some cases, a regimen of antibiotics and probiotics can be useful in reestablishing a healthy gut flora.
Nutritional augmentation strategies are frequently used as part of the integrative clinician’s toolbox to treat behavioral disorders in children. It is important for healthcare providers to collaborate and communicate with caregivers of children with behavioral disorders to discern whether other complementary therapies could be incorporated into treatment. By carefully assessing a patient’s whole health history and conducting appropriate laboratory testing, providers can make informed treatment recommendations that is tailored specifically for the individual.
References
Akhondzadeh, et al (2004). Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: A double blind and randomized trial ISRCTN64132371. BMC Psychiatry, 4, 9.
Arnold et al. (1990). Does hair zinc predict amphetamine improvement of ADD/hyperactivity? The International Journal of Neuroscience, 50(1-2), 103-7.
Arnold et al. (2005). Serum zinc correlates with parent- and teacher- rated inattention in children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 15(4), 628-36.
Arnold et al. (2011). Zinc for attention-deficit/hyperactivity disorder: Placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), 1-19.
Bilici et al. (2004). Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 28(1), 181-190.
Black et al. (2015). Low dietary intake of magnesium is associated with increased externalising behaviours in adolescents. Public Health Nutrition, 18(10), 1824-30.
Elbaz et al. (2016). Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egyptian Journal of Medical Human Genetics, Egyptian Journal of Medical Human Genetics, in press.
El Baza et al. (2016). Magnesium supplementation in children with attention deficit hyperactivity disorder. Egyptian Journal of Medical Human Genetics, 17(1), 63-70.
Hagerman & Falkenstein. (1987). An Association Between Recurrent Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26(5), 253.
Kicinski et al. (2015). Neurobehavioral function and low-level metal exposure in adolescents. International Journal of Hygiene and Environmental Health, 218(1), 139-146.
Kozielec & Starobrat-Hermelin. (1997). Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD). Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 10(2), 143-148.
Moshfegh et al. (2009). What We Eat in America, NHANES 2005–2006: Usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agriculture, Agricultural Research Service: Washington, DC, USA.
Mousain-Bosc et al. (2004). Magnesium VitB6 intake reduces central nervous system hyperexcitability in children. Journal Of The American College Of Nutrition, 23(5), 545S-548S.
Mousain-Bosc et al. (2006). Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnesium Research: Official Organ Of The International Society For The Development Of Research On Magnesium, 19(1), 46-52.
Nogovitsina & Levitina. (2007). Neurological aspects of the clinical features, pathophysiology, and corrections of impairments in attention deficit hyperactivity disorder. Neuroscience and Behavioral Physiology, 37(3), 199-202.
Oner et al. (2010). Effects of Zinc and Ferritin Levels on Parent and Teacher Reported Symptom Scores in Attention Deficit Hyperactivity Disorder. Child Psychiatry and Human Development, 41(4), 441-447.
Rucklidge et al. (2014). Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement. Progress in Neuropsychopharmacology & Biological Psychiatry, 50, 163-171.
Russo, A. (2010). Decreased Serum Cu/Zn SOD Associated with High Copper in Children with Attention Deficit Hyperactivity Disorder (ADHD). Journal of Central Nervous System Disease, 2, 9-14.
Shin et al. (2014). The Relationship between Hair Zinc and Lead Levels and Clinical Features of Attention-Deficit Hyperactivity Disorder. Journal of the Korean Academy of Child and Adolescent Psychiatry, 25(1), 28-36.
Toren et al. (1996). Zinc deficiency in attention-deficit hyperactivity disorder. Biological Psychiatry, 40(12), 1308-1310.
Üçkardeş et al. (2009). Effects of zinc supplementation on parent and teacher behaviour rating scores in low socioeconomic level Turkish primary school children. Acta Paediatrica, 98(4), 731-736.
Yorbik et al. (2008). Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 32(3), 662-667.
The Role of Oxidative Stress, Inflammation and Acetaminophen Exposure from Birth to Early Childhood in the Induction of Autism
By: William Parker, Chi Dang Hornik, Staci Bilbo, Zoie E. Holzknecht, Lauren Gentry, Rasika Rao, Shu S. Lin, Martha R. Herbert and Cynthia D. Nevison
Response to Article on the Lack of Oxalate Dangers in the Green Smoothie Diet
William Shaw, PhD
In response to the inaccurate, unscientific article by Thomas Lodi, M.D. on oxalates1 in the December 2015 issue of Townsend Letter, I will make the following point by point responses:
(1)Cartoons about Popeye.
I will not use any cartoons in my response. Anyone interested in cartoons should immediately stop reading this article and start reading their local paper’s comic section.
(2)Inaccurate references.
The tone for accuracy of the author is set in the very first paragraph of his article in which his first reference, #23, has nothing to do with my green smoothie article, which is reference #24. A better reference would actually be #2 from my article2. When the clock strikes 13, the accuracy of the other 12 hours of the clock is in serious question.
(3)Inaccuracy about the contribution of endogenous production to total oxalate load.
Lodi states that 80-90% of oxalates in the body are endogenously produced. Unfortunately, the best scientific study refutes his assertion. According to Holmes et al3, who did extremely well-controlled studies on every aspect of oxalate metabolism and has publishedforty-one scientific articles on oxalates in the peer reviewed literature, the mean dietary oxalate contribution to total oxalate in the diet is 52.6 % on a high oxalate diet which was defined as a diet of 250 mg oxalate per day. The person drinking a green smoothie with 2 cups of raw spinach ingests 1312 mg of oxalates or over five times the level of what Holmes considers a high-oxalate diet, just in the spinach consumption alone and over 26 times the amount of oxalates in a low oxalate diet (50 mg per day)4. The estimated human production of oxalates is 40 mg per day3. On a green smoothie diet with two cups of spinach, the diet in normal humans contains 33 times the endogenous human production of oxalates just based on the spinach alone.
All of Lodi’s assertions about the benefits of a vegetarian diet are meaningless since there is no single vegetarian diet; there are as many vegetarian diets as there are vegetarians.
(4)Inaccuracy about the availability of calcium and magnesium in spinach.
Lodi states that “every plant, green and otherwise (including spinach) has abundant magnesium and calcium and potassium”. Unfortunately, none of the calcium and magnesium in spinach or other high oxalate plants is bioavailable since it is strongly bound to oxalates. Furthermore, the average oxalate value of spinach is 7.5 times its calcium content, making spinach a very poor choice for someone to maintain adequate calcium stores5. According to Kohmani, who added a good deal of spinach, similar to the diet of a person ingesting a daily green smoothie or a large daily spinach salad, to the diet of rats to determine its effects5:
“If to a diet of meat, peas, carrots and sweet potatoes, relatively low in calcium but permitting good though not maximum growth and bone formation, spinach is added to the extent of about 8% to supply 60% of the calcium, a high percentage of deaths occurs among rats fed between the age of 21 and 90 days. Reproduction is impossible. The bones are extremely low in calcium, tooth structure is disorganized and dentine poorly calcified. Spinach not only supplies no available calcium but renders unavailable considerable of that of the other foods. Considerable of the oxalate appears in the urine, much more in the feces.”
(5)Lodi argues that his patients haven’t complained about kidney stones while drinking a lot of green smoothies so oxalates must not be problematic.
Lodi’s contention that his patients on a high oxalate diet don’t have kidney stones is anecdotal. He presents no data from active chart review of his patients to determine if questions about kidney stones were ever asked. Furthermore, it is doubtful that his patients would have even have connected their diet with their kidney stones. I have had numerous seminars on the connection between oxalates and kidney stones and it is common to get feedback from the audience members that they had kidney stones shortly after starting either a diet including a spinach green smoothie or a large spinach salad on a regular basis. Since these comments were not even solicited, it is likely that even a larger number of individuals may have experienced kidney stones but were shy to voice their experiences. A neurologist friend attributes his recent severely-disabling stroke to the dietary changes encouraged by his wife that placed him on a daily green spinach smoothie for a considerable time.
Furthermore, Lodi seems to think that a lack of kidney stones indicates a lack of oxalate problems. However, oxalates may form in virtually every organ of the body including the eyes, vulva, lymph nodes, liver, testes, skin, bones, gums, thyroid gland, heart, arteries, and muscles6-7. Oxalates may occur in these other organs without appearing in the urinary tract at all and in individuals without genetic hyperoxalurias7. Oxalates have been implicated in heart disease7, stroke, vulvodynia, and autism8-10. Women of child-bearing age need to be especially careful of the spinach green smoothie diet because of the autism oxalate connection and the negative effects of spinach containing oxalates on fertility5. Prisoners in the state prisons in Illinois were encouraged by the Weston-Price Nutrition Foundation to file a lawsuit against the state because of their deteriorating health due to a high amount of soy protein in the prison diet11. Soy protein is tied with spinach as the highest oxalate foods4. Oxalates are especially toxic to the endothelial cells of the arteries, leading to atherosclerosis12. Oxalate crystals are concentrated in the atherosclerotic lesions7. Such lesions have commonly been overlooked by the use of stains of atherosclerotic lesions that make the oxalate crystals difficult to visualize. The relatives of people consuming the green smoothie diet would only know of their loved ones’ oxalate deposits throughout their organs on the day of their autopsies which employed pathological examinations that can detect oxalates.
Primary genetic hyperoxaluria is not the major cause of kidney stones in adults since 80% of individuals died of this disorder before age 20 and it is so rare that it could not possibly be the cause of most cases of oxalate kidney stones13. However, a genetic polymorphism present in up to 20% of Caucasian groups called P11L codes for a protein with three times less activity of alanine: glyoxylate aminotransferase (AGT) than the predominant normal activity polymorphism, leading to excessive endogenous production of oxalates14. This substantial group of individuals would be even more susceptible to the harm of a high oxalate diet. Kidney stones were rampant in the United Kingdom during the World Wars when rhubarb, another high oxalate food, was recommended as a substitute for other low oxalate but unavailable vegetables13.
In summary, those who do not care for their health can eat or drink whatever they want. But they should realize that their diets are fad-based and/or based on quasi-religious ( “feasts” as part of the “awakening” according to Lodi) reasons, not based on hard scientific evidence. Furthermore, they should be aware that their diet may kill them15. The green smoothie fad will go down in medical history with the AMA journal allowing cigarette advertising with physician endorsements and the use of mercury-containing teething powder for babies as one of the greatest health follies in a considerable time.
References
1. Lodi, T. Green smoothie bliss: Was Popeye secretly on dialysis? Townsend Letter for Doctors. Dec 2015 pgs 28-39
2. Shaw, W. The Green Smoothie Health Fad: This Road to Health Hell is Paved with Toxic Oxalate Crystals. Townsend Letter for Doctors. Jan 2015 Available online at: http://www.townsendletter.com/Jan2015/green0115.html
3. Holmes RP, Goodman HO, and Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney International, Vol. 59 (2001), pp. 270–276
4. Harvard T.H. Chan School of Public Health Nutrition Department's File Download Site on oxalates in the diet. https://regepi.bwh.harvard.edu/health/Oxalate/files Accessed December 1,2015
5. Kohmani,EF. Oxalic acid in foods and its fate in the diet. Journal of Nutrition 18(3):233-246,1939
6. Jessica N. Lange, Kyle D.Wood, John Knight, Dean G. Assimos, and Ross P. Holmes. Glyoxal Formation and Its Role in Endogenous Oxalate Synthesis. Advances in Urology Volume 2012, Article ID 819202, 5 pages doi:10.1155/2012/819202
7. G.A. Fishbein, R. G. Micheletti, J. S. Currier, E. Singer, and M. C. Fishbein, Atherosclerotic oxalosis in coronary arteries, Cardiovascular Pathology, vol. 17, no. 2, pp. 117–123, 2008.
8. Giuseppe Di Pasquale, , Mariangela Ribani, Alvaro Andreoli, , Gian Angelo Zampa, and Giuseppe Pinelli, Cardioembolic Stroke in Primary Oxalosis With Cardiac Involvement. Stroke 1989, 20:1403-1406
9. Solomons CC, Melmed MH, Heitler SM.Calcium citrate for vulvar vestibulitis. A case report. J Reprod Med. 1991 Dec;36(12):879-82.
10. Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, Owens SC, Piotrowska-Jastrzebska J, Kaczmarski M. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012 Sep;16(5):485-91.
11. Monica Eng, Chicago Tribune reporter. Soy in Illinois prison diets prompts lawsuit over health effects. December 21, 2009. http://articles.chicagotribune.com/2009-12-21/news/0912200121_1_soy-protein-soy-cheeses-soyfoods-association. Accessed December 2,2015
12. RI Levin, PW Kantoff and EA Jaffe Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arterioscler Thromb Vasc Biol 1990, 10:198-207
13. A. J. Chaplin Histopathological occurrence and characterization of calcium oxalate: a review. J. Clin. Path., 1977, 30, 800-811
14. Michael J. Lumb and Christopher J. Danpure. Functional Synergism between the Most Common Polymorphism in Human Alanine:Glyoxylate Aminotransferase and Four of the Most Common Disease-causing Mutations. Journal of Biological Chemistry Vol. 275, No. 46, November 17, pp. 36415–36422, 2000
Sanz P, Reig R: Clinical and pathological findings in fatal plant oxalosis. Am J Forensic Med Pathol 13:342–345, 1992
The Role of Probiotics in Candida and Clostridia Treatment: What Does the Evidence Say?
Jessica Bonovich, RN, BSN
Trillions of friendly microbes are currently living symbiotically within each of us right now (give or take a few billion). In fact, there are more of “them” than there are of “us”. While this phenomenon has been known for quite some time, only recently has modern medicine starting to examine this relationship and how it affects human health. Studies on the use of probiotics have been performed on a wide range of populations. Despite the seemingly obvious importance of these microbes, there is still some confusion about the role of probiotics in reducing the colonization of opportunistic pathogens like Clostridia and Candida? For example, some people believe that probiotics alone can treat an infection. Others believe
that they “compete” for resources and “crowd out” the bad guys. So, what does the evidence say?
