Suicide and biomarkers of gastrointestinal inflammation

Suicide and gastrointestinal inflammation

Suicide mostly occurs in association with neuropsychiatric disorders characterized by neuroinflammation (brain inflammation). Neuroinflammation often results from perturbations of the brain-gut axis, with pro-inflammatory immune signaling from the gut to the brain. An important study just published in Psychiatry Research offers data showing the connection between biomarkers of gastrointestinal inflammation and recent suicide attempt. The authors were motivated by the intent to validate biomarkers to help assess, treat and prevent suicide attempts.

Most attempting suicide have an illness associated with neuroinflammation

“Psychological autopsy and epidemiological studies indicate that more than 90% of people who die by suicide have a diagnosable psychiatric illness, particularly major depression, bipolar disorder, or schizophrenia…The identification of blood-based markers would provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts.”

It is an urgent clinical need to identify causes that promote dysregulated activation of the immune system against the neuronal antigens.

The GI tract is often the source of immune activation against the brain

Biomarkers of gastrointestinal inflammation are frequently increased in neuropsychiatric disorders.

“Many individuals with schizophrenia and mood disorders have evidence of immune activation suggesting that immune dysregulation may be part of the etiopathology of these disorders. Studies by our group and others indicate that the gastrointestinal tract is often the primary source of this immune activation as evidenced by increased levels of markers of gastrointestinal inflammation in individuals with serious mental illness.”

IBD (inflammatory bowel disease) and celiac disease appear to increase risk for suicide.

“Furthermore, increased rates of suicide and suicide attempts have been found in some populations of individuals with celiac disease or inflammatory bowel diseases.”

But previous studies have focused on a lifetime history rather than attempts, so the authors set out to:

“…examine the association between levels of markers of gastrointestinal inflammation and a recent suicide attempt in individuals with schizophrenia, bipolar disorder or major depressive disorder in comparison with non-psychiatric controls.”

Elevated IL-6

Interleukin-6 (IL-6), a key pro-inflammatory cytokine which can arise from the GI tract, is associated.

“Results from other investigators indicate that inflammation may be associated not only with a proclivity for a psychiatric disorder, but specifically with suicidal behavior. Studies have found an association between a suicide attempt history and the level of cytokines such as IL-6 which are cell signaling molecules involved in the immune response and which can arise from inflammation from many sources, including the gastrointestinal tract”

Gluten and brain inflammation

Neuroinflammation triggered by non-celiac gluten sensitivity is also implicated:

“Gliadin is a component of gluten, found in wheat and related cereals. Antibody response to dietary gliadin is associated with celiac disease, an immune-mediated enteropathy, and with non-celiac wheat sensitivity and is thought to indicate intestinal inflammation and/or intestinal barrier dysfunction. We have found increased levels of antibodies to gliadin in individuals with schizophrenia and with bipolar disorder and in individuals with acute mania during a hospital stay…”

Additionally, loss of tolerance to a commensal yeast may promote neuroinflammation.

“We also have studied the antibody response to yeast mannans represented by antibodies to Saccharomyces cerevisiae (ASCA), a commensal organism present in some foods and in the intestinal tract of many individuals. Elevated ASCA levels are associated with increased intestinal inflammation. We have previously found increased levels of ASCA in individuals with mood disorders.”

Pathogens and loss of immune tolerance

Various pathogens present at low levels can elicit a persistent cross-reaction to self-antigens, including brain antigens, in individuals disposed to loss of immune tolerance.

“An association between elevated antibodies to Toxoplasma gondii, an apicomplexan parasite, and suicide attempts have also been reported. In a recent study, we found that individuals with serious mental illness who had a lifetime history of a suicide attempt had elevated levels of IgM class antibodies to Toxoplasma gondii and Cytomegalovirus (CMV); we also found an association between the levels of these antibodies and the number of suicide attempts.”

Significant link found

Association between suicide and markers of GI inflammation

The authors examined data for 282 participants: 90 with schizophrenia, 72 with bipolar disorder, 48 with major depressive disorder, and 72 non-psychiatric controls; who were enrolled in ongoing studies of the role the immune response to infections in individuals with serious psychiatric disorders. Biomarkers measured included IgA antibody to yeast mannan from Saccharomyces cerevisiae (ASCA), IgG antibody to gliadin, IgA antibody to bacterial lipopolysaccharide (LPS) from E. coli O111:B4, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and levels of C-Reactive protein.

“We found a statistically significant difference between the recent attempters and the control group in levels of IgA ASCA; the level in the recent attempt group was significantly higher…We also found that the level of IgG antibodies to gliadin was significantly higher in the recent attempters vs. the control group…We also found that the level of IgA antibodies to bacterial lipopolysaccharide (LPS) was significantly higher in the recent attempters vs. the control group…In terms of CRP, we found that there was a significantly higher level in the past attempter group.”

Predicting risk and protecting patients

These findings offer a valuable opportunity for clinicians to gauge and ameliorate risk of suicide in patients with serious neuropsychiatric disorders.

“The markers of gastrointestinal inflammation are of interest because they can be readily measured in blood samples. In addition, some of the markers studied here may be an attractive target for therapeutic intervention since intestinal inflammation can be modulated by dietary interventions as well as the administration of available prebiotic, probiotic, and antibiotic medications.”

The authors conclude:

“Suicide, for which a previous suicide attempt is the greatest risk factor, is a major cause of death worldwide and is highly prevalent in patients with serious mental illness. Unfortunately, the ability to predict suicide remains limited and no reliable biological markers are available. The identification of blood-based markers should provide for more personalized methods for the assessment and treatment, and ultimately prevention, of suicide attempts in individuals with serious mental illnesses.”

