IgG Resources

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Beyond the Gut: The Relationship Between Gluten, Psychosis, and Schizophrenia

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JAMES GREENBLATT, MD & DESIREE DELANE, MS

Introduction

The National Institutes for Mental Health provide a succinct definition for schizophrenia as periods of psychosis characterized by disturbances in thought and perception and disconnections from reality; however, diagnosis is much less straightforward.  Schizophrenia represents a wide illness spectrum with symptomatic features and severity ranging from odd behavior to paranoia.  With a prevalence rate over the past century holding steady at 1% worldwide and immovably poor patient outcomes, schizophrenia delivers profound relational and societal burdens, proving to be a complex clinical challenge and an unyielding epidemiological obstacle.

Gluten as a Trigger for Psychosis

Although the role of food hypersensitivities in disease pathologies is highly controversial in the medical community, many recognize a parallel rise with dietary evolution in modern history.  Major shifts from ancestral diets largely absent of wheat or dairy to one with these as foundational components generate reasonable arguments on their implications for human health.  Industrialized food systems that streamline the way foods are grown, processed, and stored are often charged with altering their very nature down to its most infinitesimal molecules.  Yet, despite their diminutive size, micronutrients from food are essential to the complex processes and interactions that represent optimal health.

Intolerance to gluten represents one of the most prominent food hypersensitivities arising in recent history, delivering profound impacts to both physical and mental health.  As the most severe reaction to gluten, Celiac Disease (CD) affects a growing population of men and women in the United States.  Unfortunately, an estimated 83% of cases remain undiagnosed or wrongly diagnosed with other conditions. Like other autoimmune diseases, CD is a factor of underlying genetic susceptibility combined with environmental pressures.  Sometimes remaining non-symptomatic for years, CD progressively damages the lining of the intestine, eventually presenting with severe gastrointestinal symptoms including gas, bloating, diarrhea, and constipation.  One of the most dangerous consequences is that digestion and absorption become impaired, resulting in malnutrition and increasing requirements for several key nutrients.  Furthermore, chronic, subtle inflammation keeps the immune system on high alert, promoting an environment of oxidative stress in which free radicals wreak havoc throughout the body.  By elevating the body’s overall inflammatory status, CD and other immune-mediated food allergies trigger not only immediately apparent physical symptoms, but also biochemical imbalances that alter brain function.  Notably, data showing that CD is often incorrectly and inconsistently diagnosed suggests that mental symptoms are often misinterpreted or overlooked.

A separate byproduct of gluten metabolism poses another, possibly more dramatic and direct, threat to brain function.  Gliadorphin, a peptide fragment produced through the breakdown of gluten, directly accesses the brain and attaches to opiate receptors.  Neuropeptides including gliadorphin and casomorphin, a structurally similar byproduct of dairy, mimic and interfere with normal neurotransmitter communication, producing significant mental symptoms ranging from fatigue and brain-fog to hallucinations and aggression.  Like the opiate drugs morphine and heroin, food-derived opiates hold strongly addictive properties as they promote reward, sedation, and satiety.  Sensitive individuals are typically marked by excessive cravings and dependence on food sources of gliadorphin and casomorphin, that manifest in difficulties regulating mood and behavior when levels are depleted.  Fortunately, mental health practitioners have begun to recognize the contribution of neuropeptides in many psychiatric conditions.

Gluten, Gliadorphin, & Schizophrenia

Like Celiac disease, experts agree that schizophrenia has both genetic and environmental contributors, and evidence even suggests that overlapping genetic risk factors may underlie a shared susceptibility for schizophrenia and Celiac disease.  A 2004 Danish case-control study indicated that individuals with a history of Celiac disease may have a 3x greater risk of developing schizophrenia.  Additionally, short-term immune-related exposures during gestation or early life can have long-term consequences for the brain by inducing permanent DNA modifications.  Maternal or post-natal illnesses and infections have all been linked to a greater risk for psychosis and schizophrenia.  Excessive immune activation during these critical developmental periods can also influence the body’s response to potential food allergens.  From the other direction, schizophrenia and psychosis may invoke unique immune mechanisms influencing an individual’s reactivity to gluten. 

Remarkably, the relationship between gluten and psychosis appears to go beyond Celiac disease.  Elevated levels of gliadorphin have consistently been measured in patients with schizophrenia, autism, attention-deficit-hyperactivity disorder, depression, and other psychiatric conditions.  Abnormally low activity of the dipeptidyl peptidase IV (DPP-IV) enzyme, involved in the breakdown of gluten, offers a potential link.  A clinical study in roughly 60 patients with schizophrenia or depression suggested that significant alterations in DPP-IV activity characterized patients with schizophrenia.  The prevalence of elevated gliadorphin and other opiate peptides in psychosis patients has led some researchers to believe that these psychoactive substances carry unique information to the brain that influence disease development.

Without normal breakdown of gliadorphin by DPP-IV, neurotoxic levels accumulate and produce psychoactive effects.  Significant behavioral alterations in animal models given food-based neuropeptides reflect symptoms of psychosis that were reversible by pre-treatment with opiate-blocking drugs.  Human patients with elevated urinary gliadorphin also demonstrate clinical behavioral improvements when gluten and other sources of “dietary morphine” are removed from the diet.  DPP-IV also modulates the activation and proliferation of CD4+ immune cells, providing an additional mechanistic explanation for the excessive inflammation characteristic of both Celiac disease and schizophrenia.  Finally, normal DPP-IV activity depends on adequate zinc and other nutrients, common casualties of poor intestinal function.

A New Approach to Schizophrenia Treatment

Despite evidence-based attempts to address the diverse spectrum of physical and mental impairments associated with schizophrenia, weak progress has been made over the last 100 years.  The rapid, clear clinical responses of antipsychotic drugs introduced in the 1950s and 1960s once appeared to offer miraculous promise to those suffering with psychotic illness.  At least 70 different medications have been developed targeting similar biochemical pathways and are firmly established as first-line therapies.  Modern antipsychotics can be profoundly useful with skillful use in the initial stages of illness, particularly for severe cases.  But it is no secret that these medications are rarely, if ever, totally effective, have no influence on negative or cognitive symptom categories, and bring debilitating side effects requiring further drug interventions.

A growing wealth of theory and data links nutrition and mental health, yet mainstream psychiatry remains stubbornly fixated on the status quo.  Clinical studies suggest that nutrient requirements in schizophrenia patients exceed generally recommended levels, whether due to poor diet, impaired intestinal function, or genetically induced metabolic differences.  A 2018 systematic review by Firth, et al., of 11 studies in early-stage psychosis patients found deficiencies in antioxidants, amino acids, and polyunsaturated fatty acids.  This recent evidence lends significant support for assertive nutrient-based approaches to schizophrenia treatment, particularly as preventive strategies in high-risk patients.

Normal mental processes require tightly-controlled amounts of B-vitamins, antioxidants, lipids, and many other dietary nutrients as key enzymatic components for neural growth, communication, and protection.  On top of the potentially toxic effects of gluten and its byproducts on some individuals, malabsorptive conditions resulting from food sensitivities or Celiac disease further reduce the bioavailability of these critical nutrients to the brain and exacerbate the biochemical imbalances that drive psychiatric illness.  Resulting from this malnourished state, neurotransmitter dysfunction and miscommunication dramatically alter sensory perception and distort a patient’s experience of reality, manifesting in abnormal behavior and social dysfunction. 

Nutritional and other integrative therapies provide the body and brain with optimal and familiar tools for self-healing.  By addressing the origins of symptoms first, medications can be employed as second-tier strategies that support rather than direct treatment.  The treatment paradigm for schizophrenia must be expanded to adopt strategies for early recognition and prevention and incorporate holistic therapies that empower patients to be involved in their recovery.  Long-term dietary changes, including removal of gluten, and nutritional supplements facilitate recovery and promote resilience and self-care.  The integrative care model for mental health care aims not at just the absence of disease, but for healthy minds, bodies, and futures with hope for independence, happiness, and fulfillment.

References

  1. Chien, W. T., & Yip, A. L. (2013). Current approaches to treatments for schizophrenia spectrum disorders, part I: an overview and medical treatments. Neuropsychiatric disease and treatment, 9, 1311.

  2. Chong, H. Y., Teoh, S. L., Wu, D. B. C., Kotirum, S., Chiou, C. F., & Chaiyakunapruk, N. (2016). Global economic burden of schizophrenia: a systematic review. Neuropsychiatric disease and treatment, 12, 357.