Promising data by several studies have demonstrated the use of probiotics is effective against numerous pathological conditions caused by Candida. In these studies, Lactobacillus GG, L. acidophilus, and Saccharomyces boulardi were the predominant probiotics shown to be effective, with L. GG demonstrating the ability to induce antibody formation against Candida (PMID 15932169). Supplementation with probiotics has been shown to accelerate the healing of various pathological conditions in the gastro‐intestinal tract when Candida is present (PMID 17242486, 17251510). The use of probiotics have also been shown to accelerate immune response to Candida in both human and murine model simulations (PMID 17242486, 15813696). Probiotics have shown to decrease occurrence of Candida overgrowth in the elderly population (PMID 17251510). In preterm infants, probiotics were shown to prevent colonization of Candida, a common problem in this patient population (PMID 16705580). According to these data, probiotics promote and stimulate the host immune response against intestinal Candida overgrowth and accelerate healing in the intestinal mucosa. In most of the studies, probiotics were used alongside antifungals not instead of.
So can probiotics help reduce oxalates? Since Candida can produce oxalates (PMID 11452311) many people are interested in using probiotics therapeutically to minimize the oxalate load. Many studies have demonstrated that Oxalobacter formingenes bacteria can reduce oxalate stone formation (hence the name) (PMID 16284877). As of right now, testing for Oxalobacter formingenes is available primarily in research settings and supplements are not widely available to the public (though I expect that they will be soon). Fortunately, there are other beneficial bacteria species shown to reduce oxalic acid. Many of these are already available probiotic form. These include Lactobacillus acidophilus, Lactobacillus Casei, Bifidobacterium breve, and Bifidobacterium lactis all of which are available in Lactoprime probiotic formula (PMID 17953571, 19214493, 15345383, 20602988, 20601517).
Studies on the use of probiotics in the prevention and treatment of C. difficile infections have been promising with many well‐respected institutions incorporating them into protocol, particularly for patients with reoccurring C. difficile infections. A meta‐analysis was recently conducted that reviewed several randomized controlled trials investigating the use of probiotics against C. difficile in human subjects. The results demonstrated a reduction in the reoccurrence of infection in patients with reoccurring C. difficile infection when probiotic strains of Lactobacillus or Saccharomyces boulardi were used in combination with antibiotic treatment (PMID 19324296). A separate study indicated that S. boulardi inhibits toxins associated with C. difficile and mitigates the inflammation associated with infection (PMID: 9864230). Restoration of the intestinal microbial balance is thought to be an important
aspect to preventing reoccurring infections (PMID 18199029). Patients receiving treatment with vancomycin have better outcomes when the treatment is combined with probiotic supplementation (PMID 11049785). Here probiotics can potentially prevent reoccurring infection associated with Clostridia species and reduce inflammation associated with the toxins produced by Clostridia. Here again, these are used in conjunction with antibiotic therapy, not alone to fight infection.
The majority of these studies look at the efficacy of specific strains. Doing so helps to control the variables of the study but ignores the more clinically relevant aspect of multiple species. The broader question still remains to be asked, what is the appropriate ratio of beneficial bacterium to prevent disease states and illicit an appropriate humoral immune response in vulnerable versus healthy populations? As challenging as this question is to answer, it is one worth pursuing. In the mean time, a healthy dose of probiotics is likely to be a good choice for individuals concerned with combating or preventing opportunistic pathogens.
Clostridia difficile - The Role of Toxin A and B in its Pathogenicity
Kurt Woeller, DO
There are approximately 100 species of clostridia bacteria that can inhabit the gastrointestinal tract of humans. Not all of these clostridia are disease causing, but a certain few can lead to serious illness in susceptible individuals. There are 5 main species of clostridia known to cause disease: Clostridia botulinum, Clostridia perfringens, Clostridia tetani, Clostridia sordellii, and Clostridia difficile. This article will focus on the role of Clostridia difficile (C. difficile), and its production of various gastrointestinal toxins in human illness.
What Are Clostridia Bacteria?
Clostridia difficile, like all clostridia bacteria, is an obligate anaerobe. This means it is an organism that thrives in an oxygen devoid environment and is susceptible to being killed by normal atmospheric oxygen. It is unique in its ability to survive in hostile environments in part because of its spore development. Clostridia spores, the reproductive cell of clostridia, have thick cell walls which resist heat and antimicrobial compounds. These spores of clostridia are highly contagious and can be spread person to person even from individuals without symptoms of clostridia overgrowth.
C. difficile is a complex species of clostridia because of the various toxins it can produce. There are certain strains of C. difficile that produce compounds known to alter mitochondrial function by interfering with various steps in Kreb Cycle metabolism decreasing the amount of nicotinamide adenine-dinucleotide (NADH) used by the electron transport chain for adenosine-triphosphate (ATP) production (1). Other C. difficile strains create neurochemical compounds that disrupt dopamine production leading to various issues with regards to mental health. However, the most commonly known toxins produced by C. difficile are those that disrupt gastrointestinal function and in some individuals can lead to serious health problems.
The Prevalence of C. difficile Associated Disease
The rates of C. difficile infections leading to serious illness and death have been on the rise. According to the Centers for Disease Control even as recent as 2011 there were approximately 450,000+ documented case of Clostridium difficile infections (CDI) and upwards of 29,000 deaths (2). A large number of individuals who have an initial episode of CDI will develop at least one recurrence of the disease. The recurrence rates for CDI are high, in part because of the complex nature of C. difficile, and its spore forms that resist antibiotic intervention.
One of the problems with C. difficile is that not only can it lead to serious illness in susceptible individuals, but that it can be found in people, even children, who may not necessarily be suffering with primary issues related to C. difficile. For example, a paper in 2010 out of Poland (3) discussed the prevalence of C. difficile in fecal samples taken from 178 children ages 2 months to 2 years who were hospitalized for a variety of reasons. Their stools where examined for the presence of C. difficile Toxin A and B, the two main intestinal toxins known to trigger chronic diarrhea and bowel inflammation. The percentage of children infected with C. difficile was 68.6% and many of these children were not acutely sick from C. difficile. However, as mentioned previously, toxin A and toxin B from certain strains of C. difficile can lead to serious problems.
The Role of Toxin A and Toxin B
These two toxins are the main virulence factors related to mucosal damage from C. difficile. Toxin A and B are capable of causing mucosal damage resulting in digestive tract inflammation leading to either clostridia difficile associated diarrhea (CDAD) or Pseudomembranous colitis (4).
Toxin A is categorized as an enterotoxin, which means it is a toxin released by microorganisms that target the digestive system. It functions by changing host cell metabolism and tight junction formation. This can lead to mucosal cell damage, fluid accumulation and even cell death. Toxin A is considered to be the main cause of CDAD as it causes intestinal villi and brush border destruction. In severe cases of Toxin A production, it can lead to ulceration formation seen in Pseudomembranous colitis.
Pseudomembranous colitis is a type of inflammatory bowel disease of the colon that manifests with various ulcerations from mucosal damage and the development of a “pseudo” membrane (aka. ‘inflammatory membrane’), that overlays the site of mucosal injury. This inflammatory membrane is an accumulation of fibrin and inflammatory and necrotic cells that appear as a yellowish globule spread throughout the colon. In the late 1970s it was determined that C. difficile via the production of various toxins, was the causative organism for Pseudomembranous colitis.
Like Toxin A, Toxin B also plays a significant role in damage to the mucosal lining of the digestive system. Toxin B is categorized as a cytotoxin which means it is toxic to cells. Examples of cytotoxins would be chemicals produced by the immune system that damage other cells in the body. Bee venom, as well as poisons from spiders or snakes, are all classified as cytotoxins.
Toxin B causes major cellular disruption by interfering with signaling pathways, tight junction formation, formation of the cytoskeleton of the cell, and derangement of overall cell structure. It is a major virulence factor of C. difficile leading to vascular swelling and hemorrhaging. Also, Toxin B can not only have local inflammatory effects in the digestive system, but also systemic effects through its production of proinflammatory cytokines such as Tumor Necrosis Factor-αlpha.
It was felt for many years that serious bowel inflammation from C. difficile was generated by a single toxin, but both toxins are now known to be capable of causing mucosal damage.
Treatment and Testing
Treatment of C. difficile infections are mostly done by antibiotics. The two most common antibiotics are oral Flagyl (metronidazole) and oral Vancomycin (vancocin). Traditional intervention calls for 7 to 10 days of either antibiotic. As mentioned previously recurrence rates for C. difficile can be high, primarily because of C. difficile spore formation. There is a trend in C. difficile treatment to use cyclical courses of either antibiotic to aide in reduction of recurrence rates and increase clinical outcomes.
Stool testing for C. difficile is effective and is used as a primary diagnostic tool analyzing for the presence of Toxin A and Toxin B. Prior to stool testing direct visualization of inflammatory membranes was used through colonoscopy or sigmoidoscopy.
If either Toxin A or B is detected on stool pathogen screening the practitioner needs to correlate the information to the clinical presentation of the individual and treat accordingly or refer to a specialist for further evaluation. Not everyone with C. difficile will be symptomatic of intestinal disease so each situation needs to be evaluated individually. However, the presence of Toxin A or Toxin B found on stool pathogen testing certainly documents the presence of a strain of C. difficile. The individual should be treated appropriately.
Dr. Kurt N. Woeller is an author, international speaker, practicing clinician and founder of Integrative Medicine Academy (www.IntegrativeMedicineAcademy.com), which is an online training academy that provides various courses for health practitioners interested in integrative medicine.
REFERENECS
1. Richard E. Frye, et. al. Gastrointestinal dysfunction in autism spectrum disorders: the role of the mitochondria and the enteric microbiome. Microbial Ecology in Health and Disease. Volume 26, 2015.
2. Lessa, FC, et.al. Burden of Clostridium difficile infection in the United States. N. Engl J Med, 2015;372:825-834.
3. Prevalence of Clostridium difficile in the gastrointestinal tract of hospitalized children under two years of age. Med Dosw Mikrobiol; 2010;62(1):77-84 (Poland).
4. (Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP; October 2010. "The role of toxin A and toxin B in Clostridium difficile infection". Nature 467 (7316): 711–3.
The Green Smoothie Health Fad: This Road to Health Hell is Paved with Toxic Oxalate Crystals
William Shaw, PhD
Recent internet news indicated the conviction of an oncologist who attempted to kill her boyfriend who was involved with another woman. The weapon of choice was ethylene glycol, popularly known as antifreeze, which had been placed in his coffee just after coitus. Although emergency measures saved the boyfriend's life, extensive deposits of oxalate crystals, the main toxic metabolite of ethylene glycol, had caused extensive kidney and liver damage, reducing the man's lifespan by about half.
Similar results in sabotaging your own health can occur through the regular consumption of a popular concoction called a "green smoothie". A recent Google search for "green smoothie" yielded 609,000 hits. In addition, a recent "improving your diet" seminar I attended promoted this same idea. Interestingly, on the same day, I reviewed test results of a urine organic acid test of a woman with oxalate values three times the upper limit of normal. A conversation with the patient indicated that she had recently turned to consuming daily "green smoothies" to "clean up her diet". The most common "green" components of the most popular green smoothies are spinach, kale, Swiss chard, and arugula. Each of these greens is loaded with oxalates. A typical internet recipe advises that two cups of packed raw spinach leaves is a good starting point for a good smoothie. In addition to the high oxalate greens added to the blender, green smoothie proponents frequently recommend adding a variety of berries or almonds, also containing high oxalate amounts. Similar high urine oxalate results were found in organic acid tests of a number of patients with kidney stones who had decided to eat large spinach salads daily as a "move to clean up my unhealthy diet". Unfortunately kidney stones are not the only health problems that people who regularly consume green smoothies and large spinach salads will experience with their new "clean" diet.
Seventy-five years ago, a food scientist of the Campbell Soup Company (1) reported: "Only a few foods, notably spinach, Swiss Chard, New Zealand spinach, beet tops, lamb's quarter, poke, purslane, and rhubarb have high oxalate content. In them, expressed as anhydrous oxalic acid, it is often considerably over 10% on a dry basis. In fifty-three samples, including practically all commercial and many experimental varieties grown in California and in Maryland as well as those shipped from Texas, Florida and Carolina, the average anhydrous oxalic acid content was 9.02% on the dry basis (maximum 12.6, minimum 4.5). Whereas spinach greatly increases the calcium content of the low calcium but well performing basal diet, it decidedly interferes with both growth and bone formation. If to a diet of meat, peas, carrots and sweet potatoes, relatively low in calcium but permitting good though not maximum growth and bone formation, spinach is added to the extent of about 8% to supply 60% of the calcium, a high percentage of deaths occurs among rats fed between the age of 21 and 90 days. Reproduction is impossible. The bones are extremely low in calcium, tooth structure is disorganized and dentine poorly calcified. Spinach not only supplies no available calcium but renders unavailable a considerable amount of the calcium in the other foods. Considerable amounts of the oxalate appear in the urine, much more in the feces."
The author also discovered that in addition to leading to excessive death and defective reproduction in the rats, high oxalate foods also cause soft and pliable bones and defective teeth.
Oxalate and its acid form oxalic acid are organic acids that come from three sources: the diet, fungus infections such as Aspergillus and Penicillium and possibly Candida (2-10), and also human metabolism (11).
Oxalic acid is the most acidic organic acid in body fluids and is used commercially to remove rust from car radiators. Antifreeze (ethylene glycol) is toxic primarily because it is converted to oxalate. Two different types of genetic diseases are known in which oxalates are high in the urine. The genetic types of hyperoxalurias (type I and type II) can be determined from the organic acid test done at The Great Plains Laboratory. Foods especially high in oxalates include spinach and similar leafy vegetables, beets, chocolate, soy, peanuts, wheat bran, tea, cashews, pecans, almonds, berries, and many others. Oxalates are not found in meat or fish at significant concentrations. Daily adult oxalate intake is usually 80-120 mg/d but it can range from 44-1000 mg/d in individuals who eat a typical Western diet. I estimate that the person who consumes a green smoothie with two cups (about 150 grams) of spinach leaves is consuming about 15 grams or 15,000 mg of oxalates or about 150 times the average daily oxalate intake. A complete list of high oxalate foods is available on the Internet at http://www.upmc.com/patients-visitors/education/nutrition/pages/low-oxalate-diet.aspx
High oxalate in urine and plasma was first found in people who were susceptible to kidney stones. Most kidney stones are composed of calcium oxalate. Stones can range in size from the diameter of a grain of rice to the width of a golf ball. It is estimated that 10% of males may have kidney stones some time in their lives. Because many kidney stones contain calcium, some people with kidney stones think they should avoid calcium supplements. However, the opposite is true. When calcium and magnesium are taken with foods that are high in oxalates, oxalic acid in the intestine combines with these minerals to form insoluble calcium and magnesium oxalate crystals that are eliminated in the stool. These forms of oxalate cannot be absorbed into the body. When calcium and/or magnesium are low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium and other metals, including heavy metals like lead and mercury to form crystals that may block urine flow, damage the kidney, and cause severe pain. These oxalate crystals can also form in the bones, skin, joints, eyes, thyroid gland, blood vessels, lungs, and even the brain (11-14). Oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression (14). In addition to individuals with autism and kidney disease, individuals with fibromyalgia and women with vulvar pain (vulvodynia) may also suffer from the effects of excess oxalates (15-18).