For additional categories of importance in evaluating neuropsychiatric risk see The Parents’ Guide to Brain Health.

ALS and gluten sensitivity

JAMA NeurologyALS (amyotrophic lateral sclerosis) is a devastating, lethal autoimmune disease characterized by progressive inflammatory degeneration of motor neurons in the brain cortex, brainstem and ventral (front half) of the spinal cord. Non-celiac gluten sensitivity often entails a neurological target for autoimmune attack in the absence of abdominal symptoms. In a study just published in JAMA Neurology, investigators report an association between some cases of ALS and gluten sensitivity. They state:

Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet.

To determine whether a gluten-related disorder mimicking ALS might occur in some patients they set out to look for celiac disease–related antibodies and HLA antigen alleles along with TG6 antibodies in patients with ALS compared to healthy individuals. They measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, IgA and IgG antibodies to deamidated gliadine peptide, and TG6; and performed HLA antigen genotyping in 150 patients with ALS and 115 healthy volunteers. A striking picture emerged:

All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients.”

Clinical note

Practitioners should bear in mind the authors’ conclusion:

The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.

Gluten intolerance acquired after gastroenteritis

Gastroenterology and Hepatology from Bed to BenchGluten intolerance can occur at any age due to a number of causes that contribute to loss of immune tolerance. The authors of a paper published recently in the journal Gastroenterology and Hepatology from Bed to Bench remind how a bout of viral or bacterial gastroenteritis can be the trigger. They state:

“The spectrum of irritable bowel syndrome (IBS) is narrowing and many conditions previously known/attributed to IBS seem to be related to unrecognised primary or acquired intolerances to nutrient components. Infection might act as triggering factor for inflammatory conditions in susceptible individuals…Inflammation of absorptive surface leading to various enzymatic defects, changing the microbiota and increasing intestinal permeability may result in symptoms previously known as post gastroenteritis IBS. It is time to recognise the possible pathophysiology of acquired gluten intolerance that has been miss-treated under the mask of IBS.”

By way of  authors report on a case of IBS occurring only after gastroenteritis that resolved on a gluten-free and lactose-free diet.

GI infection damages the gut barrier promoting loss of immune tolerance

Clinicians doing case management of autoimmunity are well aware that infection can trigger latent loss of immune tolerance. One mechanism is through compromise of the barrier systems (gut, respiratory, blood-brain).

“Viral or bacterial gastroenteritis can cause structural changes to the small bowel mucosa, including locally reduced digestive enzymes activities secondary to the local inflammatory reaction. Peptidase deficiency resulting from infected small bowel can cause accumulation of partially digested gluten peptides and damage the intestinal mucosal cell. We speculate that damages and deficiencies might cause transitory or permanent intolerances to gluten and other nutrients…involvement of the small bowel and colon may cause IBS-like symptoms, whereas involvement of the stomach and duodenum may cause functional dyspepsia.”

Gluten intolerance after gastroenteritis may be common

Post gastroenteritis gluten intoleranceAn earlier post reports on loss of immune tolerance to the normal commensal gut microbiota after food borne illness. Practitioners should be alert to complaints persisting after resolution of a GI infection.

Transient or permanent post gastroenteritis gluten intolerance might be a common unrecognised clinical condition. Like secondary lactose intolerance, post gastroenteritis gluten intolerance could explain the prolonged symptoms that develop in a group of patients who have suffered from infective gastroenteritis. Patients may present with diarrhoea, bloating, pain, vomiting and dyspepsia.”

Non-celiac gluten sensitivity

Gluten intolerance should be considered as a possibility under the same circumstances that would suggest lactose intolerance.

“Non-coeliac gluten sensitivity is an entity separate from coeliac disease with a much higher prevalence. The autoantibodies like anti-EMA and/or anti-tTG tests are negative although antigliadin antibodies may be present…We suggest there may be an important role for the reduction of gluten in the diet as a treatment for these patients, in a manner analogous to the reduction in lactose intake frequently advised by dieticians for symptoms attributed to transient post infectious lactose intolerance.”

The authors conclude:

“We suspect that patients who develop lactose and gluten intolerances after an episode of gastroenteritis are labelled as having IBS and can be left untreated for years or given only symptomatic treatment for pain, diarrhoea and constipation rather than advised to reduce their dietary intake of lactose and gluten. By moving toward clear diagnosis and targeted treatment of diseases that are involved in the formation of symptoms, we proportionally are approaching the end of the era of non-specific and unhelpful diagnosis like IBS and post gastroenteritis IBS. Clinician and dietician considering the possibility of a post infectious gastroenteritis irritable bowel syndrome being, in part, due to gluten intolerance may encourage colleagues to consider introducing a trial of a lactose and gluten free diet in suitable candidates after exclusion of celiac disease.”

Intestinal barrier damage from food additives and pesticides

Autoimmunity ReviewsIntestinal barrier damage from food additives and pesticides/herbicides contributes to autoimmune disease. The intestinal barrier—epithelial cells forming the inner lining of the intestines—is designed for nutrient absorption while protecting the GALT (gut associated lymphoid tissue, the greatest mass of immune system tissue in the body) from compounds that should not gain access. Damage to the tight junctions of the intestinal barrier is a major contributing cause of loss of immune tolerance and autoimmune disease. When the intestinal barrier is breached, the immune system can become sensitized to compounds that either ‘mimic’ the body’s own antigens due to similarity or combine with them to form a hybrid called a hapten. In either case, as the immune system reacts to the compound that has penetrated the intestinal barrier it can cross-react to self-antigens, thus mounting an inflammatory attack on the body’s own tissues. This is how diminished intestinal barrier integrity is contributing to the pandemic of diffuse and blatant autoimmune phenomena.