  3. Dauncey, M. J. (2013). Genomic and epigenomic insights into nutrition and brain disorders. Nutrients, 5(3), 887-914.

  4. Ellul, P., Groc, L., Tamouza, R., & Leboyer, M. (2017). The clinical challenge of autoimmune psychosis: learning from anti-NMDA receptor autoantibodies. Frontiers in psychiatry, 8, 54.

  5. Firth, J., Rosenbaum, S., Ward, P. B., Curtis, J., Teasdale, S. B., Yung, A. R., & Sarris, J. (2018). Adjunctive nutrients in first‐episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms. Early intervention in psychiatry.

  6. Jungerius, B. J., Bakker, S. C., Monsuur, A. J., Sinke, R. J., Kahn, R. S., & Wijmenga, C. (2008). Is MYO9B the missing link between schizophrenia and celiac disease?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147(3), 351-355.

  7. Lennox, B. R., Palmer-Cooper, E. C., Pollak, T., Hainsworth, J., Marks, J., Jacobson, L., ... & Crowley, H. (2017). Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study. The Lancet Psychiatry, 4(1), 42-48.

  8. Liang, W., & Chikritzhs, T. (2012). Early childhood infections and risk of schizophrenia. Psychiatry research, 200(2), 214-217.

  9. Maes, M., De Meester, I., Verkerk, R., De Medts, P., Wauters, A., Vanhoof, G., ... & Scharpé, S. (1997). Lower serum dipeptidyl peptidase IV activity in treatment resistant major depression: relationships with immune-inflammatory markers. Psychoneuroendocrinology, 22(2), 65-78.

  10. Maes, M., Scharpé, S., Desnyder, R., Ranjan, R., & Meltzer, H. Y. (1996). Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs. Acta Psychiatrica Scandinavica, 93(1), 1-8.

  11. NIMH. (2017). https://www.nimh.nih.gov/health/topics/schizophrenia/raise/what-is-psychosis.shtml. Accessed 09 April 2018.

  12. Salim, S. (2014). Oxidative stress and psychological disorders. Current neuropharmacology, 12(2), 140-147.

  13. Samaroo, D., Dickerson, F., Kasarda, D. D., Green, P. H., Briani, C., Yolken, R. H., & Alaedini, A. (2010). Novel immune response to gluten in individuals with schizophrenia. Schizophrenia research, 118(1), 248-255.

  14. Sun, Z., Cade, J. R., Fregly, M. J., & Privette, R. M. (1999). β-Casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism. Autism, 3(1), 67-83.

  15. Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

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Clinical Usefulness of IgG Food Allergy Testing

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William Shaw Ph.D

Immunoglobulin G (IgG) food allergy testing has made vast advancements since the year 2003 when the American Academy of Allergy, Asthma, and Immunology published a statement that "Measurement of specific IgG antibodies to foods is also unproven as a diagnostic tool"(1) Most of the IgG food allergy throughout the world is done using the same immunochemical technique. First, soluble food proteins in solution are reacted to a solid phase that chemically binds to a variety of proteins. The use of plastic microtiter trays with one to several hundred wells has become the most common material used as the solid phase. Then these trays are washed, dried, and stored for later use. A sample of diluted serum is then added to each of the wells. Antibodies of all types in the diluted serum bind to the specific food molecules that are attached to the plastic wells of the tray. Next, the plates are washed to remove any nonspecific antibodies in the diluted serum. At this time, food antibodies from all of the five major immunoglobulin classes called G, A, M, E, and D may be attached to the food antigens on the plate. The next step confers specificity on the assay. Antisera from sheep, goats, rabbits, or other animals that specifically binds to IgG is added to microtiter wells and only binds to IgG, not to IgA, IgM, IgE, or IgD. This antibody to IgG has previously been modified by the attachment of an enzyme that can be measured conveniently. The amount of enzyme bound to food antigen-IgG complexes on the plate is directly related to how much IgG antibody is attached to a given food. The overall technique is termed Enzyme Linked Immuno Assay or ELISA. If IgG4 is measured, an antiserum specific for IgG4 only must be used for the final step.

The clinical usefulness of IgG testing in an array of illnesses is illustrated in an early article published by an otolaryngologist who reported that the majority of his patients had substantial health improvements after an elimination of foods positive by IgG food allergy tests (2). The overall results demonstrated a 71% success rate for all symptoms achieving at least a 75% improvement level. Of particular interest was the group of patients with chronic, disabling symptoms, unresponsive to other intensive treatments. Whereas 70% obtained 75% or more improvement, 20% of these patients obtained 100% relief. Symptoms most commonly improved 75%-100% on the elimination diets included asthma, coughing, ringing in the ears, chronic fatigue, all types of headaches, gas, bloating, diarrhea, skin rash and itching, and nasal congestion. The most common IgG food allergies were cow's milk, garlic, mustard, egg yolk, tea, and chocolate.

The usefulness of IgG food allergy to design customized elimination diets has now been documented in scientific studies. Irritable bowel syndrome (IBS) is a common, costly, and potentially disabling gastrointestinal (GI) disorder characterized by abdominal pain/discomfort with altered bowel habits (e.g., diarrhea, constipation). The major symptoms of IBS are (1) abnormality of bowel movement, (2) reduction in bowel sensitivity thresholds, and (3) psychological abnormality. Many IBS patients have psychological symptoms including depression, anxiety, tension, insomnia, frustration, hypochondria. psychosocial factors (3). Atkinson et al (4)evaluated a total of 150 outpatients with irritable bowel syndrome (IBS) who were randomized to receive, for three months, either a diet excluding all foods to which they had raised IgG antibodies (ELISA test) or a sham diet excluding the same number of foods but not those to which they had antibodies . Patients on the diet dictated by IgG testing had significantly less symptoms than those on the sham diet after 120 days on the diets. Patients who adhered closely to the diet had a marked improvement in symptoms while those with moderate or low adherence to the IgG test dictated diets had poorer response. Similar results were also obtained by Drisko et al (5). They used both elimination diet and probiotic treatment in an open label study of 20 patients with irritable bowel syndrome diagnosed at a medical school gastroenterology department. The most frequent positive serologic IgG antigen-antibody complexes found on the food IgG tests were: baker's yeast, 17 out of 20 (85%); onion mix, 13 out of 20 (65%); pork, 12 out of 20 (60%); peanut 12 out of 20 (60%); corn, 11 out of 20 (55%);wheat, 10 out of 20 (50%); soybean, 10 (50%); carrot, 9 out of 20 (45%); cheddar cheese, 8 out of 20 (40%); egg white, 8 out of 20 (40%). Only 5 out of 20 reacted by IgG antibody production to dairy; however the majority of patients reported eliminating dairy prior to trial enrollment presumably clearing antigen-antibody complexes prior to testing. Significant improvements were seen in stool frequency, pain, and IBS quality of life scores. Imbalances of beneficial flora and dysbiotic flora were identified in 100% of subjects by comprehensive stool analysis. There was a trend to improvement of beneficial flora after treatment but no change in dysbiotic flora. The one-year follow up demonstrated significant continued adherence to the food rotation diet, minimal symptomatic problems with IBS, and perception of control over IBS. The continued use of probiotics was considered less helpful.

IgG food allergy testing was also proved effective in the gastrointestinal disorder Crohn's disease. Bentz et al (6) found that an elimination diet dictated by IgG food allergy testing resulted in a marked reduction of stool frequency in a double blind cross-over study in which the IgG-dictated diet was compared to a sham diet in 40 patients with Crohn's disease. IgG food allergies were significantly elevated compared to normal controls. Cheese and baker's yeast (Saccharomyces cerevisiae) allergies were extremely common with rates of 83% and 84% respectively. Main et al (7), focusing on the baker's yeast allergy, also found extremely high prevalence of IgG allergy in patients with Crohn's disease. Titers of both IgG and IgA to S. cerevisiae in the patients with Crohn's disease were significantly higher than those in the controls. In contrast, antibody titers in the patients with ulcerative colitis were not significantly different from those in the controls. Among the patients with Crohn's disease there was no significant difference in antibody titers between patients with disease of the small or large bowel. Since IgG antibodies to S. cerevisiae cross react with Candida albicans (8), Candida species colonization might be a trigger for the development of Crohn's disease.