Recent evidence also points to the involvement of oxalates in stroke, atherosclerosis, and in endothelial cell dysfunction (19-21). High amounts of oxalates were found concentrated in atherosclerotic lesions of the aortas and coronary arteries of a number of individuals at autopsy. These individuals did not have oxalate deposits in the kidney but did have oxalate deposits in other organs such as the thyroid gland and testis. Since the stains used by most pathologists examining atherosclerotic lesions cannot readily determine the presence of oxalates in diseased arteries, it seems possible that this cause of atherosclerosis may be much more common than previously realized. I suspect that oxalates are a much more common cause of atherosclerosis than high cholesterol. Furthermore, since ethylenediaminetetraacetic acid (EDTA) is effective in the removal of oxalate crystals deposited in the tissues (22,23), the benefits of intravenous EDTA in the treatment of cardiovascular disease may be mediated largely by the removal of oxalate crystals and their associated heavy metals from the tissues in which they are deposited.
Oxalate crystals may cause damage to various tissues due to their sharp physical structure and they may increase inflammation. Iron oxalate crystals may also cause significant oxidative damage and diminish iron stores needed for red blood cell formation (11). Oxalates may also function as chelating agents and may chelate many toxic metals such as mercury and lead. However, unlike common chelating agents like EDTA and DMSA that cause metals to be excreted, a reaction of oxalate with heavy metals like mercury and lead leads to the precipitation of the heavy metal oxalate complex in the tissues, increasing the toxicity of heavy metals by delaying their excretion (24).
What steps can be taken to control excessive oxalates?
Use antifungal drugs to reduce yeast and fungi that may be causing high oxalates. Children with autism frequently require years of antifungal treatment. I have noticed that arabinose, a marker indicating yeast/fungal overgrowth on the organic acid test at The Great Plains Laboratory, is correlated with high amounts of oxalates (Figure 1). Candida albicans produces high amounts of the enzyme collagenase (25), which breaks down collagen in the gastrointestinal tract to form the amino acid hydroxyproline, which in a series of reactions is converted to oxalates, especially in people with low vitamin B6. Candida organisms have also been found surrounding oxalate stones in the kidney (10).
Give supplements of calcium citrate and magnesium citrate to reduce oxalate absorption from the intestine. Citrate is the preferred calcium form to reduce oxalate because citrate also inhibits oxalate absorption from the intestinal tract. The best way to administer calcium citrate would be to give it with each meal. Children over the age of 2 need about 1000 mg of calcium per day. Of course, calcium supplementation may need to be increased if the child is on a milk-free diet. The most serious error in adopting the gluten-free, casein-free diet is the failure to adequately supplement with calcium.
Give chondroitin sulfate to prevent the formation of calcium oxalate crystals (26).
Vitamin B6 is a cofactor for one of the enzymes that degrades oxalate in the body and has been shown to reduce oxalate production (27).
Consume a low-oxalate diet, avoiding high-oxalate foods such as leafy greens, beans, berries, nuts, tea, chocolate, wheat germ, and soy. Dr. Clare Morrison, a general practitioner from the U.K. who has fibromyalgia found relief from symptoms after changing to a low-oxalate diet. In a 2012 article in the Daily Mail, she said, "I cut these out of my diet and overnight my symptoms disappeared — the disabling muscle pains, tingling legs, fatigue and inability to concentrate all went" (28).
Increase water intake to help eliminate oxalates.
Measuring oxalate toxicity
The organic acid test (Table 1) is one of the best measures for determination of both genetic and nutritional factors that lead to toxic oxalates. The organic acid test includes two additional markers, glycolic and glyceric acids, that are markedly elevated in genetic causes of excessive oxalate, the hyperoxalurias I and II. In addition, the organic acid test includes factors such as high fungal and Candida markers that make oxalate (fungus) or their precursors (Candida). Finally, although vitamin C poses little risk of excess oxalates at doses up to 2000 mg per day, I have measured marked increases in oxalates (more than ten times the upper limit of normal) in a child with impaired kidney function after a 50,000 mg intravenous vitamin C megadose. The organic acid test also includes the main vitamin B6 metabolite pyridoxic acid that diminishes the body's own production of oxalates.
Clinical References:
Kohmani EF. Oxalic acid in foods and its behavior and fate in the diet. Journal of Nutrition. (1939) 18(3):233-246,1939
Tsao G. Production of oxalic acid by a wood-rotting fungus. Appl Microbiol. (1963) May; 11(3): 249-254.
Takeuchi H, Konishi T, Tomoyoshi T. Observation on fungi within urinary stones. Hinyokika Kiyo. (1987) May;33(5):658-61.
Lee SH, Barnes WG, Schaetzel WP. Pulmonary aspergillosis and the importance of oxalate crystal recognition in cytology specimens. Arch Pathol Lab Med. (1986) Dec;110(12):1176-9.
Muntz FH. Oxalate-producing pulmonary aspergillosis in an alpaca. Vet Pathol. (1999) Nov;36(6):631-2.
Loewus FA, Saito K, Suto RK, Maring E. Conversion of D-arabinose to D-erythroascorbic acid and oxalic acid in Sclerotinia sclerotiorum. Biochem Biophys Res Commun. (1995) Jul 6;212(1):196-203.
Fomina M, Hillier S, Charnock JM, Melville K, Alexander IJ, Gadd GM. Role of oxalic acid overexcretion in transformations of toxic metal minerals by Beauveria caledonica. Appl Environ Microbiol. (2005) Jan;71(1):371-81.
Ruijter GJG, van de Vondervoort PJI, Visser J. Oxalic acid production by Aspergillus niger: an oxalate-non-producing mutant produces citric acid at pH 5 and in the presence of manganese. Microbiology (1999) 145, 2569–2576.
Ghio AJ, Peterseim DS, Roggli VL, Piantadosi CA. Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity. Am Rev Respir Dis. (1992) Jun;145(6):1499-502.
Takeuchi H, Konishi T, Tomoyoshi T. Detection by light microscopy of Candida in thin sections of bladder stone. Urology. (1989) Dec;34(6):385-7.
Ghio AJ, Roggli VL, Kennedy TP, Piantadosi CA. Calcium oxalate and iron accumulation in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. (2000) Jun;17(2):140-50.
Ott SM, Andress DL, Sherrard DJ. Bone oxalate in a long-term hemodialysis patient who ingested high doses of vitamin C. Am J Kidney Dis. (1986) Dec;8(6):450-4.
Hall BM, Walsh JC, Horvath JS, Lytton DG. Peripheral neuropathy complicating primary hyperoxaluria. J Neurol Sci. (1976) Oct;29(2-4):343-9.
Sahin G, Acikalin MF, Yalcin AU. Erythropoietin resistance as a result of oxalosis in bone marrow. Clin Nephrol. (2005) May;63(5):402-4.
Sarma AV, Foxman B, Bayirli B, Haefner H, Sobel JD. Epidemiology of vulvar vestibulitis syndrome: an exploratory case-control study. Sex Transm Infect. (1999) Oct;75(5):320-6.
http://wisewitch.blogspot.com/2006/07/guaifenesinfibromyalgia-and-oxalates.html
http://www.diagnoseme.com/cond/C510175.html
http://www.vulvarpainfoundation.org/Lowoxalatetreatment.htm
Fishbein GA, Micheletti RG, Currier JS, Singer E, Fishbein MC. Atherosclerotic oxalosis in coronary arteries. Cardiovasc Pathol. (2008) ; 17(2): 117–123.
Levin RI, PW Kantoff, EA Jaffe. Uremic levels of oxalic acid suppress replication and migration of human endothelial cells. Arterioscler Thromb Vasc Biol (1990), 10:198-207
Di Pasquale G, Ribani M, Andreoli A, Angelo Zampa G, Pinelli G. Cardioembolic stroke in primary oxalosis with cardiac involvement. Stroke (1989), 20:1403-1406.
Ziolkowski F, Perrin DD. Dissolution of urinary stones by calcium-chelating agents: A study using a model system. Invest Urol. (1977) Nov;15(3):208-11.
Burns JR, Cargill JG 3rd. Kinetics of dissolution of calcium oxalate calculi with calcium-chelating irrigating solutions. J Urol. (1987) Mar;137(3):530-3.
http://www.greatplainslaboratory.com/home/eng/oxalates.asp
Kaminishi H, Hagihara Y, Hayashi S, Cho T. Isolation and characteristics of collagenolytic enzyme produced by Candida albicans. Infect Immun. (1986) August; 53(2): 312–316.
Shirane Y, Kurokawa Y, Miyashita S, Komatsu H, Kagawa S. Study of inhibition mechanisms of glycosaminoglycans on calcium oxalate monohydrate crystals by atomic force microscopy. Urol Res. (1999) Dec; 27(6):426-31.
Chetyrkin SV, Kim D, Belmont JM, Scheinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Kidney Int. (2005) Jan;67(1):53-60.
Morrison C. Ditch healthy berries to beat muscle pain: The eating plan that helped me cure my aches and pains. The Daily Mail Online. August 13, 2012. http://www.dailymail.co.uk/health/article-2187890/Ditch-healthy-berries-beat-muscle-pain-The-eating-plan-helped-cure-aches-pains.html. (Accessed November 21, 2014)
Candida: A Factor in Depression and Mental Health
Jessica Bonovich, R.N.
One of the first psychiatrists to publish findings about the connection between Candida and depression is Dr. Orian Truss. His compelling work has been cited in numerous books and helped countless patients to date. Interestingly, his discovery in 1981 did not generate much interest from the psychiatric community who had just begun to see the effects of MAO inhibitors. While these and other modern antidepressants remain an important tool for treating psychiatric patients, studies have demonstrated that their efficacy rate is only about 20-30 percent (Kroenke, Hansen). Clearly, we do not have sufficient understanding of the complex spectrum of mental disorders that plague millions of individuals. To this end, we should leave no stone unturned. Especially if that stone has already shown to provide helpful information.
Dr. Truss hypothesized that where Candida is merely a nuisance for some, it causes chronic illness (including mental illness) in others. People with weakened immune systems are particularly at risk however they need not have HIV or leukemia to suffer. At the Huxley symposium (1981), he presented 6 case studies he believed to encompass the so-called Candida syndrome that he discovered. All individuals had been exposed to multiple rounds of antibiotics or other immune lowering agents. These individuals were often female. Depression was almost always one of many vague symptoms. Loss of memory, difficulty concentrating, sensitivity to chemicals and other symptoms were also noted. Dr. Truss began to incorporate treatment with antifungal therapy for patients with chronic mental illness. Interestingly, all of the individuals responded to the treatment and their symptoms of depression lifted.
More recently, a double blind placebo controlled study in 2001, under the direction of Heiko Santelmann found the antifungal drug nystatin to be significantly more effective at reducing symptoms of depression in polysymptomatic patients. In fact, the authors of the study noted that some of the most dramatic improvements reported were from individuals who had mental complaints. While nystatin is not specific to Candida, it is a compelling study that demonstrates yeast can affect mental health.
Dr. Truss noted the difficultly of testing for Candida since nearly everyone has had exposure to the organism. Determining the degree to which each individual suffers is based on a set of vague symptoms that often ends with the patient being labeled as psychosomatic or psychiatric. Fortunately, today we have more robust methods of detecting Candida and a better understanding of the mechanism which may be causing symptoms.
Genetic coding has helped determine the mechanisms that pathogens employ to help increase virulence. In the case of Candida albicans, a specific gene that codes for Immunogenic Alcohol Dehydrogenase was detailed in 1994 (Bertryam). This enzyme produces acetylaldehyde from glucose or ethanol (Gainza-Cirauqui). This acetylaldehyde creates an environment that is not conducive to most microbes which effectively decreases the competition. In humans, acetylaldehyde is a carcinogenic compound that easily passes the blood brain barrier where it interferes with neurotransmission (Correa). Depression and acetylaldehyde both cause a reduction in natural killer cell cytotoxicity (Irwin). Since nearly everyone has Candida in the body, it is plausible that a brief episode of depression may increase the possibility of developing a chronic condition.
For years, a yeast culture with sensitivity has been the mainstay of Candida testing. The benefit to this test is that it can determine the exact species of yeast so that appropriate treatment can be instituted. The problem with this method is that it is notorious for producing false negatives (Maaroufi). Metabolites of yeast detected in The Great Plains Laboratory Organic Acids Test are a very reliable method of detecting Candida overgrowth (Shaw). While this test cannot determine the exact organism, this is less important. Most prescriptive antifungal agents are effective at killing Candida albicans, which is the most common yeast species (Shaw).
Armed with correct information, the latest in diagnostic testing, and viable treatment options, psychiatric and primary care physicians can exercise multiple options for patients with symptoms of depression and other mental health disorders. As more and more physicians are looking outside the box to find solutions to psychiatric diseases as complex as the patients themselves, many are turning to comprehensive testing for yeast (and other pathogens) for answers. If a patient presents with a recent onset of chronic depression in the absence of major trauma, it makes sense to ask the question: Could this be related to Candida or another pathogen? Doing so may save your patient's life, or at least the life they once knew!
Clinical References
Hansen, R. et al. (2005). Efficacy and Safety of Second-Generation Antidepressants in the Treatment of Major Depressive Disorder. Annals of Internal Medicine, 143(6); 415-426.
Kroenke, K., et al. (2001). Similar Effectiveness of Paroxetine, Fluoetine, and Sertaline in Primary Care. JAMA, 286(23); 2947-2955
Truss, O. (1981). The Role of Candida in Human Illness. Presented that the Huxley symposium, September, Birmingham, AL.
Bertryam, G., et al. (1995). Structure and Regulation of the Candida albicans ADH1 Gene Encoding an Immunogenic Alcohol Dehydrogenase. Yeast, 12:115-127.