Food additives promote autoimmunity by damaging the intestinal barrier

In a paper published recently in Autoimmunity Reviews, the authors link industrial food additives to intestinal barrier damage that leads to loss of immune tolerance. They note:

“The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption…The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD [autoimmune disease]. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them.”

 Crucial role of the intestinal barrier

The authors offer a review of the intestinal barrier tight junctions that are crucial for the healthy immune system regulation:

“Only a single layer of epithelial cells separates the luminal contents from effector immune cells in the lamina propria and the internal milieu of the body. Breaching this single layer of epithelium can lead to pathological exposure of the highly immunoreactive subepithelium to the vast number of foreign antigens in the lumen. The permeability of the intestinal epithelium depends on the regulation of the mucosal immune system and intercellular tight junction (TJ).”

Integrity and protection of the intestinal barrier depends on a network of key proteins:

Zonulins, occludins, claudins and junctional adhesion molecules are a few examples that modulate movement of fluid, macromolecules and leukocytes from intestinal lumen to the blood stream and vice versa. In addition, these TJ proteins are involved in protecting the epithelial cells of the intestine against colonization by microorganisms. It is now apparent that TJs are dynamic structures that are involved in developmental, physiological and pathological processes. They regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular TJs, controls the equilibrium between tolerance and immunity to non-self antigens…in addition to genetic predisposition and exposure to triggering non-self antigens, the loss of protective function of mucosal barriers that interact with the environment is necessary for autoimmunity to develop.”

Influences on intestinal barrier tight junctions

Clinicians need to constantly bear in mind factors that commonly have an impact on intestinal barrier integrity. Here the authors note some of the very common ones:

“Pathophysiological regulation of tight junctions is influenced by many factors, including: secretory IgA, enzymes, neuropeptides, neurotransmitters, dietary peptides and lectins, yeast, aerobic and anaerobic bacteria, parasites, proinflammatory cytokines, free radicals and regulatory T-cell dysfunction.”

Food additives induce AD

Sequential steps through which industrial food additives induce autoimmune diseases. Commonly used industrial food additives abrogate human epithelial barrier function.

In addition to these ‘classics’, they list seven food additives whose increase in use has paralleled the sharp increase in autoimmune disease:

  1. Sugars: “Glucose is known as an absorption enhancer…found to increase permeability and produce changes in distribution of the main protein of the tight junction in the human cell line Caco-2, indicating intercellular leakage.”
  2. Salt: besides driving TH17-associated proinflammatory cytokines (a ‘key player’ in autoimmune inflammation), “…increased salt consumption is an enhancer of intestinal permeability through the TJ machinery.”
  3. Emulsifiers and surfactants: “… widely used in the bakery, confectionary, dairy, fat and oil, sauces, butter and margarine, ice cream, cream liqueurs, meat, coffee, gum, beverages, chocolate and convenient food industries…Numerous synthetic surfactant food additives have been shown to increase the intestinal permeability through paracellular and/or transcellular mechanisms.” By adversely affecting the hydrophobic intestinal barrier mucus layer, epithelial cell membranes and the transport protein p-glycoprotein, they cause “…destabilization of tight junctions between the GI epithelial cells, thus increasing intestinal leakage.” Note for clinicians prescribing essential fatty acids: “Surface active compounds, like oleic and docosahexaenoic acids, compromised the integrity of the intestinal epithelium and enhanced the paracellular absorption of poorly absorbed hydrophilic substances. In general, fatty acids like EPA, DHA, γLA, capric and lauric acids increase TJ permeability.”
  4. Organic solvents: “Some nutrients like glutamine and polyphenols protect TJ barrier integrity, in contrast, several organic solvents used in the food and beverage industries, like alcohol and its metabolites impair the TJ barriers.”
  5. Gluten: “Evidence exists that intestinal barrier defects have a role in initiating celiac disease. A number of in vitro studies have confirmed the cytotoxicity of gluten’s main antigen, gliadin. Gliadin has agglutinating activity, reduces F-actin content, inhibits cell growth, induces apoptosis, alters redox equilibrium and causes a rearrangement of the cytoskeleton through the zonulin pathway and the loss of TJ competence in the gastrointestinal mucosa…Gliadin causes zonulin release by binding to the CXCR3 receptor in intestinal cells via a MyD88-dependent pathway and subsequent transactivation of EGFR by PAR2, leading to small intestine TJ disassembly.” See more on intestinal barrier damage from gluten in non-celiac gluten sensitivity below.
  6. Microbial transglutaminase (mTG): used to modify the function of proteins in food products. ” There are more than half a dozen ways “…mTG may increase intestinal permeability by cross-linking amino acids or protein.”
  7. Nanoparticles: “Permeation studies showed that nanoparticles opened the tight junctions of monolayer Caco-2 cells and increased paracellular transportation. The signaling mechanism initiating the cascade of disruption of the TJ, was elucidated recently…”

Eat clean natural foods to preserve the intestinal barrier and calm autoimmunity

The bottom line is that there are several mechanisms by which industrial food additives can damage the intestinal barrier and contribute to loss of immune tolerance. The authors conclude:

“The food and beverage industries are constantly changing and transforming our food composition through new food processing technologies. The result is neo-linked, transformed molecules and delivery systems, representing intestinal mucosal load with altered physicochemical and immunogenic properties…Glucose, salt, emulsifiers, organic solvents, gluten, mTG, and nanoparticles are extensively and increasingly used by these industries to improve the qualities of the food (as claimed by manufacturers and some consumers). However, all these food additives increase intestinal permeability by bringing about TJ paracellular transfer. In fact, TJ dysfunction is common in multiple AD [autoimmune disease] and the central part played by the TJ in AD pathogenesis has been extensively described.”