IgG food allergy to wheat, gluten, gliadin, rye, and barley are prevalent in the gastrointestinal disorder celiac disease. Virtually all patients with celiac disease have elevated IgG antibodies to gliadin if they currently have wheat or related grains in their diet. The confirmation of celiac disease is confirmed by the presence of flattened mucosa with a lack of villi when a biopsy sample of the small intestine is examined microscopically. Another confirmation test with equal sensitivity is a blood test for IgA transglutaminase antibodies. The antibody confirmation test is equal in accuracy to the biopsy test with the exception that individuals with IgA deficiency may have false negative results. However, I would estimate that only 1% of people with elevated IgG antibodies to gliadin and other grains related to wheat have celiac disease. If the individual is negative for the confirmation tests for celiac disease, many patients are frequently erroneously advised that that have no problem with wheat. Hadjivassiliou et al argued that it is a significant clinical error to classify wheat allergy through the filter of celiac disease (9) and argue that celiac disease is a subtype of wheat sensitivity. Many of their patients with wheat allergy but celiac disease negative had remission of severe neurological illnesses when they adopted a gluten free diet and expressed that in these patients the gluten molecule causes an autoimmune reaction in the brain rather than in the intestinal tract, likely against the Purkinje cells that are predominant in the cerebellum.

A wide range of additional studies has proven the clinical value of IgG antibodies in autism (10), bipolar depression (11), schizophrenia (12), migraine headaches (13), asthma (14), and obesity (15).

Total IgG Versus IgG4 Food Allergy

Immunoglobulin G (IgG) is classified into several subclasses termed 1, 2, 3, and 4. IgGs are composed of two heavy chain–light chain pairs (half-molecules), which are connected via inter–heavy chain disulfide bonds situated in the hinge region (Figure 1). IgG4 antibodies usually represent less than 6% of the total IgG antibodies. IgG4 antibodies differ functionally from other IgG subclasses in their lack of inflammatory activity, which includes a poor ability to induce complement and immune cell activation because of low affinity for C1q (the q fragment of the first component of complement). Consequently, IgG4 has become the preferred subclass for immunotherapy, in which IgG4 antibodies to antigens are increased to reduce severe antigen reactions mediated by IgE. If antigens preferentially react with IgG4 antibodies, the antigens cannot react with IgE antibodies that might cause anaphylaxis or other severe reactions. Thus, IgG4 antibodies are often termed blocking antibodies. Another property of blood-derived IgG4 is its inability to cross-link identical antigens, which is referred to as "functional monovalency". IgG4 antibodies are dynamic molecules that exchange half of the antibody molecule specific for one antigen with a heavy-light chain pair from another molecule specific for a different antigen, resulting in bi-specific antibodies that are unable to form large cross-linked antibodies that bind complement and thus cause subsequent inflammation(16). In specific immunotherapy with allergen in allergic rhinitis, for example, increases in allergen-specific IgG4 levels indeed correlate with improved clinical responses. IgG4 antibodies not only block IgE mediated food allergies but also block the reactions of food antigens with other IgG subclasses, reducing inflammatory reactions caused by the other IgG subclasses of antibodies to food antigens.

In IgG mediated food allergy testing, the goal is to identify foods that are capable of causing inflammation that can trigger a large number of adverse reactions. IgG1, IgG2, and IgG3 all are capable of causing inflammation because these antibodies do not exchange heavy and light chains with other antibodies to form bispecific antibodies. Thus, IgG1, IgG2, and IgG3 antibodies to food antigens can and do form large immune complexes or lattices that fix complement and increase inflammation. The presence of IgG4 antibodies to food antigens indicates the presence of antibodies to foods that will not usually cause inflammation even though high amounts of these antibodies do indicate the presence of immune reactions against food antigens. Testing only for IgG4 antibodies in foods limits the ability of the clinician to determine those foods that are causing significant clinical reactions that are affecting their patients. The importance of measuring other subtypes of IgG antibodies is highlighted in an article by Kemeny et al. (17). They found that IgG1 antibodies to gluten were elevated in all 20 patients with celiac disease but none of the patients had elevated IgG4 antibodies to gluten.

Clinical References

  • 1. Statement of the AAAAI Work Group Report: Current Approach to the Diagnosis and Management of Adverse Reactions to Foods, October 2003. http://www.aaaai.org/ask-the-expert/usefulness-of-measurements-of-IgG-antibody.aspx (Accessed October 27,2013).

  • 2. Dixon H, Treatment of delayed food allergy based on specific immunoglobulin G RAST testing relief. Otoloryngol Head Neck Surg 2000;123:48-54.

  • 3. Nagisa Sugaya N and Nomura S, Relationship between cognitive appraisals of symptoms and negative mood for subtypes of irritable bowel syndrome. BioPsychoSocial Medicine 2008;2:9-14

  • 4.Atkinson, W et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial Gut 2004;53:1459-1464

  • 5. Drisko J, Bischoff B, Hall M, McCallum R, Treating Irritable Bowel Syndrome with a Food Elimination Diet Followed by Food Challenge and Probiotics. Journal of the American College of Nutrition 2006; 25: 514–522

  • 6. Bentz S, et al. Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study. Digestion. 2010;81:252-64.

  • 7.Janice Main, Hamish McKenzie, Grant R Yeaman, Michael A Kerr, Deborah Robson, Christopher R Pennington, David Parratt Antibody to Saccharomyces cerevisiae (bakers' yeast) in Crohn's disease BMJ 1988;297:1105-1106

  • 8. Thomas Schaffer, Stefan Mueller, , Beatrice Flogerzi, , Beatrice Seibold-Schmid,Alain M. Schoepfer, and Frank Seibold Anti-Saccharomyces cerevisiae Mannan Antibodies (ASCA) of Crohn's Patients Crossreact with Mannan from Other Yeast Strains, and Murine ASCA IgM Can Be Experimentally Induced with Candida albicans Inflamm Bowel Dis 2007;13:1339 –1346

  • 9. M Hadjivassiliou, R A Grünewald, G A B Davies-Jones Gluten sensitivity as a neurological illness. Neurol Neurosurg Psychiatry 2002;72:560–563

  • 10. Vladimir T et al Higher Plasma Concentration of Food-Specific Antibodies in Persons With Autistic Disorder in Comparison to Their Siblings. Focus Autism Other Dev Disabl 2008; 23: 176-185

  • 11. Severance EG et al Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord 2010;12: 834–842

  • 12. Severance EG, et al Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010;118:240-7.

  • 13.Huber A, et al Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial. Int Arch Allergy Immunol. 1998; 115:67-72.

  • 14.Vance G. et al. Ovalbumin specific immunoglobulin G and subclass responses through the first five years of life in relation to duration of sensitization and the development of asthma. Clia Exp Allergy 2004;34:1452-1459

  • 15.Wilders-Truschnig M et al. IgG Antibodies Against Food Antigens are Correlated with Inflammation and Intima Media Thickness in Obese Juveniles. Exp Clin Endocrinol Diabetes 2008;116:241-5.

  • 16. Marijn van der Neut Kolfschoten, et al Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange. Science 2007;317:1554-1555

  • 17. Kemeny DM, et al Sub-class of IgG in allergic disease. I. IgG sub-class antibodies in immediate and non-immediate food allergy. Clin Allergy. 1986; 16:571-81.

 

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The Role of Diet and the Gut in Mental Health

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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

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Immunodeficiency, gastrointestinal Candidiasis, wheat and dairy sensitivity, abnormal urine arabinose, and autism: a case study

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William Shaw, PhD

Abstract

A child with autism was found to have complete IgA deficiency (serum IgA < 6 mg/dL; normal 33-235 mg/dL), Candidiasis of the gastrointestinal tract based on evaluation of stool testing and elevated urine arabinose, and elevated serum antibodies to wheat and dairy products. The pretreatment urinary arabinose concentration (341 mmol/mol creatinine in this child was nearly six times the mean value (60.4 mmol/mol creatinine, n=20) of normal children and over ten times the median value (31.0 mmol/mol creatinine) of normal controls. After antifungal therapy for four months, the urine was retested. At that time the urine arabinose was measured at 51 mmol/mol creatinine, a value only 15% of the baseline sample. Restriction of wheat and dairy products from the diet and antifungal therapy led to a significant decrease in autistic behaviors and increased rate of learning. The Childhood Autism Rating Scale (CARS), an observational measure of various aspects of autism, for the child has decreased from a rating of 43 (severely autistic) prior to introduction of these therapies to a value of 29 (non-autistic) after therapy.