Santelmann, H et al. (2001). Effectiveness of nystatin in polysymptomatic patients. A randomized, double-blind trial with nystatin versus placebo in general practice. Family Practice, 18; 258-265.
Gainza-Cirauqui, ML., et al. (2013). Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders. Journal of Oral Pathology and Medicine, 42(3); 243-9.
Correa, M., et al. (2011). Piecing together the puzzle of acetaldehyde as a neuroactive agent. Neuroscience and Biobehavioral Reviews, 36; 404-430.
Irwin, M., et al. (1990). Major Depressive Disorder, Alcoholism, and Reduced Natural Killer Cell Cytotoxicity: Role of Severity of Depressive Symptoms and Alcohol Consumption. JAMA Psychiatry, 47(8); 713-719.
Maaroufi, Y., Heymans, C., De Rune, J., Duchateau, H. (2003). Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay. Journal of Clinical Microbiology, 41; 3293-3298.
Shaw ,W., (2008) Biological Treatments for Autism and PDD. Publisher: Author.
Clostridia Detection and Comparison of Organic Acid Detection Versus Stool Testing
William Shaw, Ph.D.
Continued research at The Great Plains Laboratory has resulted in new information on Clostridia bacteria markers that will soon be available for the urine organic acid test. New information will soon be available for the organic acid interpretations of 3 (3 hydroxyphenyl)-3 hydroxypropionic acid (HPHPA), 4-hydroxyphenylacetic acid, phenyllactic acid, and 3-indoleacetic acid at the beginning of 2015.
In addition, this article will help to clarify information about the increased value of organic acid testing compared to stool testing for assessing Clostridia species.
HPHPA
First, the species that are the major producers of the precursors of HPHPA have been identified and include C. botulinum, C. sporogenes, and C.caloritolerans. (It is common to use the abbreviation for the Clostridia genus "C" when giving the genus and species designation.)
C. botulinum is a gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. The botulinum toxin can cause a severe flaccid paralytic disease in humans and animals and is the most potent toxin known to humankind (natural or synthetic) with a lethal dose of less than 1 μg (microgram) in humans. Symptoms of botulism include weakness, trouble seeing, feeling tired, and trouble speaking. This may then be followed by weakness of the arms, chest muscles, and legs. In food borne botulism, symptoms generally begin 18 to 36 hours after eating a contaminated food, but they can occur as early as 6 hours or as late as 10 days after eating the food.
It is interesting that the symptoms of botulism vary widely from a mild illness for which the patient may seek no medical treatment to a fulminant disease, killing within 24 hours (1). Since laboratory testing for this organism is only available at state health departments, it seems likely that many cases of botulism, especially the mild cases, may be undiagnosed. I suspect that some children with autistic behavior,with extremely high urine HPHPA, little or no speech, and extremely severe low muscle tone might actually have undiagnosed botulism, and further research on this possibility is warranted.
C. sporogenes is virtually identical to C. botulinum except it is lacking the gene for the botulinum neurotoxin. Like C. botulinum, it is an anaerobic gram-positive, rod-shaped bacterium that produces oval, subterminal endospores, and is commonly found in soil.
C. caloritolerans is named after its extreme heat (calor) resistance (tolerans). It can survive at the boiling point for 8 hours (2); its ability to resist heat may allow transmission even in well-cooked food. No scientific papers on any disease associations (other than my own articles dealing with its production of HPHPA) were found, which means there is still a great deal of research opportunity for microbiologists in the future.
4-Hydroxyphenylacetic Acid
High 4-hydroxyphenylacetic acid is associated with small intestinal bacteria overgrowth due to its production by the following Clostridia bacteria: C. diificile, C. stricklandii, C. lituseburense, C. subterminale, C. putrefaciens, and C. propionicum. C. difficile can be distinguished from the other species by its production of 4-cresol; none of the other species produce 4-cresol. No information on the pathogenicity of the other species producing 4-hydroxyphenylacetic acid is available. However, it is likely that 4-hydroxyphenylacetic is also an inhibitor of dopamine-beta-hydroxylase and appropriate treatment with probiotics or antibiotics may be clinically useful. 4-hydroxyphenylacetic acid is associated with bacterial overgrowth of the small intestine (3). Elevated values are common in celiac disease and cystic fibrosis, and have also been reported in jejuna web, transient lactose intolerance, Giardia infection, ileal resection, ileo-colic intersusseception, septicemia, and projectile vomiting. The elevations of 4-hydroxyphenylacetic acid in celiac disease and cystic fibrosis are so prevalent that involvement of these Clostridia bacteria may play a role in these illnesses. In C. difficileinfections 4-hydroxyphenylacetic acid is utilized by this bacteria to produce 4-cresol.
Phenyllactic Acid
Very high amounts of phenyllactic acid are found in the rare genetic disease phenylketonuria (PKU). Moderate amounts of phenyllactic acid may be due to gastrointestinal overgrowth of the intestine of the following Clostridia bacteria: C. sordellii, C. stricklandii, C. mangenoti, C. ghoni, and C. bifermentans. C sordellii is usually considered a nonpathogen except in immunocompromised people, but has been implicated in catastrophic infectious gynecologic illnesses among women of childbearing age. The other species have rarely or never been reported to be pathogenic.
3-Indoleacetic Acid
High 3-indoleacetic acid in urine is a byproduct of C. stricklandii, C. lituseburense, C. subterminale, and C. putrefaciens. No information on the pathogenicity of these species producing indoleacetic acid is available. However, very high amounts of this metabolite derived from tryptophan might indicate a depletion of tryptophan needed for other physiological functions.
4-Cresol
4-cresol is predominantly produced by C. difficile, a pathogenic bacteria, that is one of the most common pathogens spread in hospitals. Toxin-producing strains of C. difficile can cause illness ranging from mild or moderate diarrhea to pseudomembranous colitis, which can lead to toxic dilatation of the colon (megacolon), sepsis, and death (4). 4-cresol (para-cresol) has been used as a specific marker for Clostridium difficile (5). 4-Cresol, a phenolic compound, is classified as a type-B toxic agent and can cause rapid circulatory collapse and death in humans (6). Yokoyama et al. (7) have recently proposed that intestinal production of 4-cresol may be responsible for a growth-depressing effect on animals. Signs of acute toxicity in animals typically include hypoactivity, salivation, tremors and convulsions. High amounts of 4-cresol have been found in autism (8); the amount of 4- cresol in the urine has been found elevated in baseline samples and in replica samples of autistic children. Higher values of 4-cresol are found in girls with autism compared to boys with autism and higher values are associated with greater clinical severity of autistic symptoms and history of behavioral regression. 4-cresol is apparently produced by Clostridia difficile as an antimicrobial compound that kills other species of bacteria in the gastrointestinal tract, allowing the Clostridia difficile to proliferate and predominate.
Organic acid test superior to stool testing for Clostridia testing
C. difficile is the only species of 100 species of Clostridia from the gastrointestinal tract to be commonly tested in hospital laboratories throughout the world. However, this species is not commonly cultured, but rather is detected by its toxin formation. The gastrointestinal damage caused by C. difficile is thought to be due to exposure to two toxins produced by C. difficile, toxin A and toxin B, with toxin B considered to be more toxic (4). The toxins can be tested by immunoassay of stool samples which is a fairly rapid test. Toxigenic stool culture, which requires growing the bacteria in a culture and detecting the presence of the toxins, is the most sensitive test for C. difficile, and it is still considered to be the gold standard (4). However, it can take 2 to 3 days for results. Polymerase chain reaction (PCR) evaluation of the C. difficile toxins is also becoming more available. Virtually all of the research on C. difficile is related to the effects of this species of bacteria on the intestinal tract. Toxin-negative C. difficile strains are considered nonpathogenic for the infection of the intestine (4) but cresol producing strains that don't produce toxins and B may be pathogenic due to their effects on brain metabolism and for the inherent toxicity of 4-cresol itself.
In addition, urinary 4-cresol elevations associated with C. difficileovergrowth are much less common than urinary HPHPA elevations associated with other Clostridia species. In a survey of 1000 consecutive samples submitted for urine organic acids tests, The Great Plains Laboratory found that 15.2% were abnormally elevated for HPHPA, 6.8% were abnormally elevated for 4-cresol, and 1.6% were abnormally elevated for both HPHPA and 4-cresol for a total positive percentage of 23.6%. Thus, if only stool testing for Clostridium difficile is performed on a patient, at least 15.2/23.6 or 64.4% (nearly two-thirds) of patients with clinically significant infections with other types of Clostridia might be missed.
Sometimes total Clostridia are tested using culture methods or PCR (polymerase chain reaction) technology. In one case, a parent showed me the stool test results of their child with autism. They had done a stool test with a laboratory using PCR technology to determine both C. difficile and total Clostridia. The total Clostridia was reported as extremely low and the C. difficile negative, but The Great Plains Laboratory organic acid test found high levels of the HPHPA marker. If the parent had relied on the stool test alone, their child might have missed an important therapeutic intervention that can restore normal neurotransmitter balance. The advantage of The Great Plains Laboratory organic acid test is that it is not necessary to determine particular species of Clostridia because it is the HPHPA and/or 4-cresol that are neurotoxic.
People sometimes assume that a test using DNA is more accurate than other types of testing. However, DNA testing is fraught with complexities. The nucleic acids of Clostridia are extremely diverse. The content of the nucleic acid bases guanosine and cytosine (G+C) is used to classify bacteria species. The G+C content of DNA of Clostridia species ranges from 21-54 % (9). The majority of intestinal species have G+C contents in the lower half of this range. Ribosomal RNA cataloging confirms that Clostridia occupy six independent sublines with multiple branches including non-Clostridia species. The failure to offer documentation on which species are being detected and how validation was performed should lead to caution by the user of such testing, especially when such tests may be labeled "experimental". Similar complexities exist with traditional culture methods for Clostridia since results are commonly reported from 0 to 4+. Since many Clostridia are not pathogenic, what does a high Clostridia level of 4+ indicate since beneficial, neutral, and harmful species are lumped together in one category? In reality, the results of stool tests for total Clostridia are virtually meaningless and may lead to inappropriate patient treatment.
It is estimated that there are about 10 billion cells of Clostridia per gram of stool. Clostridium ramosum is the most common (53% of all subjects tested) with a mean count of about one billion per gram of stool (9). The prevalence of some Clostridia species is highly dependent on diet. Stool samples of vegetarians did not contain Clostridium perfringens whereas meat and fish eaters had high amounts (10).
Since HPHPA is associated with multiple species of Clostridia but not Clostridium difficile, there is really no available confirmation test for determining the specific species of Clostridium producing HPHPA. As mentioned above, stool testing for total Clostridia is useless since it cannot currently differentiate between harmful or beneficial species. Since HPHPA, in my experience, disappears after treatment with vancomycin or metronidazole, I always recommend treatment based on the HPHPA value with a follow-up test 30 days after completion of treatment.
Confirmation testing of Clostridium difficile could be performed when 4-cresol is elevated. However, the prevalent testing for Clostridium difficile toxins A and B are focused on strains that cause gastrointestinal damage. Strains that produce 4-cresol but not toxins A or B may still cause significant psychiatric disease, so performing these toxin tests may muddy the interpretation of the clinical situation if these tests are negative. I think that it is easier to treat based on the 4-cresol results and then do follow-up testing of the 4-cresol on the organic acid test 30 days after completion of treatment.
Clinical References
Beatty, H. Botulism. In: Harrison's Principles of Internal Medicine, 10th edition, ed. R. Petersdorf, et al. McGraw Hill. New York. 1983. Pages 1009-1013.
Meyer, K.F. and Lang, O.W. A highly heat-resistant sporulating anaerobic bacterium: Clostridium caloritolerans, N. SP. The Journal of Infectious Diseases Vol. 39, No. 4 (Oct., 1926), pp. 321-327
Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
Carrico, R.M. Association for Professionals in Infection Control and Epidemiology (APIC) Implementation Guide to Preventing Clostridium difficile Infections http://apic.org/Resource_/EliminationGuideForm/59397fc6-3f90-43d1-9325-e8be75d86888/File/2013CDiffFinal.pdf (accessed Oct 30,2014)
Sivsammye, G. and Sims, H.V. Presumptive identification of Clostridium difficile by detection of p-cresol (4-cresol) in prepared peptone yeast glucose broth supplemented with p-hydroxyphenylacetic acid. J Clin Microbiol. Aug 1990; 28(8): 1851–1853.
Phua, T.J., Rogers, T.R., and Pallett, A.P. Prospective study of Clostridium difficile colonization and paracresol detection in the stools of babies on a special care unit. J. Hyg., Camb. (1984). 93. 17-25 17
Yokoyama, M. T., Tabori, C., Miller, E. R. and Hogberg, M. G. (1982). The effects of antibiotics in the weanling pig diet on growth and the excretion of volatile phenolic and aromatic bacterial metabolites. The American Journal of Clinical Nutrition 35, 1417-1424.
Persico, A.M. and Napolioni, V. Urinary p-cresol (4-cresol) in autism spectrum disorder. Neurotoxicology and Teratology 36 (2012) 82–90
Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
10. Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24
The Role of Diet and the Gut in Mental Health
Terri Hirning
While the traditional mental health model focuses on brain function, neurotransmitters and potentially pharmaceutical medications, the ever burgeoning integrative mental health field understands there is more to it than that. Even mainstream media is starting to get the hint. Our gut influences our mind, emotions, cognition and mental health more than we've given it credit for in recent history. Whether we want to focus on the role food allergies play on mental health (1), (2) or how the gut-brain axis impacts our mental health (3), or even how the microbiome shapes our mental functioning (4) we can see the trend in research confirming what many integrative physicians and clinicians know: the gut matters
When we talk about the gut, we must cover diet. Some literature even suggests that a debilitating mental health disorder like Alzheimer's now be called "Type 3 Diabetes" (5) because of its links to certain kinds of foods and a generally poor diet. What is causing the alarming trend of food allergies, food sensitivities and the increase in auto-immune conditions? Is it GMO's? Is it Glyphosate (the herbicide used in products like Monsanto's Roundup)? Is it the prevalence of processed grains in our diets now? It may be all of thesethings, or none of these things, but as physicians and clinicians, the data suggests we take a closer look at our patients' diets and here are some things to consider:
Is there an underlying food allergy or multiple allergies? This can be an easy and yet very powerful place to start. Research shows that food allergies can indeed cause manifestations of mental health disorders. Running a simple IgG food allergy test from the Great Plains Laboratory, which also includes markers for Candida (harmful fungus in the gut) can be a great first step. More mainstream information on the treatment of Celiac disease can be also helpful in finding its connections to many mental health disorders like dementia, seizures, schizophrenia, etc.(6), and one does not have to be diagnosed with Celiac disease to be sensitive and reactive to gluten.