 Glyphosate (Roundup®) promotes celiac disease and gluten intolerance

Interdisciplinary ToxicologyThe herbicide glyphosate (Roundup®) persists in the wheat kernel when used as a ‘dessicant’ to speed harvesting and causes damage to the intestinal barrier as described in an extensive paper published in Interdisciplinary Toxicology. The authors note:

Celiac disease is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on gut bacteria. Characteristics of celiac disease point to impairment in many cytochrome P450 enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in iron, cobalt, molybdenum, copper and other rare metals associated with celiac disease can be attributed to glyphosate’s strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine and selenomethionine associated with celiac disease match glyphosate’s known depletion of these amino acids.”

Glyphosate causes gut dysbiosis

Disruption of the gut microbial ecology is one mechanism by which the intestinal barrier is compromised leading to loss of tolerance to gluten (and other foods).

“…a broad-spectrum herbicide, considered to be nearly nontoxic to humans…Glyphosate suppresses 5-enolpyruvylshikimic acid-3-phosphate synthase (EPSP synthase), the rate-limiting step in the synthesis of the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, in the shikimate pathway of bacteria, archaea and plants…Humans do not possess this pathway, and therefore we depend upon our ingested food and our gut microbes to provide these essential nutrients. Glyphosate…has been shown to disrupt gut bacteria in animals, preferentially killing beneficial forms and causing an overgrowth of pathogens….celiac disease is associated with a reduced presence in the gut of commensal bacteria such as Lactobacilli and Bifidobacteria, which are known to be preferentially killed by glyphosate, and with an overabundance of C. difficile, which is known to be promoted by glyphosate exposure.”

 Pesticides and herbicides—it’s much worse than it already seems

BioMed Research InternationalWhen the designated active principle (AP) is combined with the other chemicals in a commercial formulation toxicity is greatly increased. Studies done to assess the toxicity of pesticides typically test the main active ingredient, such as glyphosate in Roundup® (hence it’s classification as relatively non-toxic to humans). In practice, however, these primary agents are applied as compound formulations. The authors of a study published in BioMed Research International compared the toxicity of the ‘active ingredients’ of nine major pesticides, herbicides and fungicides with that of the commercial compound formulations actually used in practice. They state:

Pesticides are used throughout the world as mixtures called formulations. They contain adjuvants, which are often kept confidential and are called inerts by the manufacturing companies, plus a declared active principle, which is usually tested alone. We tested the toxicity of 9 pesticides, comparing active principles and their formulations, on three human cell lines (HepG2, HEK293, and JEG3). Glyphosate, isoproturon, fluroxypyr, pirimicarb, imidacloprid, acetamiprid, tebuconazole, epoxiconazole, and prochloraz constitute, respectively, the active principles of 3 major herbicides, 3 insecticides, and 3 fungicides. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities.”

The results of their investigation are hair-raising:

“Fungicides were the most toxic from concentrations 300–600 times lower than agricultural dilutions, followed by herbicides and then insecticides, with very similar profiles in all cell types…Most importantly, 8 formulations out of 9 were up to one thousand times more toxic than their active principles. Our results challenge the relevance of the acceptable daily intake for pesticides because this norm is calculated from the toxicity of the active principle alone. Chronic tests on pesticides may not reflect relevant environmental exposures if only one ingredient of these mixtures is tested alone.”

Commenting on these principles and the current regulatory practice in general:

“Adjuvants in pesticides are generally declared as inerts, and for this reason they are not tested in long-term regulatory experiments. It is thus very surprising that they amplify up to 1000 times the toxicity of their APs in 100% of the cases where they are indicated to be present by the manufacturer. In fact, the differential toxicity between formulations of pesticides and their APs now appears to be a general feature of pesticides toxicology. As we have seen, the role of adjuvants is to increase AP solubility and to protect it from degradation, increasing its half-life, helping cell penetration, and thus enhancing its pesticidal activity and consequently side effects. They can even add their own toxicity. The definition of adjuvants as “inerts” is thus nonsense; even if the US Environmental Protection Agency has recently changed the appellation for “other ingredients,” pesticide adjuvants should be considered as toxic “active” compounds.”

Regarding Roundup® in particular:

“It is commonly believed that Roundup is among the safest pesticides. This idea is spread by manufacturers, mostly in the reviews they promote, which are often cited in toxicological evaluations of glyphosate-based herbicides. However, Roundup was found in this experiment to be 125 times more toxic than glyphosate. Moreover, despite its reputation, Roundup was by far the most toxic among the herbicides and insecticides tested. This inconsistency between scientific fact and industrial claim may be attributed to huge economic interests, which have been found to falsify health risk assessments and delay health policy decisions.”

Contributing to the vast increase in autoimmunity

There are multiple environmental factors contributing to the widespread increase in both undifferentiated and full-blown autoimmune disorders in clinical practice. Damage to the intestinal barrier is one of the most important. This data highlights the importance of consuming natural, unprocessed, non-toxic organic food for immune system health, with implications for regulatory and public health policy.

Gluten free labeled foods not always gluten free

Journal of Food ProtectionGluten free labeling is, sadly, not a guarantee of safety for those with celiac disease or non-celiac gluten sensitivity as demonstrated in a study recently published in the Journal of Food Protection. The authors state:

“Gluten is the main storage protein in grains and consists of gliadin and glutenin occurring in the same ratio. Persons suffering from intolerances, including celiac disease, must avoid foods containing gluten or products containing wheat, barley, and rye… This study was designed to determine the concentrations of gluten in foods labeled “gluten free” available in the United States.”