Introduction

Studies done by the late Reed Warren Ph.D. at Utah State University and others indicate that most children with autism have a substantial immune abnormality of some type (1-20). Kontstantareas and Homatidis (21) at the University of Guelph in Ontario, Canada found a high correlation between the prevalence of ear infections and the incidence of autism. They found that the earlier the child had an ear infection, the more likely that child had a more severe form of autism. They also found that increased incidence of ear infections was associated with a more severe rather than a mild form of autism. Candida infection has been reported as a consequence of frequent antibiotic usage in both humans and animals (22-30) and an abnormal increase in the sugar arabinose probably from Candida has been reported in urine samples of two siblings with autism (31). However, Candida infection may also be common in children with immunodeficiencies who do not have an unusually high number of infections treated with antibiotics. The pattern of gastrointestinal Candida overgrowth, immunodeficiency, metabolic disorder and autism is well illustrated in the medical history of the child evaluated by us.

Previous medical evaluation

The child evaluated is a five-year-old Caucasian male with a normal birth at term and normal apgar scores. Newborn metabolic screens for phenylketonuria, hypothyroidism, galactosemia, and sickle-cell disease were within normal limits. Both parents are college graduates; both parents are considered socially well adjusted. The maternal grandmother suffered from multiple sclerosis and is now deceased. The maternal grandfather died secondary to viral cardiomyopathy; as a child he did not speak until three years of age but then talked and developed normally. The paternal grandparents are in good health.

A pediatric ophthalmologist evaluated the child at six months of age for intermittent crusting and tearing of the left eye, which was non-responsive to antibiotic drops. The patient had surgery for the blocked tear-duct and a possible undescended testicle at 16 months. Exploratory surgery did not locate the missing testicle; the patient was put on prophylactic antibiotics after surgery. Up to the age of three years, the patient had had only one or two ear infections treated by antibiotics, a couple of colds, and an upper respiratory infection. Immunizations were all on schedule. A routine physical examination at 15 months of age assessed development as normal although parents expressed concerns about lack of speech. The MMR vaccine was administered at this checkup. Assessment by the pediatrician at 18 months was "healthy 1.5 year old" who "does not need to return until 2 years of age." Deficiency of expressive language was noted in the medical record but the parents were not advised to seek additional consultation.

At a pediatric evaluation at 2 years of age, lack of expressive language (only 5 words) was again noted but no follow-up was recommended. At a pediatric evaluation at 2.5 years of age, no expressive language was noted and the child was referred to a hearing and speech clinic for evaluation. Diet was noted to consist of bread, pancakes, milk, peanut butter, and chicken. He was noted to always have loose stools. The subsequent hearing evaluation revealed normal hearing but recommended a developmental assessment of the child. Three months later at the age of 27 months, the child was diagnosed with autism by a developmental pediatrician at a university autism clinic using DSM-IV diagnostic criteria; developmental age was assessed as at the 19-20 month level. At this exam, otitis media was diagnosed and treated with Amoxicillin. A MRI scan of the head revealed some atrophy of the frontotemporal lobe. EEG and fragile X chromosome studies were normal. The child was seen by a second university autism clinic in another state, which confirmed the original diagnosis. The parents of the child were referred to support groups, to speech therapists, and to special schools for education and behavioral modification but were not referred for any evaluation of the child's immune or gastrointestinal function.

When the child was 4.75 years of age, the parents decided to embark on additional biochemical assessments of their child including allergy assessment, routine chemistry and hematology, evaluation of stool microorganisms, evaluation of immune function, and urine organic acid testing.

Comprehensive food allergy testing for 96 foods was performed using IgG specific enzyme linked immunoassay. The following allergens were positive by IgG-specific enzyme linked immunoassay: barley, gluten, wheat, bran, cow's milk, cheeses (cheddar, cottage, and Swiss), beef, grapefruit, orange, peanut, soybean, and sugar. The IgA endomysial antibody test, which is considered to be specific for celiac disease, was negative in this child.

Normal serum values were found for all of the following: glucose, urea nitrogen, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, LDH, calcium, phosphorus, blood lead, sodium, potassium, chloride, bicarbonate, uric acid, triglycerides, cholesterol, anion gap, thyroxine, antinuclear antibodies, thyrotropin (highly sensitive), iron, copper, magnesium, cortisol, zinc, and ferritin. White cell count was slightly low (4900/mm3); normal: 5500-15,500/mm.3 Hemoglobin and hematocrit were normal. The white cell differential was normal except for a slight elevation of atypical lymphocytes. The absolute number and percentage of CD3, CD4, and CD8 cells, evaluated by flow cytometry were all within normal limits.

Analysis of serum immunoglobulins revealed normal values for serum IgG, IgM, IgE, and IgG subclasses but undetectable values for serum IgA (Table 1). Stool analysis revealed a 4+ overgrowth of Candida parapsilosis; normal is 0 and the highest possible overgrowth is 4+. Antifungal sensitivity of the organism indicated sensitivity to fluconazole, itraconazole, nystatin, and ketoconazole. Bacteria in the stool sample usually considered beneficial were Lactobacillus (2+) and Bifidobacteria (4+). Stool analysis also revealed 3+ levels of gamma streptococci and 4+ hemolytic E. coli. An evaluation of a urine sample by gas chromatography-mass spectrometry as described previously (31) taken at the same time indicated significant increases of the sugar arabinose as the major abnormality; there were no abnormalities associated with any recognized inborn error of metabolism.

Therapy

Because of elevated Candida in the stool sample, indicating a gastrointestinal yeast overgrowth, the child was placed on 100,000 Units nystatin four times a day plus alternating weeks of Nizoral or Diflucan (2 mg/kg) and was also placed on a gluten and casein free diet approximately two months after beginning antifungal therapy. Both dietary and antifungal therapies are continuing five months later. The pretreatment urinary arabinose concentration (341 mmol/mol creatinine in this child was nearly six times the mean value (60.4 mmol/mol creatinine, n = 20) of normal children and over ten times the median value (31.0 mmol/mol creatinine) of normal controls. After antifungal therapy for four months, the urine was retested. At that time the urine arabinose was measured at 51 mmol/mol creatinine, a value only 15% of the baseline sample. With two additional months of antifungal treatment, the urine arabinose value decreased to 26 mmol/mol creatinine. A follow-up stool test indicated the absence of Candida in the sample.

Results of therapeutic interventions

The mother of the child reports a significant increase in eye contact, a significant decrease in self-stimulatory behavior, and increased use of spontaneous language shortly after beginning antifungal therapy. After beginning the casein and gluten free diet, the mother reports the child was able to follow three step verbal directions versus only one step directions previously. The mother also reported increased learning speed in the schooling program, increased verbal labeling, and increased spontaneous verbal initiations. The score for the child on the Childhood Autism Rating Scale (CARS), an observational measure of various aspects of autism has decreased from a rating of 43 (severely autistic) prior to introduction of these therapies to a value of 29 (non-autistic) after therapy. Cutoff for autism is 30 or above. The child is now considered by the assessment team at the state university autism clinic to be a high-functioning individual with autism. The child can now parallel play with other children in class, demonstrates an interest in peers, shares toys, and is engaging in some imaginative play.

Discussion

Selective IgA deficiency
The most striking laboratory abnormality of this child is the absence of detectable IgA. IgA is the antibody that is involved with protection of the lining of the nasal passages and intestinal lining from microorganisms. Secretory IgA or sIgA is a special form of the IgA antibody that is secreted to protect the mucosa, which is the lining of the intestinal tract. Secretory IgA on a stool sample from this child was also noted as deficient. Secretory IgA is apparently secreted by the gall bladder and then trickles down the bile ducts into the small intestine. Some children with autism such as this one have very low or even completely absent levels of IgA (1,20); in such cases there is probably also a deficiency of a secretory IgA since secretory IgA is derived from IgA.

This extremely common immunodeficiency occurs in 1 in 600-1000 persons of European ancestry (32). The causes of IgA deficiency are not completely known. There are some cases in which the deficiency runs in families while in other cases it does not. It has been reported in association with abnormalities of chromosome 18, but most individuals with IgA deficiency have no detectable chromosomal abnormalities (32). IgA deficiency may also be caused by drugs or viral infection (rubella, cytomegalovirus, toxoplasmosis) and may be also be associated with intrauterine infections. Patients with IgA deficiency are usually deficient in both subtypes of IgA, IgA1 and IgA2.

In Gupta's study (20), 20% of the children with autism had a deficiency of IgA and 8% lacked it completely. Reed Warren and his colleagues (1) also found that 20% of individuals with autism had low serum IgA compared with none of the normal controls. Thus, complete IgA deficiency in autism is somewhere between 48 and 80 times higher in the autism population compared to a normal Caucasian population.

