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Is Nonceliac Gluten Sensitivity Real?

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When patients with nonceliac gluten sensitivity (NCGS) unknowingly ingested small amounts of gluten for 1 week, they developed more severe abdominal pain and bloating that patients who ingested a matched placebo, researchers report in the September issue of Clinical Gastroenterology and Hepatology. The study provides evidence for a form of gluten sensitivity without an autoimmune or allergic basis.

NCGS is characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food in people without wheat allergy or celiac disease. However, there is no clearly defined mechanism for this disorder or biomarkers that can be used in diagnosis, so its existence as a discrete entity has been questioned.

Most information on NCGS has been obtained from patients mostly self-reported to be gluten sensitive, and nobody knows how many symptoms in these individuals are actually caused by gluten. Antonio Di Sabatino et al therefore performed a double-blind, placebo-controlled, cross-over, gluten-challenge trial of 59 patients who believed gluten to be the cause of their intestinal or extra-intestinal symptoms, but for whom celiac disease and gluten allergy had been ruled out. Patients with sensitivity to dietary FODMAPs were excluded from the study.

After a 1-week run-in period in which all subjects adhered to gluten-free diets, they were randomly assigned to groups given 1 week of capsules containing purified wheat gluten (4.375 g/day, equivalent to ∼2 slices of white bread) or 1 week of placebo capsules (containing 4.375 g rice starch). The authors performed preliminary studies to ensure that the capsules were indistinguishable.

Subjects then spent 1 week without exposure (a washout period) and crossed over to the other group another week. They reported symptoms after each week.

Di Sabatino et al found that patients in the gluten group had significantly more severe symptoms than in the placebo group. Two of 15 intestinal symptoms measured (abdominal bloating and abdominal pain), and 3 of 13 extra-intestinal symptoms measured (foggy mind, depression, and apthous stomatitis), were significantly more severe when the patients received gluten than the placebo.

These findings appear to support the existence of NCGS as a distinct disorder. However, the authors point out that the severity of most intestinal and extra-intestinal symptoms measured was similar when patients received gluten vs when they received the placebo. This could mean that NCGS is associated with only specific symptoms.

Further studies are therefore needed to better characterize NCGS, identify reliable biomarkers, and determine mechanisms of pathogenesis. Di Sabatino et al say that preliminary findings from analyses of cytokines in the duodenum of the subjects do not seem to support the involvement of innate or adaptive immune mechanisms in gluten sensitivity.

In an editorial that accompanies the article Benjamin Lebwohl and Daniel A. Leffler write that although gluten caused more severe symptoms than placebo, this overall finding was mediated by a small group of subjects (3 subjects); most of the subjects had no or only modest symptoms, compared with placebo. Also, the study did not include a control group of subjects without gluten sensitivity.

Lebwohl and Leffler state that this trial, like its predecessors, seems only to contribute to the uncertainty about NCGS. However, it does provide evidence that NCGS is distinct from irritable bowel syndrome (IBS) in that extra-intestinal symptoms are prominent and respond to dietary modification.

The editorial emphasizes the difficulty in performing dietary intervention trials—particularly when attempting to define an ill-understood clinical entity. Lebwohl and Leffler explain that trials that involve dietary changes are more complicated and unpredictable than drug studies because foods are complex, and any prescribed dietary change inevitably leads to secondary dietary changes.

Regardless, it is counterproductive to debate whether NCGS is real, say Lebwohl and Leffler—many NCGS patients are in distress and require medical attention. This involves ruling out celiac disease, testing for additional food intolerances or gastrointestinal conditions, and explaining the latest research on what we do and do not know about this evolving entity.

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Kristine Novak

Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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