What about healthy gut function and microbiome population? Our microbiome is sensitive to our diets, and quickly reactive to changes. Looking at potential gut dysbiosis and the levels of beneficial flora in the gut is very important. An organic acids test will show you a wide range of metabolic markers, including several for bacteria (like Clostridia) and fungus (like Candida albicans) in the gut. If a patient has high levels of these, a course of treatment can be started to rid them of these invaders, possibly including dietary restrictions (like a low sugar, low carb diet) and adding helpful antibacterial or antifungal supplements. Then, to assess the beneficial bacteria in the gut, you may want to run a comprehensive stool analysis. This will help determine whether a patient needs to add a high-quality probiotic supplement to their diet and possibly increase his/her intake of probiotic-rich and fermented foods like kefir and sauerkraut.
Today's mental health disorders are very complex. Their treatment requires a well-rounded look at the many factors impacting the body and brain, including diet, lifestyle, the microbiome, and more. When an integrative approach is used and these many factors considered when creating a treatment plan, time and time again we see improvements in functioning and a reduction in clinical symptoms.
Clinical References:
Jackson J1, Eaton W2, Cascella N3, Fasano A4, Santora D5, Sullivan K6, Feldman S6, Raley H7, McMahon RP6, Carpenter WT Jr6, Demyanovich H6, Kelly DL8.Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia Schizophr Res. (2014) Oct 10. pii: S0920-9964(14)00511-8. doi: 10.1016/j.schres.2014.09.023.
Genuis SJ1, Lobo RA2. Gluten sensitivity presenting as a neuropsychiatric disorder . Gastroenterol Res Pract. (2014);2014:293206. doi: 10.1155/2014/293206.
Nemani K1, Hosseini Ghomi R2, McCormick B3, Fan X3. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. (2014) Sep 19;56C:155-160. doi: 10.1016/j.pnpbp.2014.08.018.
Severance EG1, Yolken RH2, Eaton WW3. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res. (2014) Jul 14. pii: S0920-9964(14)00319-3. doi: 10.1016/j.schres.2014.06.027.
De la Monte S, Wands J. Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed. J Diabetes Sci Technol. (2008) 2(6): 1101–1113.
Velasquez-Manoff Moises (2014 October 12). Can Celiac Disease Affect the Brain? The New York Times. Retrieved from:http://www.nytimes.com/2014/10/12/opinion/sunday/can-celiac-disease-affect-the-brain.html?smid=tw-share&_r=0
The Role of Vitamins, Antioxidants, and Anti-Inflammatories in Breast Cancer Prevention and Treatment
Terri Hirning
October is Breast Cancer Awareness Month. As such, we would like to take a moment to focus on how nutritional and supplement therapy can play a role in the prevention and treatment of cancer. When we look at how antioxidants impact cancer, we can see that there is scientific documentation of reduced development of breast cancer in those with high dietary intake of antioxidants. One study in late 2014 titled The Rotterdam Study provides this information: "These results suggest that high overall dietary antioxidant capacity are associated with a lower risk of breast cancer."1 Women who had higher rates of antioxidant intake via diet were less likely to develop breast cancer. What about those who already had breast cancer? Could it help with treatment? A March 2014 issue of Anticancer Research featured a study showing the use of lycopene and beta-carotene in cell death of human breast cancer cell lines. "Our findings show the capacity of lycopene and beta-carotene to inhibit cell proliferation, arrest the cell cycle in different phases, and increase apoptosis."2 Vitamin C has also been studied in terms of its potential impact on breast cancer deaths and has been shown to have a positive effect on mortality rates. "Dietary vitamin C intake was also statistically significantly associated with a reduced risk of total mortality and breast cancer-specific mortality."3
If we can look at the data and determine that higher intake of antioxidants and nutrients can not only reduce development of breast cancer but can also positively impact the mortality rates of cancer, the question then becomes how do we encourage our patients and clients to incorporate these into their diets with higher frequency? We must educate them on the role antioxidants play and the resources available to obtain them, whether from foods or supplements. For example, lycopene is a nutrient that is highlighted for its anticancer properties, specifically in reference to breast cancer. Lycopene is a carotenoid that gives many fruits and vegetables their red color. Unlike other carotenes, lycopene does not get converted into vitamin A. The top 10 sources of dietary lycopene are:
Guava
Watermelon
Tomatoes (cooked)
Papaya
Grapefruit
Sweet Red Peppers (cooked)
Asparagus (cooked)
Red (purple) cabbage
Mango
Carrots
Continued from BioMed Today:
Encouraging patients to incorporate more foods with lycopene, like those listed above, into their diets is one component. Supplements can also be suggested as a potential option. This is especially true in the case of vitamin D, for which there are many studies showing its role in the prevention of cancers. Adequate vitamin D is being revealed as a critical factor for preventing many diseases, including breast cancer, today.8 "Case-control studies and laboratory tests have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer."9 Unfortunately due to a variety of reasons, many people are deficient in vitamin D which then can then compromise optimal health. Testing for vitamin D levels, ideally twice a year, is a great way to monitor this critical nutrient and help your patients optimize their health and wellness. Supplementation can then also be recommended to optimize levels. Another promising resource for warding off disease and cancer is curcumin, the extract of the turmeric root. Because of its potent antioxidant and antimicrobial properties, it is being studied extensively for its potential in cancer treatment. The American Cancer Society's website has this to say about it: "Curcumin can kill cancer cells in laboratory dishes and also slows the growth of the surviving cells. Curcumin has been found to reduce development of several forms of cancer in lab animals and to shrink animal tumors."4 The typical therapeutic dose, between 3 and 10 grams per day, exceeds what is normally used in cooking and obtained through dietary consumption so a supplement would be most effective.
Could another reason for the efficacy of curcumin on cancer cell death be its potent anti-inflammatory properties? Curcumin has been studied widely for both its safety and anti-inflammatory potential.5,6 "The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12)."7 We see science validating the role our lifestyle has in development of cancer. Diet, exercise, supplementation, our stress level, and other factors all contribute to the whether or not we develop disease and also to our ability to reverse it. It is important to find ways to offer a variety of prevention and treatment options that work with our patients' lifestyles.
Clinical References:
Pantavos A, Ruiter R, Feskens E, E deKeyser C, Hofman A, H Stricker B, H Franco O, C Kiefte-deJong J (2014). Total dietary antioxidant capacity, individual antioxidant intake and breast cancer risk: The rotterdam study, International Journal of Cancer. 2014 Oct 4. doi: 10.1002/ijc.29249. [Epub ahead of print]
Gloria NF, Soares N, Brand C, Oliveira FL, Borojevic R, Teodoro AJ (2014).Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in human breast cancer cell lines, Anticancer Research. 2014 Mar;34(3):1377-86.
Harris HR, Orsini N, Wolk A (2014). Vitamin C and survival among women with breast cancer: a meta-analysis,European Journal ofCancer. 2014 May;50(7):1223-31. doi: 10.1016/j.ejca.2014.02.013. Epub 2014 Mar 7.
Turmeric (2012). Retrieved on October 5, 2014 from Link
Chainani-Wu NJ (2003). Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa), Journal of Alternative and Complementary Medicine. 2003 Feb; 9(1):161-8.
Jurenka, JS (2009). Anti-inflammatory Properties of Curcumin, a Major Constituent of Curcuma longa: A Review of Preclinical and Clinical Research, Alternative Medicine Review. Volume 14, Number 2, 2009.
Nita Chainani-Wu (2003). The Journal of Alternative and Complementary Medicine. February 2003, 9(1): 161-168. doi:10.1089/107555303321223035.
Vitamin D and Cancer Prevention (2013). Retrieved on October 5, 2014 from http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D
Walentowicz-Sadłecka M, Sadłecki P, Walentowicz P, Grabiec M (2013). The role of vitamin D in the carcinogenesis of breast and ovarian cancer, Ginekologia Polska. 2013 Apr;84(4):305-8.
The SCD, GAPS, and Paleo Diets: How They Compare and How They May Help Your Patients
Terri Hirning
Special diets have become increasingly common and more popular in recent years. Reports from both physicians and patients, many with laboratory tests confirming, say they can be helpful for a variety of diseases including autism, ADHD, multiple sclerosis, auto-immunity, rheumatoid arthritis, bowel conditions, and many more. Three diets in particular appear to help address gut dysbiosis, the overgrowth of microbes such as yeast and bacteria, which can be problematic for many individuals. Research shows that more than 70% of children with an Autism Spectrum Disorder (ASD) report a history of GI complaints.1 "Leaky Gut", or intestinal permeability, results from larger than normal spaces between the cells of the gut wall. These spaces allow undigested food and toxins to enter the blood stream. When this happens, the immune system can mount an attack against the foreign particles which may result in food sensitivities and/or allergies. When the offending foods are eaten again, the release of antibodies triggers inflammation. This chronic inflammation further exacerbates the cycle by lowering Immunoglobulin A (IgA) levels. Adequate IgA levels are required to protect the intestinal tract from the gut pathogens such as clostridia and yeast. This continuous cycle can increase gut dysbiosis and negatively impact the overall health of your patients. All three of these special diets – SCD, GAPS, and Paleo may help address these issues by reducing the amount of undigested and allergenic foods being consumed and healing both the gut and brain.
Understanding how the SCD, GAPS, and Paleo diets may help the gut and brain, as well as the major differences between the three diets, can help you provide guidance to your patients when addressing food allergies, autoimmunity, and gut dysbiosis. All three diets share the basic foundations of reducing carbohydrates, avoiding grains (including those that are gluten-free) avoiding refined sugar, avoiding packaged/processed foods, focusing on nutrient-dense foods, and emphasizing the importance of eating a variety of vegetables. Each diet also has its own unique elements, and here is how they compare:
SCD – Specific Carbohydrate Diet:
This diet was pioneered by Dr. Sidney V. Haas.
Patients are encouraged to follow the program in the book Breaking the Vicious Cycle by Elaine Gottschall.
Carbohydrates allowed on this diet are classified by their molecular structure.
Allowed carbohydrates are monosaccharides and have a single molecule structure that allow them to be easily absorbed by the intestine wall.
Disaccharides (double molecules) and polysaccharides (chain molecules) are not allowed.
Some dried beans and legumes can be added in after symptoms resolve and in accordance with the soaking and preparing instructions from the book.
This diet does allow some dairy (fermented/cultured).
Results of a Rush University SCD study show the diet leads to better microbial gut diversity.2
This diet focuses on reduction of pathogenic organisms in the gut rather than introducing beneficial bacteria.
GAPS – Gut and Psychology Syndrome Diet:
Dr. Natasha Campbell-McBride expanded on the principles of GAPS in her book The Gut and Psychology Syndrome.
GAPS is very similar to SCD except for that it adds many probiotic-rich, cultured foods.These foods may help recolonize good bacteria and counteract bad bacteria.
This diet has more phases and may be seen as more rigorous than SCD.
GAPS emphasizes addressing brain health over gut health, but should certainly assist with both.
Website: http://www.gapsdiet.com
Paleo Diet:
This diet is based upon the concept that the optimal diet is the one to which we are genetically adapted. It recommends modern, everyday foods that mimic the food groups of our pre-agricultural, hunter-gatherer ancestors
Paelo allows some starches that the other diets do not allow.
It does not allow dairy products.
It does not allow legumes or beans.
This diet may be seen as the least restrictive of the three diets.
Website: http://thepaleodiet.com/
How to know when to suggest a diet like SCD, GAPS or Paleo for your patients: Have clinical tests like our Organic Acids Test or Microbial Organic Acids Test indicated yeast and/or bacterial overgrowth? Have repeated courses of antibiotics and/or antifungals failed to resolve these often chronic disorders? Have you tried multiple probiotics which have failed to repopulate the gut with good bacteria and yeast? Has IgG food allergy testing shown continued food allergies despite removal of the common allergens like wheat, dairy, and soy? Has your patient developed new or increasing food allergies despite being on an "allergy-friendly" diet? If you answered yes to any of these questions, considering a more specific and restrictive diet beyond GFCF (Gluten Free, Casein Free) could be the next step in healing for your patients.
Diet can be a very effective way to reduce harmful gut pathogens by removing their food supply and decreasing the inflammation they cause. Diligence, dedication, and strict adherence is required from your patients to see the full benefits of these special diets. In cases where antibiotics, antifungals, supplements, and probiotics have not been successful, these diets may help reverse the gut dysbiosis, after which reintegrating various supplements and probiotics may be effective . For newly diagnosed patients, implementing one of these diets may be a good way to begin their healing process quickly and effectively. As Ann Wigmore, health practitioner, nutritionist, and whole foods advocate said, "The food you eat can be either the safest and most powerful form of medicine or the slowest form of poison".
Clinical References
1. Can J Gastroenterol. Feb 2009; 23(2): 95–98. PMCID: PMC2694587 Autistic enterocolitis: Fact or fiction? Polymnia Galiatsatos, MD FRCPC,1 Adrian Gologan, MD,2 and Esther Lamoureux, MD FRCPC2
Rickets and eye-poking in autism associated with calcium deficiency
William Shaw Ph.D
I strongly disagree with the assertion by some individuals in the autism field that calcium is a problem to individuals on the autistic spectrum. Failure to provide adequate calcium is very dangerous and could lead to the loss of the eyes due to severe eye-poking behavior. Calcium deficiency can be a severe problem in normal children on a milk free diet since milk is a significant source of protein, vitamin D, and calcium needed for strong bones and teeth. Some physicians have reported rickets (1), a severe bone deformity, occurs in children with autism on the gluten and casein free diet who did not receive added calcium supplements. Calcium and vitamin D supplementation is essential to children on a casein free diet since most children with autism do not eat substantial amounts of other calcium-rich foods. Use of milk substitutes like B-Unique® provides adequate calcium, protein, and fat comparable to whole milk without the presence of casein and lactose that are problematic in most children with autism.