IgA replacement therapy cannot be used currently because the short half-life of IgA would make it an extremely expensive therapy. However, bovine colostrum, which is commercially available, is high in IgA and might be considered as a possible therapy for IgA-deficient patients. IgG therapy can be used with patients with low IgA values. If the IgA values are so low that they cannot even be detected, however, giving IgG therapy is too risky. It is possible that the immunodeficient person's body would produce antibodies against IgA present in gamma globulin, causing potentially fatal anaphylactic shock.

The clinical consequences of IgA deficiency range from severe systemic infection to a perfectly healthy state. Many IgA-deficient persons are never aware of their antibody deficiency while others may have recurrent infections, allergic diseases, and autoimmune diseases (32). This child with autism had significant Candidiasis of the gastrointestinal tract despite the fact that the child had only two courses of antibiotics during his lifetime. Thus, intestinal Candidiasis following antibiotic therapy appears to be a much greater risk in a child with immunodeficiency. The decrease in symptoms of autism after antifungal therapy and gluten and casein restriction has been noted in many children with autism (33). (The authors are aware of three children with autism diagnosed at university autism centers who are now considered symptom-free after antifungal treatment and gluten and casein restriction.)

The child being presented was never considered a "sickly" child by the parents. It is possible that the difficult to treat eye crusting may have been related to the IgA deficiency since IgA is secreted in tears, saliva, and gastric juice; the deficient IgA in the tears may have led to a greater number of eye infections. The occurrence of multiple sclerosis in the maternal grandmother might be of significance but she was never evaluated for IgA deficiency. The remarkable spectrum of clinical manifestations of this immunodeficiency may be related to variations in the ability to replace IgA antibodies in the mucous secretions with IgM antibodies. IgG2 and IgG4 subclass deficiencies are common in IgA deficiency but were not present in this individual.

IgA Deficiency and Celiac Disease

The incidence of selective IgA deficiency is 10 times higher in patients with celiac disease compared to the general population (34). The diagnosis of celiac disease cannot be excluded in an IgA deficient child because the endomysial antibody test uses IgA antibody specificity and may yield false negative results in such cases (35) so the possibility that the child may have celiac disease cannot be excluded. The parents elected to place the child on a wheat and dairy-free diet based on the ELISA-allergy test results so a diagnosis of celiac disease by intestinal biopsy would not be valid for this child. Positive IgG antibodies to gluten were found in 100% of IgA-deficient persons with biopsy proven celiac disease but who were negative by the endomysial antibody test (35). Most children with autism are sensitive to both gluten, the major protein in wheat and barley, and to casein, the major protein in cow's milk (36-40). Elevation of IgG antibodies to wheat, barley, and several dairy products is common in autism even though most children with autism do not have celiac disease (36-40). Behavioral improvements after restriction of gluten and casein are attributed to a decrease in peptides (casomorphin and gliadorphin) derived from gluten and casein that have central nervous system opioid effects (36-40).

Candidiasis and abnormal arabinose: possible implications in brain structure and function

The exact biochemical role of elevated arabinose is unknown but a closely related sugar alcohol, arabitol, has been used as a biochemical indicator of invasive candidiasis (41-43). We have never found elevated arabitol in thousands of urine samples tested, including many samples with elevated arabinose and high yeast counts in the stool. Elevated arabinose in the urine of two brothers with autism was first reported by Shaw et al. in 1995 (31) and has since then has been reported to be prevalent in urine samples from people with autism (33); values as high as 4000 mmol/mol creatinine have been found in children with autism (unpublished data). We have found arabitol but not arabinose in the culture media of multiple isolates of Candida albicans isolated from stool samples of autistic children (unpublished data). Presumably elevated arabitol in the urine may only occur in systemic rather than gastrointestinal Candidiasis since arabitol in portal blood is converted to arabinose in the liver. Arabinose in the urine decreased markedly after antifungal therapy, concomitantly with an elimination of stool Candida. Arabinose, a sugar aldehyde or aldose reacts with the epsilon amino group of lysine in a wide variety of proteins and may then form cross-links with arginine residues in an adjoining protein (44), thereby cross-linking the proteins and altering both biological structures and functions of a wide variety of proteins (Figure 1) including proteins involved in the interconnection of neurons. Decreased clinical symptoms of autism after antifungal treatment would be due to decreased arabinose and pentosidine formation, resulting in fewer random neural connections (neural noise) and increased numbers of neural connections that are oriented to the child's environment.

This adduct of arabinose, lysine, and arginine is called a pentosidine (Figure 1). The epsilon amino group of lysine is a critical functional group of many enzymes to which pyridoxal (vitamin B-6), biotin, and lipoic acid are covalently bonded during coenzymatic reactions (45); the blockage of these active lysine sites by pentosidine formation may cause functional vitamin deficiencies even when nutritional intake is adequate. In addition, this epsilon amino group of lysine may also be important in the active catalytic site of many enzymes. Protein modification caused by pentosidine formation is associated with crosslink formation, decreased protein solubility, and increased protease resistance. The characteristic pathological structures called neurofibrillary tangles associated with Alzheimer disease contain modifications typical of pentosidine formation. Specifically, antibodies against pentosidine react strongly to neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease (46). In contrast, little or no reaction is observed in apparently healthy neurons of the same brain.

Thus, it appears that the neurofibrillary tangles of Alzheimer's disease may be caused by the pentosidines. The modification of protein structure and function caused by arabinose could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks. Similar damage to the brains of autistic children might also be due to the pentosidines; neurofibrillary tangles have also been reported in the brain tissue of an individual with autism (47). Improvement of symptoms of autism after antifungal therapy might be mainly due to a decrease in the concentration of arabinose and a concomitant decrease in the production of pentosidine cross-links. Since pyridoxal (vitamin B-6) reacts with the same critical epsilon amino group of lysine, it is possible that the beneficial effects of vitamin B-6 in autism reported in multiple studies (48) may be mediated by prevention of further pentosidine formation. Analysis of brain tissue of people with autism for increased brain pentosidines could be invaluable in the confirmation of this hypothesis.

Women with vulvovaginitis due to Candida were found to have elevated arabinose in the urine (49); restriction of dietary sugar brought about a dramatic reduction in the incidence and severity of the vulvovaginitis. Thus, one of the mechanisms of action of antifungal drug therapy for autism might be to reduce the concentration of an abnormal carbohydrate produced by the yeast that can not be tolerated by the child with defective pentose metabolism or an inability to remove harmful pentosidines. Arabinose tolerance tests should be able to rapidly determine if such biochemical defects are present in children with autism.

A Model for Autism

The success of Gupta (20) in treating the autistic symptoms of children with autism with gamma globulin therapy indicates an immune abnormality in autism. Based on these findings and our findings of abnormal arabinose and other organic acids in other children with autism (31,33), we propose the following model for autism (Figure 2). According to this model, immune deficiencies, which may be genetic or acquired, lead to an increased frequency of infections, which in the United States are almost always treated with broad-spectrum oral antibiotics that result in intestinal yeast overgrowth. Furthermore, many isolates of Candida albicans produce gliotoxins (50,51) and other immunotoxins (52,53) which impair the immune system and increase the likelihood of additional infections which lead to additional antibiotic usage and greater proliferation of yeasts and antibiotic-resistant bacteria, setting up a vicious cycle. These organisms produce high amounts of abnormal carbohydrates such as arabinose and Krebs cycle analogs such as citramalic and tartaric acids (31).

There is no inherent reason that dramatic biochemical changes in multiple biochemical systems caused by microorganisms would not be expected to alter brain structure and function. In PKU, correction of the metabolic defect by restriction of phenylalanine during infancy allows for normal development; negative impacts on development occur if dietary intervention occurs too late. If abnormally elevated metabolites cause autism, then it is reasonable to think that elevations of these compounds would have maximum negative impact during periods of critical brain growth and development. As in PKU, metabolic intervention in autism might only be possible in the early stages of the disorder before the brain has matured. The differences in severity of disease and individual differences in symptoms might be due to different combinations of metabolites, how elevated they are, the duration of the elevation, the age at which the metabolites become abnormally elevated, and the susceptibility of the individual developing nervous system to the different microbial metabolites.

Some children with autism have a history of frequent infections: two different parents of children with autism indicated to the authors that their children had over 50 consecutive infections (predominantly otitis media) treated with antibiotics. However, some children with autism such as the child presented here did not have excessive use of oral antibiotics and was not considered to be a "sickly child" by the parents or attending physicians. In this child the underlying immune deficiency and two uses of antibiotics apparently led to a persistent yeast overgrowth of the intestinal tract.