Gluten found in diverse products

Many sources of gluten are far from obvious and it may not occur to question whether a product is gluten free.

“Gluten is found not only in all products made with wheat, rye, and barley but also as an ingredient in foods including meat, sausages, soups, and ready-to-eat meals. Due to its physicochemical characteristics, gluten is used in food products to modify both texture, e.g., as a thickener to improve texture and water or fat retention, and form, e.g., to increase the extensibility. Gluten can also be used as an animal protein substitute in meat products to reduce manufacturing costs. Furthermore, gluten and wheat starch are found in some drugs as a filler.”

 Standards for ‘Gluten Free’ labeling

There is a significant difference between gluten free and ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’.

“To be labeled ‘‘gluten free,’’ products must contain less than 20 mg/kg gluten, i.e., equivalent to 10 mg/kg gliadin, while foods labeled as ‘‘foods specially processed to reduce gluten content’’ or ‘‘very low gluten’’ must comply with levels between 20 and 100 mg/kg. In October 2013, the U.S. Food and Drug Administration (FDA) issued a final rule to define the term ‘‘gluten free’’ for voluntary use in the labeling of foods. According to the final rule, gluten free means that the food bearing the claim does not contain (i) an ingredient that is a gluten-containing grain (e.g., spelt wheat), (ii) an ingredient that is derived from a gluten-containing grain and has not been processed to remove gluten (e.g., wheat flour), or (iii) an ingredient that is derived from a gluten-containing grain and has been processed to remove gluten (e.g., wheat starch) if the use of that ingredient results in the presence of 20 mg/kg or more gluten in the food, or it means that the food (iv) inherently does not contain gluten, and food with any unavoidable presence of gluten that is below 20 mg/kg gluten can be labeled as gluten free.”

Cross-contamination

Cross-contamination of products inherently gluten free can occur in production, transportation and storage.

“Cross-contamination of inherently gluten-free foods can occur at all stages of the food chain, including when they are grown, harvested, and/or processed. Comingling of grain in the field can occur because of crop rotation with wheat, barley, or rye if they are grown next to or in rotation with these grains. It is possible that seeds of the gluten-containing grains will linger in the soil and, as a result, some of the gluten-containing grain may be collected during the same harvest with the inherently gluten-free grain. Sharing of storage facilities where relevant, such as in grain elevators, can result in co-mingling of grains. Further, using the same transportation vehicles for moving the grains to the processing site and sharing of processing facilities and equipment within those facilities can also result in cross-contamination. The presence of wheat in oats is a good example of on-farm cross-contamination…If cross-contamination occurs at any stage in the food chain, undeclared glutens can end up in the processed food products…A few small studies have shown that contamination may occur in gluten-free foods or inherently gluten-free grains and their milled fractions, such as oats, millet flour, and sorghum flour. In addition, gluten has been detected in rice-, corn-, oat-, and buckwheat-based foods with or without the gluten-free label. Hence, the aim of the present study was to analyze foods in the U.S. market labeled gluten free for gluten contamination.”

So the authors randomly collected 78 commercially available samples labeled gluten free were from different local markets in Moscow, Idaho and analyzed them for gliadin content by competitive enzyme-linked immunosorbent assay. Their data engenders concern and vigilance for anyone who truly needs to avoid gluten:

Breakfast cereals were the most frequently contaminated

“Based on the gluten levels of samples, 48 of the 78 (61.5%) products contained gluten below the limit of quantification (less than 10 mg/kg gluten). Fourteen of the 78 (17.9%) products contained a detectable amount of gluten ranging from 10.9 to 18.7 mg/kg. Sixteen (20.5%) of the 78 would not be considered gluten free under the proposed FDA rules for gluten-free labeling. Among other parameters, foods labeled gluten free must contain <20 ppm gluten to be labeled gluten free. The gluten contamination frequency was highest in breakfast cereal (62.5%), followed by bread (37.5%), pasta (23.1%), snack food (13.3%), and baking mix (11.1%).”

Rice and corn products are attractive to those avoiding gluten but are not free of treachery:

“Being the most popular ingredients in gluten-free products, rice and corn might be considered to be safer cereal-based foods for CD patients…of the 16 gluten-contaminated samples, the most contaminated gluten-free food samples were made with rice, corn, or mixed grains, including seven rice-based foods, three corn-based foods, and six mixed-grain-based foods. Moreover, all of 6 mixed-grain-based samples included rice flour. According to our data, the most contaminated samples labeled gluten free were made from rice or corn and the levels of contamination were less than 50 mg/kg gluten.”

 Gluten free mislabeling is a world-wide problem

The concern is similar for Europeans and Canadians:

“A few previous studies have examined gluten in gluten- free foods and reported cross-contamination of 14 to 22% in inherently gluten-free foods and 46% in products based on gluten-free wheat starch produced by a deglutination process. According to Valde ́s et al., a study of more than 3,000 gluten-free foods in Europe showed that one third had gluten levels higher than 20 mg/kg, which is above the gluten-free threshold. Another study reported that 5% of 1,583 different products labeled as gluten free contained gluten. In a study of Canadian cereal foods, about 10% of the 77 gluten-free foods were contaminated with gluten.”

Bottom line on gluten free labeling

More rigorous standards of compliance are necessary to ensure the dependability of products labeled or presumed to be gluten free. A product such as rice or corn is being intrinsically gluten free is not sufficient to confirm that it is.

Products made from inherently gluten-free crops that are labeled gluten free but are not tested to be gluten free may be deemed misbranded if the label implies that all inherently gluten-free crops are free of gluten, since these inherently gluten-free grains, such as rice, corn, and buckwheat, can be contaminated with gluten.”