Children with autism may have an even more severe problem with calcium deficiency. Mary Coleman, M.D. (2) reported that children with autism who are calcium deficient are much more likely to poke out their eyes and a substantial number of children with autism have done so. I have talked to numerous parents of children with autism that began to touch their eyes after starting the casein-free diet. This abnormal behavior is associated with low urine calcium; blood calcium levels were usually normal. Treatment with calcium supplementation prevents this behavior. (I suspect that this behavior is due to increased eye pain due to high substance P or to deposits of oxalate crystals in the eye. Low calcium may act to intensify this pain and poking out the eye relieves the pain.) Dr. Coleman also found that speech developed very quickly after calcium supplementation in a portion of mute children with autism who had low urine calcium. Parathyroid hormone, calcitonin, and vitamin D were all normal in patients with autism but all of them had low urine calcium. In one case, according to a parent who contacted me, her child with autism persisted in poking at the eyes even after one eye had been poked out and surgically replaced. Calcium supplementation stopped this behavior immediately. I am aware of many other children with eye-poking behavior in which calcium supplements stopped this behavior in less than two days. Verbal autistic children say that their eye pain is severe and that calcium supplementation stopped their pain quickly. The urine calcium and magnesium tests will soon be a part of the Organic Acids Test offered by The Great Plains Laboratory, Inc.
It is important that calcium, magnesium, and zinc be in balance for optimal nutrition. Vitamin D supplementation may also be needed when milk is eliminated unless other sources of vitamin D are included in the diet or the child is exposed to adequate sunlight. Children with autism also need additional calcium to prevent oxalate deposition in the tissues. Although sardines and dark leafy greens like spinach, kale, turnips, and collard greens are high in calcium, all of these foods except sardines are high in oxalates. High oxalates can be fatal if formed in the renal tract. Oxalates in the urine are much higher in individuals with autism than in normal children. As a matter of fact, 36% of the children on the autistic spectrum had values higher than 90 mmol/mol creatinine, the value consistent with a diagnosis of genetic hyperoxalurias while none of the normal children had values this high. 84% of the children on the autistic spectrum had oxalate values outside the normal range (mean ± 2 std dev). None of the children on the autistic spectrum had elevations of the other organic acids (glyceric and glycolic acids) associated with genetic diseases of oxalate metabolism, indicating that oxalates are high due to external sources. When calcium is taken with foods that are high in oxalates, oxalic acid in the intestine combines with calcium to form insoluble calcium oxalate crystals that are eliminated in the stool. This form of oxalate cannot be absorbed into the body. When calcium is low in the diet, oxalic acid is soluble in the liquid portion of the contents of the intestine (called chyme) and is readily absorbed from the intestine into the bloodstream. If oxalic acid is very high in the blood being filtered by the kidney, it may combine with calcium to form crystals that may block urine flow and cause severe pain. However, such crystals may also form in the bones, joints, blood vessels, lungs, eyes, skin, heart, thymus, skeletal muscle, joints, fat, teeth, mouth, nerves, and even the brain. In addition, oxalate crystals in the bone may crowd out the bone marrow cells, leading to anemia and immunosuppression. Calcium citrate is the best source of calcium to prevent oxalate absorption because citrate ion blocks the absorption of oxalates in the intestinal tract (3). A combination of calcium citrate and magnesium citrate is the best form of supplement to provide calcium and magnesium needs while preventing excess oxalate buildups in the body.
Clinical References:
1. Hediger ML, England LJ,Molloy CA, Yu KF, Manning-Courtney P, Mills JL. Reduced bone cortical thickness in boys with autism or autism spectrum disorder. J Autism Dev Disord. 2008;38(5):848–856
2. Coleman, M. Clinical presentations of patients with autism and hypocalcinuria. Develop. Brain Dys. 7: 63-70, 1994
3. Caudarella R, Vescini F, Buffa A, Stefoni S. Citrate and mineral metabolism: kidney stones and bone disease. Front Biosci. 2003 Sep 1;8:s1084-106.
Tiny Friends in Hidden Places (But Sometimes They "Unfriend" You): Man's Evolving Relationship with the Microbiome
Pamela Gilford, MA, CCN
Acceptance of the germ theory of disease unleashed a two-century war between humanity and the unseen microbial world. First, better sanitation, and after WWII, the advent of antibiotic treatment, saved millions of lives. Bacteria were the enemy; babies were even bathed in a toxic, chlorinated wash now withdrawn from the market. The presence of bacteria in the GI tract was treated as nature's "mistake." Who cared that oral antibiotics killed off some gut flora? Oral delivery avoided that unpleasant shot in the buttocks.
The mysterious rise in autoimmune disease since the development of modern antibiotic therapy has been one clue that humans might not be winning the war against microbes (see references below). A slow reassessment of the microbes, grudgingly referred to as "GI commensals" (harmless organisms) began. The genesis of pathogenicity has been discovered to be a two-way street between the human immune system and microbes, now referred to as a "relationship". Multi-celled, "higher" organisms clearly coevolved with one-celled organisms to mutual benefit. Microbes help us digest our food and provide certain vitamins. The microbes that line most of our GI tract defend our GI mucosal lining against invading pathogens, and as they begin to colonize the sterile gut of a newborn, they "educate" the child's immune system.
Multi-celled host organisms (like us) provide food, water, physical safety, and transportation. How else could microorganisms have extended their range without transportation? Humans have been particularly helpful. If this notion seems odd, think about syphilis coming to the New World with the first ocean explorers, and more recently, HIV and ebola making the crossing.
Although the variety of our GI flora has been known for a long time (See Theodor Rosebury's Life on Man, 1969), the advent of DNA tools to catalog species has spurred new interest in how human metabolism interacts with GI flora. The National Institute of Health's huge Human Microbiome Project is now nearing completion (seehttp://www.hmpdacc.org/). Evidence-based probiotic supplements for medical use are eagerly anticipated, although the first truly "evidence-based"probiotic was probably Lactobacillus GG, or Culturelle, discovered in cheek swabs by two researchers from Tufts University (see references below). Goldin and Gorbach patented Culturelle in 1985 for treatment of diarrhea caused by Clostridia difficile in children and has since been the subject of several hundred studies. Subsequent DNA analysis has granted this strain of bacteria a species designation of Lactobacillus rhamnosus and it is now incorporated into many commercial probiotic blends.
Studies have shown that variations in the species composition of gut microflora are related to the risk of obesity and that probiotic treatment often improves mood (see references below). Inflammation, which can be modulated by healthy gut flora, has become definitively linked to the epidemic of depression worldwide, as well as the genesis of many chronic diseases (see www.Medscape.com – many articles).
Clinical Endocrinology News reports that 64% of family physicians are stressed and uncomfortable when faced with treating autoimmune disease (see reference below) The fact that available allopathic therapies come with substantial side effects does not improve the practitioners' or patients' comfort levels. The frustration of both in finding safe therapies for autoimmune and chronic disease has certainly contributed to the growing popularity of integrative or CAM approaches. An article in Science magazine from November 2013 (see reference below) cited research by Mathis and Littman who found that Prevotella copri was present in 75% of RA patients' intestines. Later, they were able to trigger inflammation in mice by inoculating with the bacterium. Such studies add weight to clinicians' observations that probiotic treatments and even fecal implants can often halt the progress of chronic diseases.
We have been discussing our microbial passengers and an important part of the organic acids test is the assessment of the level of metabolites of pathogenic microbes, including yeast and Clostridia bacteria. The COMP stool test cultures both beneficial and potentially pathogenic microbes and microscopic examination can catch both yeast and one-celled parasites. When we added the Candida marker to the IgG food allergy test, we discovered a very useful tool for determining if a patient has become sensitive to his/her own native fungal flora. At The Great Plains Laboratory, we believe that the metabolic and and toxic element assessments we offer assist in directing treatment protocols that can mediate many chronic conditions, eliminate harmful microbes, and reinforce beneficial gut flora for improvement in overall health.
Clinical References:
Hunter, P. 2012. The changing hypothesis of the gut. The intestinal microbiome is increasingly seen as vital to human health. Science and Society DOI 10.1038/embor.2012.68 |Published online 15.05.2012, EMBO reports(2012)13,498-500
Thomas Jefferson University. 2014. Can antibiotics cause autoimmunity? ScienceDaily. March 31, 2014:http://www.sciencedaily.com/releases/2014/03/140331153520.htm
Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
Whiteman, H. 2014. Antibiotic use in children linked to juvenile idiopathic arthritis. Medical News Today. November 16, 2014:http://www.medicalnewstoday.com/articles/285453.php
Parry, W. 2011. Overuse of antibiotics is seen behind many human ills. LiveScience. August 24, 2011:http://www.livescience.com/15740-helpful-bacteria-antibiotics.html
Golden, B.R. and Gorbach, S.L. 2008. Clinical indications for probiotics: An overview. Clinical Infectious Dieases 46(12): S96-S100.
Mason, J. 2013. Can probiotics keep my gastrointestinal system happy? Tufts Now. September 16, 2013:http://now.tufts.edu/articles/can-probiotics-keep-gastrointestinal-health
Baumler, M.D. 2013. Gut bacteria. Today's Dietitian. June 2013: http://todaysdietitian.com/newarchives/060113p46.shtml
Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
10. Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24
A Primer on Natural Antifungal Agents: Evidence and Rationale for Their Use
Jessica Bonovich RN, BSN
Guidelines for the treatment of yeast have been documented in the literature for nearly every major organ system (Pappas). Yet, a standard of care for gastrointestinal yeast treatment is surprisingly absent despite the large body of work demonstrating that pathogenic yeast causes harm to various aspects of the gastrointestinal tract (Zwolinska, Brzozowski). Clinicians suspicious of GI yeast overgrowth typically perform a fecal analysis with culture and sensitivity. While this method is ideal for the effective treatment of yeast, it is poorly understood why patients with yeast overgrowth often test negative upon laboratory examination of stool (Maaroufi, Shaw). Up to 50% of stool analysis negative for yeast species returned positive on PCR (Maaroufi). Metabolites of yeast detected in The Great Plains Laboratory Organic Acids Test are a very reliable method of detecting yeast (Shaw). However, this test cannot determine the exact organism and therefore its susceptibility to antifungals (Shaw). It also cannot determine the exact location of the yeast overgrowth but clinical experience has shown that the majority of cases are in fact GI related. The documentation set forth is based broadly on in vivo and in vitro studies on the antifungal properties of the natural agents, documentation of yeast infections involving organ systems other than the GI tract, and yeast overgrowth in the GI of the irritable bowel patient population.
Probiotic Support
Evidence:
Candida: Promising data by several small studies has demonstrated the use of probiotics as effective against numerous pathological conditions caused by Candida. In these studies, Lactobacillus GG, L. acidophilus, and Saccharomyces boulardi were the predominant probiotics shown to be effective with L. GG demonstrating the ability to induce antibody formation against Candida in immune deficient mice. Probiotics have been shown to accelerate the healing of various pathological conditions in the gastro-intestinal tract when Candida is present (Zwolinska 2006 & 2009, Hatakka). Probiotics have also been shown to accelerate immune response to Candida in several murine simulations (Wagner, Zwolinska 2006 & 2009).
Aspergillus: Data on the effectiveness of probiotics against Aspergillus infection is not available. Aspergillus infections are thought to be rare in comparison to other yeast species such as Candida. However, a recent study indicated a high percentage of Aspergillus in stool samples of patients with Crohn's disease. (Li) Aspergillus infections are usually associated with pulmonary infection and or post-surgical complications that are often very acute. The severity of the Aspergillus complications and small numbers of infection are presumably responsible for the lack of research in this regard. The relative safety of Lactobacilli, bifidobacteria, and lactococci has been demonstrated extensively in the literature. Incorporation of these probiotics into a protocol for Aspergillus treatment may be considered appropriate in many cases.
Studies on the use of probiotics for gastrointestinal healing have been aimed at a wide range of populations. To date, the most promising studies have been in the treatment and prevention of acute infectious diarrhea, viral gastroenteritis, antibiotic associated diarrhea, ulcerative colitis, and necrotizing enterocolitis in preterm infants (Manzoni, Zwolinska, Szajewska). In all of these conditions, inflammation is of a primary concern.
Risks: Reports of bacteremia and even a few isolated cases of sepsis have been documented in the literature from the Lactobacillus genera including L. rhamnosis, L. plantarum, L. casei, L. paracasei, L. salivarius, L. acidophilus (Snydman, Borriello). Cases of sepsis have also been documented for the usually beneficial yeast Saccharomyces boulardi. In some cases, the cultures were linked to a probiotic supplement, in others, the bacteria were found to be intrinsic to the patient's own microflora (Snydman, Borriello). In all of the cases, the patients were severely immunocompromised and often had feeding tubes, short gut syndrome, and/or a central line (Snydman, Borriello, Munoz, Herbrecht). The cases of sepsis have most commonly been associated with S. boulardi (Munoz, Herbrecht). However, fungemia from S. boulardi infection is rare in comparison to the population believed to be taking the supplement (Herbrecht, Munoz). In one study, increase in bacteremia from Lactobacillus did not increase over a decade, despite the 6 fold increase in probiotic use (Borriello). These data indicate that individuals taking probiotics are not at any greater risk than the general population for bacteremia associated with Lactobacillus. Regardless, the practitioner should exercise caution in severely immunocompromised patient populations to reduce any risk to the patient.
Rationale:
Promote the immune response against intestinal yeast overgrowth. To promote healing and reduce inflammation in the intestinal mucosa during yeast overgrowth.
Dosing:
The strain most commonly championed in the literature is that of Lactobacillus GG in doses of 10 billion colony forming units (CFU's) taken early in treatment. Saccharomyces thermophilus and S. boulardi were found to be effective in some studies and less effective in others. A daily intake of 10^6 to 10^9 CFUs is reportedly the minimum effective dose for therapeutic purposes.
Allicin
Evidence:
Allicin is the active ingredient found in garlic. The most commonly understood mode of action for allicin is linked to its ability to cross cell membranes and combine with sulfur-containing molecular groups in amino acids and proteins, thus interfering with cell metabolism (Davis, Singla). The antimicrobial properties of allicin have been demonstrated in numerous in vitro and in vivo murine models (Davis, Guo, Shadkchan). The antifungal properties of allicin have been shown to potentiate the effectiveness of fluconazole, the synergistic combination being the most effective at killing Candida species in kidney cells (Guo). Human studies have been targeted largely toward cardiovascular and antihypertensive effects and little has been done to demonstrate the antimicrobial properties (Fugh-Berman, NACAM). However, a study in China reports successful use of intravenous allicin against invasive fungal infections (Davis).