Genetic immunodeficiencies proposed as the major genetic factors in autism

Ritvo et al. (54) found a concordance rate for autism of 23.5% in dizygotic twins and 95.7% in monozygotic twins, indicating a strong genetic basis for autism. However, the results of the Stanford autism genetics study of 90 families affected by autism (55) indicate " that there are no genes with a major effect for autism. That is, our analyses show that autism is almost surely not a simple single major gene disorder, such as Huntington disease. Rather, the analyses from these 90 families indicate that there are likely to be a relatively large number of different genes related to the susceptibility for autism, each with a minor effect." We suspect that many of these "relatively large number of genes" are those that regulate the immune system. We have been impressed with the large number of studies that have indicated a wide number of abnormalities of the immune system in autism (1-20) including IgG deficiency, IgA deficiency, IgG subclass deficiency, myeloperoxidase deficiency (a genetic defect in an enzyme of the leukocytes that produces hypochlorite ion to kill yeast), reduced natural killer cell activity, markedly elevated serum levels of the cytokines interleukin-12 and interferon-gamma, increased anti-myelin and serotonin receptor antibodies, increased DR+ T cells, and a deficiency in complement C4b. In addition, some immune abnormalities in autism have been linked to adverse reactions to vaccinations (56). The two brothers with autism in which abnormal arabinose and abnormal organic acids were first reported (31) both had abnormally low concentrations of serum IgG. Autism has also been diagnosed in other children with defined inborn errors of metabolism such as biotinidase deficiency and isovaleric acidemia (Lombard, Personal Communication) in which yeast infections are common.

Efforts to locate a single autism gene would fail since any genetic factor that severely impairs the immune system may eventually lead to the proliferation of antibiotic-resistant yeasts and bacteria which then alter behavior of children at critical periods of development through the excretion of abnormal microbial metabolic products. Thus, autism appears to be a complex metabolic disorder involving immune deficiencies, autoimmune abnormalities, abnormal food sensitivities, and gastrointestinal microbial overgrowths that may result in altered human metabolism and protein function.

Figure 1. Reaction of arabinose from yeast with amino groups of lysine to form a Schiff base adduct. The rearranged Schiff base then reacts with a guanido group on an arginine residue of a second protein, resulting in two different proteins crosslinked through a pentosidine moiety.

Figure 2. Immunodeficiency model for autism. In this model, immunodeficiencies lead to antibiotic use that stimulates yeast overgrowth (primarily Candida) of the gastrointestinal tract. Certain strains of Candida produce immunosuppressant compounds called gliotoxins that further weaken the immune system and may lead to additional infections. Arabitol produced by Candida in the gastrointestinal tract is converted to arabinose by the liver. Elevated arabinose then leads to pentosidine formation, leading to increased neurofibrillary tangles in the brain.

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Candida and Overgrowth - The Problem & Bacteria By-products

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My discovery about the role of abnormal organic acids from gastrointestinal microorganisms in human disease began as many discoveries do, as an accident.

In the 1960’s, a great deal of progress had been made in discovering the biochemical abnormalities that caused a number of diseases called "inborn errors of metabolism" using a technology called gas chromatography-mass spectrometry. These diseases included phenylketonuria (PKU), tyrosinemia, maple syrup urine disease and many others.

It seemed possible that this new testing called organic acid testing or metabolic profiling might be applied to any disease. However, thirty years later, very little progress had been made in solving the mystery of a number of diseases like autism, fibromyalgia, schizophrenia, and Alzheimer’s disease.

There is a long list of diseases in which a substantial number of patients excrete elevated microbial metabolites in the urine which have been detected by urine organic acid testing:

  • Autism

  • Attention deficit disorder (ADD)

  • Rett's syndrome

  • Ulcerative colitis

  • Seizures

  • Depression

  • Child Psychosis

  • Fibromyalgia

  • Chronic fatigue syndrome

  • Pervasive developmental disorder (PDD)

  • Colitis

  • Schizophrenia

  • Migraine headache

  • Alzheimer's disease

  • Systemic Lupus Erythematosus (SLE)

  • Obsessive compulsive disorder (OCD)

  • Tourette's syndrome

  • Inflammatory bowel disease

  • Down syndrome

  • Crohn's disease

Microbial Ecology of the GI Tract

The number of microorganisms in the GI tract approaches the total number of cells in the body. Approximately 500 species of bacteria are present, of which 30-40 species of bacteria predominate, including several species of yeast and fungi.

The greatest number of species are anaerobic or facultative anaerobes. Yeast/fungi and Clostridia species are widely known to accompany the use of broad spectrum antibiotics. Furthermore, recent research indicates that the growth of certain Candida types is markedly stimulated by antibiotic addition to the culture media.

Books like The Yeast Connection and Yeast Syndrome have spread the knowledge about the health effects of Candida to the general public, but are widely ignored by a large segment of the medical community.

Detecting GI Microbial Overgrowth (Dysbiosis)

I became interested in using gas chromatography-mass spectrometry (GC/MS) to detect abnormal microbial metabolites when I worked at the Center for Disease Control (CDC). At CDC, GC/MS was used to identify the species of pure cultures of isolated bacteria. I wondered why you couldn’t directly test human body fluids directly for products of microorganisms.

Later, while working at Children’s Mercy Hospital, the pediatric hospital for the University of Missouri at Kansas City Medical School, I became interested in the role of abnormal urinary metabolites detected by GC/MS while evaluating two brothers who had autism as well as occasional severe muscle weakness.

Since some inborn errors of metabolism are associated with muscle weakness, I was really looking for metabolites characteristic of genetic diseases which were all negative. Instead, I noticed that several unusual compounds were consistently elevated in urine samples. None were adequately described in the medical literature. Colleagues in the field of metabolic diseases said they were probably from gut flora (microorganisms) and were therefore unimportant. Since several of these compounds were analogs (or altered forms) of normal Krebs cycle compounds, I thought these compounds might be significant, perhaps as anti-metabolites.

During the same time period, I was testing the culture media of a large number of different yeast and bacteria strains from the human gastrointestinal tract in order to find out which compounds in the human might be derived from the yeast and bacteria in the gastrointestinal tract.

Yeast Metabolites in the Urine of Children with Autism

The compound that led to the discovery of yeast as the source of many of these compounds in the urine of autistic children was tartaric acid.

The brothers with autism and severe muscle weakness had extremely high values of tartaric acid in their urine. Another child with autism had a urine value of tartaric acid 600 times that of normal children.

The only source of tartaric acid is yeast. This compound forms a sludge in the wine brewing process and has to be removed. Wine is sugar-water fermented by yeast (Saccharomyces cerevisiae) to alcohol and other yeast products. Humans do not produce this chemical.

When I pulled the medical charts of several other children with autism, they had similar abnormalities and immediately I wondered about a possible causal connection. The next step seemed obvious. If these compounds were from yeast and were causing some of the symptoms of autism, antifungal drugs which kill yeast should reduce some of the symptoms of autism. However, the two brothers did not receive antifungal therapy until nearly a year later.

At nearly the same time, a two-year-old boy was currently being evaluated for autism in the neurology department at the children’s hospital where I worked and I had just done the urine organic acid test. The child had been developing normally up to about 18 months of age and had a vocabulary of about 200 words.

He was treated several times for ear infections with antibiotics and developed thrush (a Candida or yeast infection of the mouth and tongue). His behavior deteriorated quickly after that. He lost all speech, became extremely hyperactive, woke up all night long, lost eye contact with his parents and was diagnosed with autism.

This pattern of normal development and regression associated with antibiotics is extremely common in autism and is especially common in males with autism (about a 20/1 male/female ratio). His organic acids were very elevated, which I thought was due to the yeast, including tartaric acid. The neurologist at the hospital would not prescribe the antifungal drug Nystatin for the child so the parents and I convinced their family physician to prescribe it.

The child’s eye contact returned by the following day and the elevated organic acids decreased markedly, although it took over 60 days for the urine tartaric acid to return to the normal range (Figure 1).

At day zero (Figure 1), the day that the child had the organic acid test done, the tartaric acid value in urine was over 300 mmol/mol creatinine, a very high value--about twenty times the normal value. (Most chemicals measured in urine are divided by the urine creatinine concentration to compensate for different amounts of fluid intake in different individuals.) Following the treatment with the Nystatin, the level of the tartaric acid decreased considerably and continued to decrease as the Nystatin was continued.