The authors conclude by recommending the measurement of gluten in all grain based products:

“Under the proposed FDA rule for labeling of foods as gluten free, manufacturers who voluntarily choose to label their single-ingredient grain products as gluten free will have to imply to consumers that since all inherently gluten-free grains, such as rice, corn, millet, buckwheat, and sorghum, are gluten free by nature, their products using these grains are gluten free; this does not guarantee, though, that there will be no gluten contamination. …Statements such as ‘‘all millet is gluten free’’ can be misleading and potentially harmful to the consumer with CD who requires a strict gluten-free diet. Therefore, the determination of gluten in all grain-based products, including those made with inherently gluten-free grains or ingredients, is recommended. This study shows that there is no guarantee that products labeled gluten free are in fact gluten free, which could be harmful for patients with CD.”

What should practitioners and patients do?

Avoiding gluten is necessary in cases of celiac disease or non-celiac gluten sensitivity but is not recommended in the absence of objective evidence of intolerance. The clinical manifestations of both can be widely diverse and a high degree of suspicion is warranted, not only with chronic unexplained gastrointestinal complaints but also a wide range of disorders with an autoimmune component. A comprehensive Wheat/Gluten Proteome Reactivity & Autoimmunity™ panel is necessary to avoid false negatives.

When indicated diligence in remaining gluten free is warranted, but it is unrealistic to expect that inadvertent exposure will never occur. Overall case management mandates a treatment plan that includes support for immune tolerance and regulation of inflammation. Additionally, supplementation during times of heightened risk (such as eating meals outside the home) with enzymes that break down gliadin and wholesome natural anti-inflammatory agents can significantly ameliorate the effect of inadvertent exposure.

Neuropsychiatric illness in non-celiac gluten sensitivity

Gastroenterology Research and PracticeNeuropsychiatric illness can result from neuroinflammation due to a variety of causes. Recent studies offer more evidence that depression and other neuropsychiatric disorders can be a manifestation of non-celiac gluten sensitivity. A paper published in Gastroenterology Research and Practice explores the pathophysiologic mechanisms by which gluten sensitivity can present as a variety of neuropsychiatric conditions in the absence of celiac disease. The authors note:

“…emerging scientific literature has noted a link between gluten ingestion and symptomatology from nearly every organ system, often in the absence of classic histological findings of CD on intestinal biopsy…It has been hypothesized for quite some time that gluten sensitivity may also impair central nervous system functioning. In 1996, Hadjivassiliou et al. found a significant difference in the prevalence of patients with positive antigliadin antibodies amongst those with neurological symptoms of unknown cause (57%) compared to a control group of healthy patients (12%). Amid the 57% who did have positive antibody titres, the majority did not demonstrate histological evidence diagnostic of celiac disease. In a 2010 article published in Lancet Neurology, Hadjivassiliou and colleagues published additional support for the link between gluten sensitivity and neurological manifestations, including ataxia, neuropathy, encephalopathy, epilepsy, myopathy, and myelopathy. Similar results continue to be reported in the medical literature and give credence to the association between gluten sensitivity and neurological symptoms in the absence of celiac disease.”

They present an illustrative case of a 23-year-old woman with a longstanding history of auditory and visual hallucinations that completely resolved by avoiding gluten, and would recur when provoked by a gluten exposure. The authors state:

“There have been multiple reports linking celiac disease and/or gluten sensitivity with mental health manifestations including isolated psychosis and full blown schizophrenia. As in our case history, these cases report complete symptom resolution with removal of gluten. There is also evidence of frequent gluten sensitivity (but not celiac disease) in schizophrenic patients. Furthermore, similar reports are published dealing with various other neurological manifestations in response to gluten exposure including “idiopathic” ataxia and neuropathies, epilepsy, mood swings, and autism. In addition to neuropsychiatric phenomena, there are reports of other organ system involvement including reversible cardiomyopathy, resolved primary infertility, uveitis, and osteoporosis in relation to the gluten exposure in celiac disease.”

Regarding causation in autoimmunity or sensitivity related illness (SRI), the authors discuss a topic of premiere clinical importance: toxicant induced loss of tolerance (TILT):

“This mechanism of disease has recently been described and discussed in the scientific literature, whereby accumulated toxic insults often resulting from adverse chemical exposures lead to hypersensitivity and impaired tolerance of the immune system (known as toxicant induced loss of tolerance or “TILT”). With growing attention in the medical literature to the escalating problem of toxicant exposure and bioaccumulation within contemporary society, this mechanism of illness has become compelling indeed. Notable groups such as the World Health Organization and the Centers for Disease Control have recently drawn attention to the reality of ubiquitous toxicant exposures and the chemical erosion of human health associated with toxicant accrual within the human body.”

Sensitivity related illness- a causative pathway to multimorbidityAs for TILT in gluten-induced neuropsychiatric disease:

After the bioaccumulation of a toxicant burden and the consequent immune dysregulation, seemingly insignificant environmental triggers can lead to the release of proinflammatory cytokines, antibodies, chemokines, and interleukins and produce a variety of symptoms, including neuropsychiatric issues, in the affected patient. Gluten is one such common trigger, and is hypothesized to be the culprit in the above case report. With the ability of SRI to induce multisystem manifestations and with its increasing and widespread prevalence, this mechanism of disease is the preferred explanation of the authors for gluten-induced neuropsychiatric disease…This mechanism also explains the apparently inexplicable onset of gluten sensitivity in patients who were previously well and fully tolerant of gluten and accounts for the reversal of gluten sensitivity in some patients who are successful in eliminating their toxicant burden.”