The strength of the supplement is affected by the preparation of garlic. Studies have shown that water, oil, and high temperatures can degrade allicin content (Singla). Interestingly powdered garlic is found to be the highest in allicin (Singla). Interestingly, powdered preparations of garlic for cooking were found to have a greater allicin content than nine supplement tablets studied (PDR). There are also pure allicin extracts available on the market for use.
Risks: Studies have demonstrated that allicin can inhibit platelet aggregation in blood and several cases of bleeding complications have been documented. All of which were following an invasive procedure (Fugh-Berman). Allicin may also increase production of insulin by pancreatic cells causing the potential for hypoglycemia in some patient populations. Allicin may also inhibit cholesterol synthesis in the liver causing exacerbation of developmental delay in children with low cholesterol levels. Physicians should use caution in patients with bleeding conditions, on blood thinners, with hypoglycemia, or diabetics who are insulin dependent. Cholesterol testing is advised for children with developmental disorders prior to supplementation with allicin.
Rationale:
Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children). Promote the synergistic modulation of antifungal therapy with fluconazole.
Dosing:
Insufficient evidence exists in US literature for dosing recommendations, especially for children. However, there are several governing bodies outside of the US that regulate supplementation and provide a guideline for dosing. According to the National Center for Complementary and Alternative Medicine in the US, allicin is considered safe for most adults. Use of allicin for antifungal treatment may be appropriate in doses as high as one milligram per kilogram of body weight. Human studies have demonstrated that doses of allicin effectively potentiated the effects of antifungal treatment in doses of 7.8 - 27 mg per dose. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 3 to 5 milligrams allicin daily (1 clove or 0.5 to 1.0 gram dried powder) for the prevention of atherosclerosis. The World Health Organization (WHO) recommends 2 to 5 grams fresh garlic, 0.4 to 1.2 grams of dried powder, 2 to 5 milligrams oil, 300 to 1,000 milligrams of extract, or other formulations that are equal to 2 to 5 milligrams of allicin daily. The European Scientific Cooperative on Phytotherapy (ESCOP) recommends 2 to 4 grams of dried bulb or 2 to 4 milliliters of tincture (1:5 dilution in 45% ethanol), by mouth three times a day for upper respiratory tract infections.
MCT Oil/ Caprylic Acid/Monolauren/Coconut Oil
Evidence:
There are numerous in vitro and in vivo animal studies that demonstrate the effectiveness of coconut oil and/or its medium chain fatty acid constituents (Caprylic Acid, Capric Acid, and Lauric Acid) against Candida and other pathogens (Bergsson, Batovska, Huang, Dayrit). Human trials are much more limited. Therefore the evidence for treating yeast with this substance is based on the clinical observation of physicians who commonly treat yeast conditions. Physicians who routinely treat patients for Candida report very good success with using MCT oil/Caprylic acid. In his book, The Yeast Connection, Dr. Crook sites numerous examples of physicians who have reported this supplement as clinically useful (Crook).
Immunomodulating Properties: Like Omega-3 fatty acids, MCT's produce fewer inflammatory eicosanoids of the two- and four-series (Wan). Several in vivo studies have demonstrated anti-inflammatory properties of MCT oil and antipyretic and analgesic properties have also been documented (Canela, Intahphuak). In vivo MCTs may reduce intestinal injury and protect from hepatotoxicity which is a concern in patients taking fluconazole and itraconazole antifungal therapy (Berit, Kono). Human studies are few but promising as many of the studies are on severely immunocompromised patients who require total parernteral nutrition (TPN) and the HIV/AIDS patient population (Wanke, Dayrit, Craig, Wolfram, Chen). This patient population has responded well to the addition of MCT's. The degree to which these results apply to the general population is unclear. However, the safety of this supplement can be inferred given its effective use in severely immune compromised patient populations.
Risks: Acute toxicity tests conducted in several species of animal demonstrate that MCTs are essentially non-toxic. Ninety-day toxicity tests did not result in notable toxicity, whether the product was administered in the diet up to 9375mg/kg body weight/day or by intramuscular injection (up to 0. 5ml/kg/day, rabbits). Levels of up to 1g/kg/day have been confirmed safe in several clinical human trials (Traul). The use of MCT is only contraindicated in patients with impaired states of fat metabolism such as ketosis, acidosis, and cirrhosis (Bach).
Rationale:
Mild antifungal therapy when prescriptive agents are unavailable or contraindicated and where dosing by weight is required (such as for children).
Dosing:
Caprylic acid: PDR for nutritional supplements indicate dose as 300-1200 mg daily
Monolauren: 240 – 720 mg three times daily (adults)
Virgin coconut Oil: 2 ml/kg/day of virgin coconut oil in children
MCT: levels of up to 1g/kg/day have been confirmed safe in several clinical human trials.
Clinical References:
Bach, AC., Babayan, VK. (1982). Medium Chain Triglycerides: un update. American Journal of Clinical Nutrition, 36(5); 950-962
Batovska, D., et al. (2009). Antibacterial study of the medium chain fatty acids and their 1-monoglycerides: individual and synergistic relationships. Polish journal of Microbiology, 58(1); 43-7.
Bergsson, G., et al. (2001). In vitro killing of Candida albicans by fatty acids and monoglycerides. Antimicrobial Agents and Chemotherapy, 45(11); 3209-12.
Berit, M., Pfeuffer, M., Schrezenmeir, J., (2006). Medium Chain triglicerides. International Dairy Journal, 16(11) 1378-1382.
Borriello, S., et al. (2003). Saftey of Probiotics that Contain Lactobacilli or Bifidobacteria. Clinical Infectious Disease, 36(6); 775-780. Doi 10.1086/368080
Brzozowski, T., et al (2005). Influence of gastric colonization with Candida albicans on ulcer healing in rats: Effect of ranitidine, asprin and probiotic therapy. American Journal of Gastroenterology, 40(3); 286-296.
Canani, R., et al. (2007). Probiotics for treatment of acute diarrhea in children: randomized clinical trial of five different preparations. BMJ, 335-340. Doi 10.1136/bmj.39272.581736.55
Canela, GO., (2007). Anti-inflammatory activity of virgin coconut oil. The Philippine Journal of Internal Medicine, 45(2) 85-88.
Craig, GB., et al. (1997). Decreased fat and nitrogen losses in patients with AIDS receiving medium chain triglyceride-enriched formula vs those receiving long-chain-triglyceride containing formula. Journal of the American Dietetic Association, 97(6); 605-11.
Chen, FM., et al. (2005). Efficacy of medium-chain triglycerides compared with long-chain triglycerides in total parenteral nutrition in patients with digestive tract cancer undergoing surgery. The Kaohsiung Journal of Medical Sciences, 21(11); 487-94.
Crook, W. (2000). The Yeast Connection Handbook. Jackson, TN: Woman's Health Connection.
Davis, S. (2005). An overview of the antifungal properties of allicin and its breakdown products-the possibility of a safe and effective antifungal prophylactic. Mycoses, 48(2); 95-100. DOI: 10.1111/j.1439-0507.2004.01076.
Dayrit, C. (2000). Coconut oil in Health and Disease: Its and Monolauren's potential as cure for HIV/AIDS. Read at the XXXVII Cocotech Metting Chennai, India July 25, 2000. http://coconutresearchcenter.org/article10526.pdf
Fugh-Berman, A., (2000). Herbs and Dietary Supplements in the Prevention and Treatment of Cardiovascular Disease. Preventive Cardiology, 3(1); 24-32. Doi:10.1111/j.1520-037X.2000.80355.
Guo, N., Wu, X.,, et al. (2010). In vitro and in vivo interactions between fluconazole and allicin against clinical isolates of fluconazole-resistant Candida albicans determined by alternative methods. FEMS Immunology and Medical Microbiology, 58(2); 193-201. Doi: 10.1111/j.1574-695X.2009.00620.
Hatakka, K., et al. (2007). Probiotics Reduced the Prevalence of Oral Candida in the Elderly – a Randomized Controlled Trial. Journal of Dental Research, 86 (2); 125-130. doi: 10.1177/154405910708600204
Herbrecht, R., Nivoix, Y., (2005). Saccharomyces cervisiae Fungemia: an adverse effect of Saccharomyces boulardi probiotic Administration. Clinical Infectious Disease, 40(11); 1635-1637. Doi 10.1086/429926
Huang, CB., Alimova, Y., Myers, TM., Ebersole, JL. (2011). Short and medium chain fatty acids exhibit antimicrobial activity for oral microorganisms. Archives of Oral Biology, 56(7); 650-4.
Intahphuak, S. et al. (2010). Anti-inflammatory, analgesic, and antipyretic activities of virgin coconut oil. Pharmaceutical Biology, 48(2); 151-7.
Khodavandi, A., Alizadeh, F., et al. (2011). Comparison between efficacy of allicin and fluconazole against Candida albicans in vitro and in a systemic candidiasis mouse model. FEMS Microbiology Letters, 315. Kono, H., et al. (2003). Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. Annals of Surgery, 237(2); 246-55.
Li, Qiurong., et al. (2014). Dysbiosis of Gut Fungal Microbiota is Associated with Mucosal Inflammation in chrohn's Disease. Journal of Clinical Gastrointerology, 48:513-523.
Maaroufi, Y., Heymans, C., De Rune, J., Duchateau, H. (2003). Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay. Journal of Clinical Microbiology, 41; 3293-3298.
Manzoni, P., et al. (2006). Oral Supplementation with Lactobacillus casei Subspecies rhamnosus Prevents Enteric Colonization by Candida Species in Preterm Neonates: a Randomized Study. Clinical Infectious Diseases, 42(12); 1735-1742. doi: 10.1086/504324
Munoz, P., et al. (2005). Saccharomyces cerevisiae fungemia: and emerging infectious disease. Clinical Infectious Disease, 40(11); 1625-34.
National Center for Complimentary and Alternative Medicine (NCCAM). Herbs at a Glance: Garlic. Retrieved on 3/3/2014 from http://nccam.nih.gov/health/garlic/ataglance.htm
Snydman, D. (2008). The Safety of Probiotics. Clinical Infectious Diseases, 46(2); S104-S111. Doi 10.1086/523331
Pappas, P., et al. (2004). Guidelines for Treatment of Candidiasis. Clinical Infectious Diseases. 38; 161-189
Shadkchan, Y., Shemesh, E., et al. (2004). Efficacy of allicin, the reactive molecule of garlic, in inhibiting Aspergillus spp. In vitro, and in a murine model of disseminated aspergillosis. Journal of Antimicrobial Chemotherapy, 53; 832-836. doi: 10.1093/jac/dkh174.
Shaw ,W., (2008) Biological Treatments for Autism and PDD. Publisher: Author.
Singla, V., Bhaskar, R, (2011). Garlic: a review. International Journal of Drug Formulation, 2. Retrieved from http://www.ordonearresearchlibrary.org/Data/pdfs/IJDFR80.pdf
Szajewska, H., Skorka, A., Dylag, M. (2006) Meta-analysis: Saccharomyces boulardii for treating acure diarrhea in children. Alimentary Pharmacology and Theraputics, 25(3); 257-264. Doi 10.1111/j.1365-2036.2006.03202.x
Szajewska, et al., (2006). Probiotics in Gastrointestinal Diseases in Children: Hard and Not-So-Hard Evidence of Efficacy. Journal of Pediatric Gastroenterology and Nutrition, 42(5); 454-475. Doi 10.1097/01.mpg.0000221913.88511.72
Wagner, D., et al. (2000). Effects of probiotic bacteria on humoral immunity to Candida albicans in immunodeficient bg/bg-nu/nu and bg/bg-nu/+ mice. Journal of Microbiology/Immunology, 17; 55-59. Pdf http://www.reviberoammicol.com/2000-17/055059.pdf
Traul, KA., Driedger A., Ingle DL., Nakhasi, D. (2000). Review of the toxicologic properties of medium-chain triglycerides. Food and Chemical Toxicology, 38(1), 79-98.
Wan, JM., TEO, TC., Babayan, VK., Blackburn GL. (1988). Invited Comment: lipids and the development of immune dysfunction and infection. Journal of Parenteral and Enteral Nutrition, 12(6 supplment); 43s-52s.
Wanke, CA., et al. (1996). A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea reduces diarrhea and malabsorbtion: a prospective, controlled trial. Nutrition, 12(11-12); 766-71.
Wolfram, G., (1986). Medium Chain Triglicerides for Total Parenteral Nutrition. World Journal of Surgery, 10; 33-37.
Zwolinska, M., et al. (2009). Effect of Candida colonization on Human Ulcerative Colitis and the Healing of Inflammatory Changes of the Colon in the Experimental Model of Colitis Ulcerosa. Journal of Physiology and Pharmcology, 60(1); 107-108. Pdf http://jpp.krakow.pl/journal/archive/03_09/pdf/107_03_09_article.pdf
Zwolinska-Wcislo, M., et al. (2006). Are probiotics effective in the treatment of fungal colonization of the gastrointestinal tract? Eperimental and clinical studies. Journal of Physiology and Pharmcology, 57(9); 35-49. Pdf http://www.jpp.krakow.pl/journal/archive/11_06_s9/pdf/35_11_06_s9_article.pdf
A New Generation of Organic Acid Testing: Pushing the Limits of Detection with New Technology
Shaw, William Ph.D
More than 50 phenotypically different organic acidemias have been discovered since the first known disease of this type, isovaleric academia, was described in 1966. An organic acid is any compound that generates protons at the prevailing pH of human blood. Although some organic acidemias result in lowered blood pH, other organic acidemias are associated with relatively weak organic acids that do not typically cause acidosis.
Organic acidemias are disorders of intermediary metabolism that lead to the accumulation of toxic compounds that derange multiple intracellular biochemical pathways, including glucose catabolism (glycolysis), glucose synthesis (gluconeogenesis), amino acid and ammonia metabolism, purine and pyrimidine metabolism, and fat metabolism. The accumulation of an organic acid in cells and fluids (plasma, cerebrospinal fluid, or urine) leads to a disease called organic academia, or organic aciduria.
Although this technology has commonly been used for diagnosing genetic disease in children, genetic diseases in adults have also been detected with it. New applications of organic acid testing include detection of factors in psychiatric disorders, mitochondrial disease and dysfunction, and exposure to a wide variety of toxic chemicals from the environment, and assessment of inflammation due to overproduction of quinolinic acid from tryptophan.