Within a couple of days of starting the antifungal drug Nystatin, the child--who had lost most of normal development--began to improve and eye contact came back. His extreme hyperactivity began to go away and he began to have a greater amount of focus. The sleep pattern improved as well. Nystatin is an antifungal drug which indicated to me that a yeast or fungus (these terms are somewhat interchangeable in that they are very closely related biologically) was causing the secretion of this compound in the intestinal tract.

After 68 days the child’s mother started running out of Nystatin and began giving only half doses so that she didn’t run out of it. During that time the tartaric acid starting increasing. When she got the Nystatin prescription refilled and restored the full dose of Nystatin, the tartaric acid decreased.

What this indicated to me was that the Nystatin was causing a marked reduction in this urine tartaric acid. The other significant finding was that even after two months of Nystatin, the biochemical abnormality would reappear within a short time of stopping the antifungal drug.

I have now detected this same phenomenon in hundreds of other cases. Even after six months of antifungal treatment, there is often a biochemical "rebound" and loss of improvements after discontinuing antifungal therapy. This rebound also occurs after other antifungal drugs as well.

Several explanations are possible for this phenomenon:

  • Because of one or more defects in the immune system such as IgA deficiency, IgG deficiency, or severe combined immunodeficiency disease (SCID) which are found in most children with autism, the yeast, which are everywhere in our environment including the food we eat, repopulate the intestinal tract very rapidly.

  • The yeast are very resistant and have not been completely eliminated even after six months of antifungal therapy

  • The yeast have genetically transformed some of the human cells that line the intestinal tract so that some of the human cells now contain yeast DNA. These genetically transformed human cells produce both yeast and human products and are somewhat sensitive to antifungal drugs but are not killed by them and produce yeast products whenever antifungal drugs are absent.

  • Some of the yeast are hidden in recesses of the intestinal tract or in the deeper layers of the mucosa that lines the intestine where they are relatively safe from the drug. Although their numbers are small, they readily repopulate the intestine after antifungals are stopped.

  • In addition to the immune system taking inventory of its own cells, it seems increasingly likely that the immune system also takes an inventory of bacteria and yeast cells present in the intestinal tract soon after birth. This inventory is performed by a group of cells called the CD5+ B-cells, which are among the very first immunological cells to appear in the developing embryo and appear to play a role in tolerance to intestinal microorganisms in postnatal life. These cells may play a role in regulating the secretion of IgA, the antibody class that is secreted into the intestinal tract and which may select which microorganisms are tolerated in the intestinal tract. Furthermore, the eradication of normal flora especially when antibiotics are administered repetitively during infancy may cause the CD5+ cells to reject these normal organisms at a later age. Any cells that are on this early inventory may be awarded immune tolerance and will not be attacked later on by the immune system. Either antibiotic use in infancy or yeast infection of the mother during pregnancy may result in later immune tolerance to yeast.

Response of Children with Autism to Antifungal Therapy

Improvements commonly cited by parents of autistic children treated with antifungal therapy include: decreased hyperactivity, more eye contact, increased vocalization (more words and more usage), better sleep patterns, better concentration, increased imaginative play, reduced stereotypical behaviors (such as spinning objects), and better academic performance. Two children with autism treated with a combination of antifungal therapy, EPD treatment for food allergies, and gluten and casein free diet have completely recovered from autism.

More than 1000 children with autism have been treated with a wide variety of antifungal agents such as Nystatin, Lamisil, Sporanox, Nizoral, Diflucan, caprylic acid, grapefruit seed extract, and garlic extract with good clinical response in perhaps 80-90%. A survey of parents of autistic children by Rimland reports that antifungal therapy is ranked the most effective (by a wide margin) of all drug therapies used for the reduction of autistic symptoms.

Molecular Basis of Tartaric Acid Toxicity

The abnormal metabolites derived from yeast were first discovered in two brothers with autism. In addition to their autism, these brothers had a muscle weakness that was so severe that sometimes they could not even stand up. A neurologist colleague, Enrique Chaves, MD, told me that virtually all the autistic children he examined had hypotonia.

Both of these brothers excreted high amounts of tartaric acid in the urine. Biopsy of the muscle and examination by electron microscopy revealed normal structural features except for an unexplained "granularity." Electromyography, EEG’s, brain scans, and nerve conduction velocities were all normal.

A toxicology manual indicates that tartaric acid is a highly toxic substance. As little as 12 gm has caused human fatality with death occurring from 12 hours to 9 days after ingestion. Gastrointestinal symptoms were marked (violent vomiting and diarrhea, abdominal pain, thirst) and followed by cardiovascular collapse and/or acute renal failure. A gram is approximately the weight of a cigarette.

This compound especially damages the muscles and the kidney and may even cause fatal human nephropathy (kidney damage) which was of interest to me, since the two brothers with autism had the extreme muscle weakness as well as evidence of impaired renal function.

A young Korean child with autism had a value of 6000 mmol/mol creatinine, a value that is about 600 times the median normal value. Assuming that the yeast in the intestine of the child were producing tartaric acid at a constant rate, this child would be exposed to 4.5 grams per day of tartaric acid, over one-third of the reported lethal dose of tartaric acid! (The child’s value returned to normal after a few weeks of antifungal treatment.)

Tartaric acid is an analog (a close chemical relative) of malic acid (Figure 2). Malic acid is a key intermediate in the Krebs cycle, a biochemical process used for the extraction of most of the energy from our food. Presumably tartaric acid is toxic because it inhibits the biochemical production of the normal compound, malic acid (Figure 3). Tartaric acid is a known inhibitor of the Krebs cycle enzyme fumarase which produces malic acid from fumaric acid.

Yeast Byproducts, Malic Acid Supplementation, & Fibromyalgia

Interestingly, I have found that tartaric acid and/or other yeast byproducts are also elevated in urine samples of adults with the disorder fibromyalgia, a debilitating disease associated with muscle and joint pain, depression, foggy thinking, and chronic fatigue. (Dr. Kevorkian has assisted in the suicide of two people with this disorder, which is tragic since a simple antiyeast treatment may help relieve the symptoms of this disorder.)

A large percentage of patients with fibromyalgia respond favorably to treatment with malic acid which is present in health food supplements such as Fibrocare and Supermalic. I presume that supplements of malic acid are able to overcome the toxic effects of tartaric acid by supplying deficient malic acid.

Treatment with the antifungal drug Nystatin kills the yeast and values for tartaric acid steadily diminish with antifungal treatment. Fifty percent of patients with fibromyalgia often suffer from hypoglycemia even though their diet may have adequate or even excessive sugar.

One of the reasons for the hypoglycemia may be due to the inhibition of the Krebs cycle by tartaric acid. The Krebs cycle is the main provider of raw materials such as malic acid that can be converted to blood sugar (Figure 3) by the process called gluconeogenesis when the body uses up its glucose supply.

If sufficient malic acid cannot be produced, the body cannot produce the sugar glucose, which is the main fuel for the brain. The person with hypoglycemia feels weak and their thinking is foggy because there is insufficient fuel for their brain. Of course, consumption of sugar may provide short-term relief but which also stimulates yeast overgrowth and within a short time symptoms are even worse.

Arabinose, Yeast, Autism, Alzheimer's Disease & Schizophrenia

Arabinose is a five carbon sugar with an aldehyde function called an aldose, which is frequently elevated in autism.

In some children with autism, arabinose concentrations may exceed 50 times the upper limit of normal. A scattergram of urine arabinose values comparing normal and autistic children in the same age range is given below (Figure 4).

The exact biochemical role of arabinose is unknown, but a closely related yeast alcohol arabitol has been used as a biochemical indicator of invasive candidiasis. We have never found elevated arabitol in any of the urine samples tested and we have not found arabinose in the culture media of multiple isolates of Candida albicans isolated from stool samples of autistic children (unpublished data).

We suspect that arabitol produced by yeast in the intestinal tract is absorbed into the portal circulation and then converted to arabinose by the liver. Hypoglycemia occurs in inborn errors of fructose metabolism in which fructose inhibits gluconeogenesis and it is possible that children with autism might be deficient in one or more enzymes involved in the metabolism of pentoses. Elevated protein-bound arabinose has been found in the serum glycoproteins of schizophrenics and in children with conduct disorders and alteration of protein function by arabinose is another mechanism by which arabinose might effect biochemical processes.