Commenting in conclusion on their case presentation:

“The individual in the presented case demonstrates a clear sensitivity to gluten with remission of longstanding hallucinations with gluten elimination and relapsing symptoms upon reintroduction of dietary gluten. The scientific literature contains numerous case reports where unexplained symptoms are significantly improved and, at times, completely resolved when similar dietary changes are made. Therefore, when clinicians are faced with physical symptoms that have not been otherwise explained, celiac testing may be warranted. If this is found to be negative, the possibility of NCGS and SRI ought to be considered. Although NCGS cannot be definitively diagnosed at this time based on laboratory investigations, a trial of gluten elimination should be incorporated as part of the clinical assessment and potential management.”

Clinical note: non-celiac gluten sensitivity (NCGS) can now be assessed with the Wheat/Gluten Proteome Reactivity & Autoimmunity panel from Cyrex Laboratories and correlated with their Multiple Autoimmune Reactivity Screen that includes anti-brain antibodies.

The authors summarize their key points:

  1. Gluten ingestion in gluten sensitive individuals can lead to a variety of clinical presentations including psychiatric, neurological, gynecological, and cardiac symptoms.
  2. Dietary elimination of gluten may lead to complete symptom resolution.
  3. Health practitioners are advised to consider gluten elimination in patients with otherwise unexplained symptoms.
  4. Non-celiac gluten sensitivity may be a part of a constellation of symptoms resulting from a toxicant induced loss of tolerance (TILT).

 Depression In Non-Celiac Gluten Sensitivity

Alimentary Pharmacology & TherapeuticsA recent clinical trial investigating depression in non-celiac gluten sensitivity was recently published in Alimentary Pharmacology and Therapeutics that demonstrated depression in the absence of gastrointestinal symptoms. The authors state:

“Current evidence suggests that many patients with self-reported non-coeliac gluten sensitivity (NCGS) retain gastrointestinal symptoms on a gluten-free diet (GFD) but continue to restrict gluten as they report ‘feeling better’.”

So they set out to discriminate between mental and gastrointestinal symptoms in NCGS by a double-blind cross-over study in which their subjects received one of three dietary challenges for 3 days, followed by a minimum 3-day washout before crossing over to the next diet ( the challenge gluten-free food was supplemented with gluten, whey (16 g/day) or not supplemented = placebo. Depression scores as assessed by the Spielberger State Trait Personality Inventory (STPI) stood out in association with gluten exposure:

Gluten ingestion was associated with higher overall STPI state depression scores compared to placebo but not whey. No differences were found for other STPI state indices or for any STPI trait measures. No difference in cortisol secretion was identified between challenges. Gastrointestinal symptoms were induced similarly across all dietary challenges.”

Clinical note: In gluten intolerance there is often cross-reactivity to bovine dairy proteins due to similarities in antigen morphology.

The authors conclude:

Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms.”

Clinical note: Practitioners should bear in mind that FODMAP (Fermentable Oligo-Di-Monosaccharides and Polyols) intolerance can coexist with non-celiac gluten sensitivity wherein the former produces gastrointestinal symptoms while the latter accounts for depression and other neuropsychiatric illness.

Hyperexcitable brain syndrome and gluten

Journal of Neurology, Neurosurgery & PsychiatryHyperexcitable brain, with potentially severe consequences, is recognized as among the gluten-related autoiimmune neurological disorders in a paper just published in the Journal of Neurology, Neurosurgery & Psychiatry. The authors state:

Hyperexcitable brain and refractory coeliac disease: a new syndrome Gluten related disorders (GRD) is the newly proposed term to encompass a spectrum of immune mediated diseases triggered by gluten ingestion. Whilst coeliac disease (gluten sensitive enteropathy) remains one of the best characterised GRD, neurological dysfunction is one of the commonest extraintestinal manifestations with a range of presentations such as cerebellar ataxia, neuropathy, sensory ganglionopathy and encephalopathy (headaches and white matter abnormalities). Neurological manifestations can occur with or without enteropathy.”

They documented the clinical and electrophysiological characteristics of this hyperexcitable brain syndrome in a severely afflicted group of seven patients:

“The 7 patients (5 male, 2 female) were identified from a cohort of 540 patients with neurological manifestations of GRD that regularly attend our gluten/neurology clinic. The mean age at onset of the neurological symptoms was 58 years (range 46 to 76). Unlike myoclonic ataxia (eg in the context of opsoclonus myoclonus ataxia syndrome) the myoclonic tremor in these patients was initially focal (face, tongue one arm and/or one leg) but then spread to affect other parts of the body. Epilepsy was a feature in 5 of the patients, 3 of which gave a history of Jacksonian march before progression to generalised seizures. In one patient the neurological presentation was with status epilepticus. All patients had a mild degree of limb ataxia and more prominent gait ataxia. Electrophysiology showed evidence of cortical myoclonus. Four had a phenotype of epilepsia partialis continua and three later developed more widespread jerking. There was clinical, imaging and/or pathological evidence of cerebellar involvement in all cases but this was not the main source of disability by contrast to patients with gluten ataxia, where cerebellar ataxia is the most disabling feature.”

Neuroinflammation due to celiac and non-celiac gluten sensitivity can cause a range of neurological disorders. These cases are notable for their severity and association with refractory celiac disease (CD that fails to heal after gluten is eliminated). They are especially troubling because the damage and hyperexcitable brain symptoms remained after gluten was eliminated:

“All patients adhered to a strict gluten–free diet with elimination of gluten–related antibodies, despite which there was still evidence of enteropathy in keeping with refractory celiac disease (type 1 in 5 and type 2 in 2). One of the 2 patients with type 2 refractory enteropathy died 13 years later from metastatic enteropathy–associated lymphoma. The other died 1 year after the neurological presentation from presumed enteropathy associated lymphoma. Four were treated with mycophenolate and one in addition with rituximab and IV immunoglobulins. Whilst their ataxia improved the myoclonus remained the most disabling feature of their illness with a tendency to spread and affect other parts of the body.”