Testing now includes markers for the following metabolites:
Glycolysis
Krebs Cycle
Amino acid Metabolism
DNA, RNA metabolism
Neurotransmitter metabolism
Organophosphate metabolism
Yeast, fungal markers
Markers for beneficial bacteria
Oxalate markers for kidney stones, genetic disease
Specific marker for ammonia toxicity
Markers of fatty acid catabolism
Metabolic diseases causing autism spectrum disorders
Phthalates
Solvents
Pyrethrins
Dry cleaning solvents
Preservatives
Vinyl chloride
Specific Clostridia marker
Specific mitochondrial disease markers
Vitamin deficiency markers
Phosphate marker of bone function
Marker for glutathione precursor
Genetic screening with extremely sensitive markers
Organic acids are most commonly analyzed in urine because they are not extensively reabsorbed in the kidney tubules after glomerular filtration. Thus, organic acids in urine are often present at 100 times their concentration in the blood serum and thus are detected in urine with greater accuracy and precision than with blood samples. The number of organic acids found in urine is enormous: over 1000 have been detected since this kind of testing started 25 years ago. The challenge of dealing with so many compounds led to the use of gas chromatography-mass spectrometry (GC/MS) to analyze these complex body fluids.
With GC/MS, organic acids are chromatographically separated on the basis of their polarity and volatility and then bombarded by an electron beam that fragments the eluting molecules in a characteristic pattern. The patterns, or spectra, are stored by a computer system and then compared with known spectra that are compiled in a spectral "library." The software then compares an unknown spectrum to all the spectra on the hard drive and prints out those with the best fit. Since a single organic acid analysis generates over 1000 spectra, and each spectrum may consist of 600 ions, the software must be optimized to analyze the data in the most efficient and clinically relevant manner. Recently, the Great Plains Laboratory Inc. increased the sensitivity of this technology by approximately 1000-fold with the use of new triple-quadrupole MS technology so that a large number of toxic compounds can be measured at levels of micromoles/mole creatinine compared with urine compounds, such as vanillylmandelic (VMA), which is measured at levels of millimoles/mole creatinine.
The scope of organic acid testing has been markedly widened by commercial laboratories such that it can monitor physiological changes in nongenetic diseases and offer tremendous help in diagnosis and treatment of most chronic illnesses. Some examples are given below:
An adult with a movement disorder and bilateral temporal arachnoid cysts by brain imaging was found to have very elevated glutaric acid, indicating the presence of the genetic disease glutaric aciduria type 1.1Symptoms of this potentially fatal disorder include headaches, ataxia, memory loss, and many other neurological effects. Treatment with high doses of carnitine may be helpful in relieving symptoms in such cases, and of course such information is important for genetic counseling.
High levels of urine oxalates in an adult with frequent kidney stones led to a closer examination of the patient's dietary history. The patient ate a large spinach salad with pecans almost every day. Spinach is one of the foods highest in oxalates, and all nuts are high in oxalates as well. Treatment is directed at reducing dietary oxalates as well as calcium citrate and vitamin B6 supplementation.
After organic acid testing, a child with autism was found to have very high values (more than four times the upper limit of age-appropiate normals) of the catecholamine metabolites VMA and HVA, indicating a possible neuroblastoma. Follow-up imaging near the spine confirmed the presence of a previously undiagnosed neuroblastoma, likely saving the child's life.
Another child thought to have autism had very low amino acids, and the neurologist recommended high doses of amino acid supplements, which made the child severely ill. Organic acid testing revealed a massive excretion of methylmalonic acid, indicating that the child had methlmalonic aciduria, a severe genetic disorder. Treatment of this disorder requires extensive supplementation with vitamin B12 and a low-protein diet. Continued amino acid supplementation or a high-protein diet might have been fatal.
A person with severe depression was found to have low amounts of the serotonin metabolite 5-hydroxy-indoleacetic acid, which is derived from tryptophan. Depression is associated with decreased brain serotonin. However, the tryptophan metabolite by an alternate pathway, quinolinic acid, was much higher. Quinolinic acid is associated with inflammation such as arthritis and is considered to be neurotoxic, with a probable role in Parkinson's syndrome, Alzheimer's disease, Huntington's disease, and schizophrenia.2,3 The condition eosinophilia myalgia syndrome (EMS), associated with excessive tryptphan intake, is probably not due to tryptophan itself but to the inflammatory effects of its major metabolite quinolinic acid. Quinolinc acid administered by itself generated all of the symptoms of EMS.4,5 This research indicates that various conspiracy theories about contaminated tryptophan batches as the cause of EMS are unnecessary and probably wrong. 100% pure tryptophan at high enough doses will produce significant quantities of toxic quinolinic acid and EMS in susceptible individuals. Administration of 5-hydroxytryptophan (5-HT or 5-HTP) is a much safer option than tryptophan since 5-HT cannot be converted to the neurotoxic quinolinic acid, whereas only about 1% of tryptophan is converted to serotonin.6 Both the serotonin metabolite and quinolinic acid are measured by organic acid testing (Figure 1).
I recently proved that the dibiosis marker 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), the predominant dihydroxy-phenylpropionic acid isomer in urine measured in the organic acid test, is due to a combination of human metabolism and the metabolism by a group of Clostridia species, including but not limited to C. difficile.7 The same article indicates that 3,4-dihydroxyphenylpropionic acid (DHPPA) is a marker for beneficial bacteria in the gastrointestinal tract such as Lactobacilli, Bifidobacteria, and E. coli. The exception is one species of Clostridia orbiscindens that can convert the flavonoids luteolin and eriodictyol (which occur only in a relatively small food group that includes parsley, thyme, celery, and sweet red pepper) to DHPPA. The quantity of C. orbiscindens in the gastrointestinal tract is negligible (approximately 0.1% of the total bacteria) compared with the predominant flora of Lactobacilli, Bifidobacteria, and E. coli.7 DHPPA is an antioxidant that lowers cholesterol, reduces proinflammatory cytokines, and protects against pathogenic bacteria.
Outdated literature has referred to HPHPA as due to dietary origin based mainly on conjecture, but this conjecture was clearly disproved by my 2010 article which indicates that the metabolite is abolished by the antibiotic metronidazole.8 DHPPA, a different isomer, has been claimed to be a metabolite of Pseudomonas species, but the literature indicates that this compound is formed by the in vitro action of these species on quinolone, a component of coal tar – a substance missing from the diet of virtually all humans.9
HPHPA has been one of the most useful clinical markers in recent medical history. Treatment of individuals with high urinary values with metronidazole, vancomycin, or high doses of probiotics has led to significant clinical improvements or remissions of psychosis, tic disorders, seizures, autistic behaviors, hyperactivity, chronic fatigue syndrome, and obsessive compulsive behavior.
One of the newest aspects of organic acid testing is the screening for 74 different toxic chemicals in the environment by testing their organic acid metabolites. Solvents such as benzene, toluene, styrene, and others may be present for only short periods in body fluids and may also be lost in transit due to their volatility, but their metabolites are very stable. Using this screening technique, most metabolites of different organophosphates and pyrethrins can be measured as well as trichloroethylene, tetrachloroethylene, and vinyl chloride. Phthalates, an extremely toxic group of compounds implicated in infertility and abnormal sexual development in both males and females, can be measured by their metabolite phthalate, a specific chemical entity.
The chemical structure of phthalic acid (or phthalates) is nearly identical to quinolinic acid. A toxic effect occurs when phthalic acid competitively inhibits the reaction by which quinolinic acid is converted to the beneficial coenzyme NAD. High concentrations of phthalic acid or quinolinic acid may be associated with increased toxicity due to phthalate blockage of NAD formation and potential mitochondrial dysfunction due to deficient NAD for mitochondrial energy production.
One of the most important advances in the organic acid test is the addition of a biochemical marker, tiglylglycine, as a specific indicator for mitochondrial dysfunction.11 Mitochondrial dysfunction has been implicated in Parkinson's and Alzheimer's syndromes, diabetes, autism, chronic fatigue syndrome, aging, and many others. Tiglylglycine has been shown to be elevated in the urine in mitochondrial disorders involving defects of complexes I, II, III, and IV, protein complexes attached to the mitochondrial membrane that are involved in energy production. In addition to mutations in mitochondrial or nuclear DNA, mitochondrial dysfunction may also be due to exposures to toxic chemicals such as organophosphates and the solvent trichloroethylene. The advantage of the organic acid test is that if a mitochondrial dysfunction is detected, a number of different toxic chemicals implicated in mitochondrial damage can be reviewed to find the potential cause. Trichloroethylene has been found as a contaminant in the municipal water supply of many cities in both the US and Canada, and is used as a degreaser military bases and as a common solvent throughout the chemical industry. Mitochondrial disorders can be treated with a cocktail of nutritional substances including coenzyme Q10, carnitine, riboflavin, and others, when chemical exposure is not detected. If toxic chemicals are found, treatment with the Hubbard protocol can be highly successful for the removal of a wide array of toxic substances.12
Clinical References:
1. Martinez-Lage J et al. Macrocephaly, dystonia, and bilateral temporal arachnoid cysts: glutaric aciduria type 1. Childs Nerv Sys. 1994;10(3): 198-203.
2. Guillemin GJ et al. Quinolinic acid in the pathogenesis of Alzheimer's disease. Adv Exp Med Biol. 2003;527:167-176.
3. Stoy N et al. Tryptophan metabolism and oxidative stress in patients with Huntington's disease. J Neurochem. 20015;93:611-623.
4. Silver RM et al. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322(13):874-881.
5. Noakes R, Spelman L, Williamson R. Is the L-tryptophan metabolite quinolinic acid responsible for eosinophilic fasciitis? Clin Exp Med. 2006;6(2):60-64.
6. Shah GM et al. Biochemical assessment of niacin efficiency among carcinoid cancer patients. Am J Gastroenterol. 2005;100:2307-2314.
7. Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia species in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010;13(3):1-10.
8. Kumps A, Duez P, Mardens Y. Metabolic, nutritional, latrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem. 2002,48:708-717.
9. Shukla OP. Microbial transformation of quinolone by a pseudomonas sp. Appl Environ Microbiol. 1986;51(6):1332-1342.
10. Fukuwatari T et al. Phthalate esters enhance quinolinate production by inhibiting alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarbocylase (ACMSD), a key enzyme of the tryptophan pathway. Toxicol Sci. 2004;81:302-308.
11. Bennett M et al. Tiglylglycine excreted in urine in disorders of isoleucine metabolism and the respiratory chain measured by stable isotope dilution GC-MS. Clin Chem. 1994;40(10):1879-1833.
12. Shaw W. The unique vulnerability of the human brain to toxic chemical exposure and the importance of toxic chemical evaluation and treatment in orthomolecular psychiatry. J Orthomol Med. 2010;25(3).
Usefulness of HPHPA marker in a wide range of neurological, gastrointestinal, and psychiatric disorders
William Shaw, Ph.D.
The dysbiosis marker 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), the predominant dihydroxyphenylpropionic acid isomer in urine, is also measured in the Organic Acids Test offered by The Great Plains Laboratory. This marker was proven by Dr. William Shaw to be due to a combination of human metabolism and the metabolism by a group of Clostridia species, including but not limited to C. difficile.
HPHPA has been one of the most useful clinical markers in recent medical history. Treatment with metronidazole, vancomycin, or high doses of probiotics of individuals with high urinary values has led to significant clinical improvements or remissions of psychosis.
The biochemical role of Clostridia in altering brain neurotransmitters is due to the fact that Clostridia metabolites inactivate dopamine beta-hydroxylase, leading to an excess production of brain dopamine and reduced levels of the neurotransmitter norepinephrine. Excess dopamine is associated with abnormal or psychotic behavior. This imbalance can be demonstrated in the Organic Acids Urine Test by observing the ratio of the major dopamine metabolite, homovanillic acid (HVA), to that of the major norepinephrine metabolite, vanillylmandelic acid (VMA) when the Clostridia marker HPHPA is elevated. After treatment with metronidazole or vancomycin, HPHPA values return to normal along with normal ratios of HVA/VMA and normal behavior.
The highest value of HPHPA was measured in the urine of a young woman with first onset of schizophrenia. Treatment of Clostridia bacteria resulted in loss of auditory hallucinations. In autism, children with gastrointestinal Clostridia commonly exhibit aggressive behavior, agitation, obsessive compulsive behavior, and irritability. They may have very foul stools with diarrhea with mucus in the stools although some individuals may be constipated. Stool testing for Clostridia is usually of limited usefulness since most Clostridia species are considered probiotics or beneficial. There are about 100 species of Clostridia that are commonly found in the gastrointestinal tract. Only seven of these species are producers of HPHPA including C. sporogenes, C.botulinum, C. caloritolerans, C. angenoti, C. ghoni, C.bifermentans, C. difficile, and C. sordellii while C. tetani,C. sticklandii, C. lituseburense, C. subterminale, C.putifaciens, C. propionicum, C. malenomenatum, C.limosum, C. lentoputrescens, C. tetanomorphum, C.coclearium, C. histolyticum, C. aminovalericum, and C.sporospheroides do not produce compounds that are converted to HPHPA.
The same article by Dr. Shaw indicates that 3,4-dihydroxyphenylpropionic acid (DHPPA) is a marker for beneficial bacteria in the gastrointestinal tract such as Lactobacilli, Bifidobacteria, and E. coli. The exception is one species of Clostridia orbiscindens that can convert the flavanoids luteolin and eriodictyol, that occur only in a relatively small food group that includes parsley, thyme, celery, and sweet red pepper to 3,4-dihydroxyphenylpropionic acid. The quantity of C. orbiscindens in the gastrointestinal tract is negligible (approximately 0.1% of the total bacteria) compared to the predominant flora of Lactobacilli, Bifidobacteria, and E. coli (7). DHPPA is an antioxidant that lowers cholesterol, reduces proinflammatory cytokines, and protects against pathogenic bacteria. 2,3-Dihydroxyphenypropionic acid, a different isomer has been claimed to be a metabolite of Pseudomonas species but the literature indicates that this compound is formed by the in vitro action of these species on quinoline, a component of coal tar, a substance missing from the diet of virtually all humans.
References:
1. Shaw W. Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. Nutr Neurosci. 2010 Jun;13(3):135-43.