Neuropsychiatric illness in non-celiac gluten sensitivity

Neuropsychiatric 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."

As 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

A 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.