Women with vulvovaginitis due to Candida were found to have elevated arabinose in the urine; restriction of dietary sugar brought about a dramatic reduction in the incidence and severity of the vulvovaginitis. Thus, one of the mechanisms of action of antifungal drug therapy for autism might be to reduce the concentration of an abnormal carbohydrate produced by the yeast that can not be tolerated by the child with defective pentose metabolism. Arabinose tolerance tests should be able to rapidly determine if such biochemical defects are present in children with autism.

Arabinose, Pentosidine, Protein Modification & Vitamin Deficiencies

Arabinose, a sugar aldehyde or aldose, reacts with the epsilon amino group of lysine in a wide variety of proteins and may then form cross-links with arginine residues in an adjoining protein, thereby cross-linking the proteins and altering both biological structures and functions of a wide variety of proteins.

This adduct of arabinose, lysine, and arginine is called a pentosidine (Figure 5). The tissue concentration of this adduct is almost linearly related to age (Figure 6). The epsilon amino group of lysine is a critical functional group of many enzymes to which pyridoxal (vitamin B-6), biotin, and lipoic acid are covalently bonded during coenzymatic reactions; the blockage of these active lysine sites by pentosidine formation may cause functional vitamin deficiencies even when nutritional intake is adequate. In addition, this epsilon amino group of lysine may also be important in the active catalytic site of many enzymes.

Pentosidines, Autism, Alzheimer’s & Neurofibrillary Tangles in the Brain

Protein modification caused by pentosidine formation is associated with crosslink formation (Figure 7), decreased protein solubility, and increased protease resistance. The characteristic pathological structures associated with Alzheimer disease contain modifications typical of pentosidine formation. Specifically, antibodies against pentosidine immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease.

In contrast, little or no staining with anti-pentosidine antibodies is observed in apparently healthy neurons of the same brain. The modification of protein structure and function caused by arabinose could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.

Since the process of pentosidine formation is an oxidative one, the use of antioxidants as well as antifungal therapy appears to be a promising therapy for Alzheimer’s disease. Glutathione has been reported to inhibit pentosidine formation. Supplementation with the vitamins biotin, pyridoxal (B-6), and lipoic acid (whose function at protein epsilon amino groups may be blocked by pentosidines derived from arabinose) might also be beneficial because of functional deficiencies due to pentosidine formation (Figure 8).

Not surprisingly, neurofibrillary tangles similar to those found in the brains of Alzheimer’s victims have also been reported in the brain of an autistic person at autopsy. It has been reported that frequent urinary tract infections and high amounts of circulating immune complexes are associated with more severe Alzheimer disease. The use of antibiotics to treat urinary tract infections would of course lead to yeast overgrowth of the gastrointestinal tract.

Summary

Elevation of yeast metabolites such as tartaric acid and arabinose are found in many of the same disorders and are even more common in autism, SLE, Alzheimer’s disease, fibromyalgia, attention deficit hyperactivity, and chronic fatigue syndrome. The arabinose may interfere with gluconeogenesis and also may through pentosidine formation significantly alter protein structure, transport, solubility, and enzymatic activity as well as triggering autoimmune reactions to the modified proteins.

The finding of pentosidine in the neurofibrillary tangles of Alzheimer’s brains and its absence from normal areas of the brain may indicate a direct role of a yeast byproduct in accelerating the normal aging process. Tartaric acid from yeast overgrowth has a direct toxic effect on muscles and is an inhibitor of a key Krebs cycle enzyme that supplies raw materials for gluconeogenesis and offers an explanation for many of the symptoms of fibromyalgia.

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Reasons to Perform Total IgG Food Allergy Testing Instead of IgG4 Food Allergy Testing

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William Shaw, PhD

Immunoglobulins (Igs) consist of 5 different classes termed G, A, M, E, and D. IgG is broken into several subclasses termed 1, 2, 3, and 4. IgGs are composed of two heavy chain–light chain pairs (half-molecules), which are connected via inter–heavy chain disulfide bonds situated in the hinge region. IgG4 antibodies usually represent less than 6% of the total IgG antibodies. IgG4 antibodies differ functionally from other IgG subclasses in their anti-inflammatory activity, which includes a poor ability to induce complement and cell activation because of low affinity for C1q (the q fragment of the first component of complement). Consequently, IgG4 has become the preferred subclass for immunotherapy, in which recruitment of host effector function is undesirable.

IgG4 antibodies are dynamic molecules that exchange half of the antibody molecule specific for one antigen with a heavy-light chain pair from another molecule specific for a different antigen. The results in bispecific antibodies that are unable to form large cross-linked antibodies via complement binding thus producing inflammation. The production of large amounts of these IgG4 antibodies is the reason that immunotherapy with various antigens is used to reduce severe reactions caused by IgE mediated allergies. If antigens react with IgG4 antibodies, the antigens cannot react with IgE antibodies that might cause anaphylaxis or other severe reactions. Thus, IgG4 antibodies are often termed blocking antibodies. For example, in specific immunotherapy for allergic rhinitis, increases in allergen-specific IgG4 levels correlate with improved clinical responses. IgG4 antibodies not only block IgE mediated food allergies but also block the reactions of food antigens with other IgG subclasses, reducing inflammatory reactions caused by the other IgG subclasses of antibodies to food antigens.

[Structure of IgG Antibodies]

In IgG mediated food allergy testing, the goal is to identify foods that are capable of causing inflammation that can trigger a large number of adverse reactions. IgG1, IgG2, and IgG3 all are capable of causing inflammation because these antibodies do not exchange heavy and light chains with other antibodies to form bispecific antibodies. Thus, IgG1, IgG2, and IgG3 antibodies to food antigens can and do form large immune complexes or lattices that fix complement and increase inflammation. The presence of IgG4 antibodies to food antigens indicates the presence of antibodies to foods that will not usually cause inflammation even though high amounts of these antibodies do indicate the presence of immune reactions against food antigens. Testing only for IgG4 antibodies in foods limits the ability of the clinician to determine those foods that are causing significant clinical reactions that are affecting their patients. The importance of measuring other subtypes of IgG antibodies is highlighted in an article by Kemeny et al. They found that IgG1 antibodies to gluten were elevated in all 20 patients with celiac disease but none of the patients had elevated IgG4 antibodies to gluten.

Read a scientific article indicating that testing for IgG4 against foods is not recommended as a diagnostic tool.

 

Clinical Documentation of Use of Total IgG Food Allergy Test in Many Illnesses

Irritable Bowel Syndrome

W. Atkinson, et al Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53:1459-1464.

Crohn’s Disease

Bentz S,Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study. Digestion. 2010;81(4):252-64. Epub 2010 Jan 30.

Migraine Headache

Huber A,et alInt Arch Allergy Immunol. 1998 Jan; 115(1):67-72. Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial.

Bipolar Disorder

Severance EG et al Immune activation by casein dietary antigens in bipolar disorder. Bipolar Disord 2010: 12: 834–842.

Schizophrenia

Severance EG, et al Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010 May;118(1-3):240-7. Epub 2010 Jan 13.

Obesity

Wilders-Truschnig M et al. IgG Antibodies Against Food Antigens are Correlated with Infl ammation and Intima Media Thickness in Obese Juveniles. Exp Clin Endocrinol Diabetes DOI 10.1055/s-2007-993165. Published online: 2007.

Juvenile-Onset Diabetes

Tahmeed Ahmed; et al Circulating antibodies to common food antigens in Japanese children with IDDM. Diabetes Care; Jan 1997; 20, 1; Research Library, pg. 74-76.

Autism

Vladimir Trajkovski et al Higher Plasma Concentration of Food-Specific Antibodies in Persons With Autistic Disorder in Comparison to Their Siblings.

Rheumatoid Arthritis

O’Farrelly, C., Price, R., McGillivray, A.J. and Fernandes, L. (1989), IgA rheumatoid factor and IgG dietary protein antibodies are associated in rheumatoid arthritis, Immunological Investigations, Vol. 18, pp. 753-64.

Clinical References

  • Marijn van der Neut Kolfschoten, et al Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange. SCIENCE VOL 317 14 SEPTEMBER 2007 pgs1554-1555.

  • Volpi, Nicola and Maccari, Francesca(2009) 'Serum IgG Responses to Food Antigens in the Italian Population Evaluated by Highly Sensitive and Specific ELISA Test', Journal of Immunoassay and Immunochemistry, 30: 51 — 69.

  • Kemeny DM, et al Sub-class of IgG in allergic disease. I. IgG sub-class antibodies in immediate and non-immediate food allergy. Clin Allergy. 1986 Nov; 16(6):571-81.

  • Stapel SO, Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report.Allergy. 2008 Jul;63(7):793-6. Epub 2008 May 16.