Clinical note: Practitioners should not underestimate the potential severity of gluten-associated neuroinflammation. We should be alert to the far more common milder manifestations of hyperexcitable brain that can present as sleep disorders, anxiety, attention disorders, sympathetic nervous system hyperarousal syndromes, etc. The authors conclude:

“This syndrome whilst rare, appears to be the commonest neurological manifestation of refractory CD. The clinical manifestations extend from focal reflex jerks to epilepsia partialis continua, covering the whole clinical spectrum of cortical myoclonus. This entity is possibly under–diagnosed and difficult to treat.”

Non-celiac gluten sensitivity

American Journal of GastroenterologyCeliac disease is but one consequence of autoimmunity or autoinflammation triggered by gluten among a host of others better characterized by the term non-celiac gluten sensitivity (NCGS). The lack of standardization in terminology has obscured this fact, so two recent papers that help to clear the air are welcome. The authors of a study in published in The American Journal of Gastroenterology state:

Non-celiac wheat sensitivity (WS) is considered a new clinical entity. An increasing percentage of the general population avoids gluten ingestion. However, the real existence of this condition is debated and specific markers are lacking. Our aim was thus to demonstrate the existence of WS and define its clinical, serologic, and histological markers.”

They focused on irritable bowel syndrome (IBS), and examined data for subjects who had been diagnosed with WS using a double-blind placebo-controlled (DBPC) challenge over a ten year period. For controls they used one hundred celiac disease (CD) and fifty IBS patients. Their data showed that wheat exposure could trigger allergic reactions different from celiac disease:

“Two hundred and seventy-six patients with WS, as diagnosed by DBPC challenge, were included. Two groups showing distinct clinical characteristics were identified: WS alone (group 1) and WS associated with multiple food hypersensitivity (group 2). As a whole group, the WS patients showed a higher frequency of anemia, weight loss, self-reported wheat intolerance, coexistent atopy, and food allergy in infancy than the IBS controls. There was also a higher frequency of positive serum assays for IgG/IgA anti-gliadin and cytometric basophil activation in “in vitro” assay. The main histology characteristic of WS patients was eosinophil infiltration of the duodenal and colon mucosa. Patients with WS alone were characterized by clinical features very similar to those found in CD patients. Patients with multiple food sensitivity were characterized by clinical features similar to those found in allergic patients.”

This alerts those not already aware of the fact that gluten/wheat sensitivity can derange the gastrointestinal mucosa without necessarily being characterized as celiac disease. The authors conclude:

Our data confirm the existence of non-celiac WS as a distinct clinical condition. We also suggest the existence of two distinct populations of subjects with WS: one with characteristics more similar to CD and the other with characteristics pointing to food allergy.”

GUTThe authors of another paper recently published in GUT (An International Journal of Gastroenterology and Hepatology) cast a wider net to encompass more of the autoimmune disorders associated with gluten sensitivity and further clarify the distinction between celiac disease and non-celiac gluten sensitivity. The authors recognize that…

CD and related diseases are now common chronic diseases in children and adults, and increased diagnosis has led to a proliferation of research activities. As with many other chronic conditions, the boundaries of CD are not always clear, with the consequence that there is considerable confusion and a lack of consensus regarding diagnostic criteria of CD and related conditions…the scientific community has come to recognise that there is a spectrum of disorders related to gluten ingestion.”

This range of disorders has not been defined by a settled nomenclature, so…

“Due to a lack of common definitions for the spectrum of terms and disorders related to CD, a multidisciplinary task force of 16 physicians from seven countries with particular expertise in diagnosis and treatment of CD proposes the following definitions for the variety of vague and often confusing terms currently in use in the literature. These definitions are based on thorough literature reviews, a discussion in Oslo at the 14th International Coeliac Disease Symposium in June 2011, and agreement on consensus statements by a web survey and phone conferences. We refer to our definitions as the ‘Oslo definitions’.”

Disorders associated with gluten sensitivity span a wide spectrum…

“In addition to ‘CD’, the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies.”

The authors suggest the term gluten sensitivity be replaced by non-celiac gluten sensitivity:

“In some papers the term gluten sensitivity is used synonymously with CD. Other papers used the concept of gluten sensitivity as an umbrella term to include CD and other conditions related to gluten ingestion, such as DH [dermatitis herpetiformis], gluten ataxia and NCGS. Most recently several authors employed the term gluten sensitivity to describe a condition in which symptoms are triggered by gluten ingestion, in the absence of TTG or EMA antibodies and enteropathy, with variable HLA status and variable anti-gliadin (AGA) presence. It is important to distinguish CD from less well characterised diseases related to gluten ingestion. We therefore recommend that the term gluten sensitivity should not be used and that NCGS [Non-celiac gluten sensitivity] be used instead.”

Further defining non-celiac gluten sensitivity…

“The term NCGS relates to one or more of a variety of immunological, morphological or symptomatic manifestations that are precipitated by the ingestion of gluten in people in whom CD has been excluded…NCGS is a condition in which gluten ingestion leads to morphological or symptomatic manifestations despite the absence of CD. As opposed to CD, NCGS may show signs of an activated innate immune response but without the enteropathy, elevations in tTG, EMA or DGP antibodies, and increased mucosal permeability characteristic of CD. Recently, in a double-blind randomised trial, Biesiekierski et al showed that patients with NCGS truly develop symptoms when eating gluten.”

Clincial note: Practitioners must bear in mind that the absence of celiac disease does not rule out an autoimmune or autoinflammatory disorder triggered by gluten consumption.