Randomised Clinical Trial

Gluten May Cause Depression in Subjects With Non-Coeliac Gluten Sensitivity

An Exploratory Clinical Study

S. L. Peters; J. R. Biesiekierski; G. W. Yelland; J. G. Muir; P. R. Gibson


Aliment Pharmacol Ther. 2014;39(10):1104-1112. 

In This Article

Abstract and Introduction


Background. 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'.

Aim. To investigate the notion that a major effect of gluten in those with NCGS is on mental state and not necessarily on gastrointestinal symptoms.

Methods. Twenty-two subjects (24–62 years, five male) with irritable bowel syndrome who had coeliac disease excluded but were symptomatically controlled on a GFD, undertook a double-blind cross-over study. Participants randomly received one of three dietary challenges for 3 days, followed by a minimum 3-day washout before crossing over to the next diet. Challenge gluten-free food was supplemented with gluten (16 g/day), whey (16 g/day) or not supplemented (placebo). End-points included mental state as assessed by the Spielberger State Trait Personality Inventory (STPI), cortisol secretion and gastrointestinal symptoms.

Results. Gluten ingestion was associated with higher overall STPI state depression scores compared to placebo [M = 2.03, 95% CI (0.55–3.51), P = 0.010] but not whey [M = 1.48, 95% CI (−0.14 to 3.10), P = 0.07]. 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.

Conclusions. 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.


Gluten, the major protein of wheat, has been established as the causative agent in the development of coeliac disease, characterised by small intestinal injury and immunological activation.[1] Gluten has also been implicated as a causal factor in the development of chronic functional gastrointestinal symptoms similar to those classified as irritable bowel syndrome (IBS).[2] In fact, non-coeliac gluten sensitivity (NCGS) has been proposed as a defined entity in which IBS-like symptoms markedly improve on a gluten-free diet (GFD), but coeliac disease has been excluded.[3,4] However, understanding of this putative entity remains poor and controversial. Several descriptions of it have included patients with intraepithelial lymphocytosis in the duodenum and evidence of immunological activation that potentially might be part of the spectrum of coeliac disease.[5–8] Furthermore, descriptions of the entity often do not take into account the potential for symptomatic improvement by reduction in other symptom-inducing components of wheat, especially fructans, one of the short-chain poorly absorbed carbohydrates (FODMAPs).[9]

Two recent studies have challenged NCGS patients on a GFD, who had normal duodenal biopsies and/or were HLA-DQ2/8 negative, with carbohydrate-deplete gluten in a blinded fashion.[9,10] The first, a parallel group study found that patients were significantly worse with gluten for overall symptoms, pain, bloating, satisfaction with stool consistency and tiredness. No clues to the mechanisms were elucidated.[10] The second (comprising two back-to-back challenges) used a cross-over design on a low FODMAP dietary background and could find no evidence of gluten-specific triggering of symptoms in such patients.[9] Interestingly, participants opted to continue following a GFD upon study completion as they subjectively described "feeling better" (unpublished observations).

Psychological health has been extensively explored within the coeliac population, where several neurological and psychiatric illnesses are common.[11,12] Among them, a high prevalence of anxiety and depression has been reported in treated patients.[13–17] In the majority of cases, this anxiety and depression is reported particularly as a personality trait whereby the behaviours and feelings are consistent and relatively enduring.[13–17] However, a high prevalence of transitory mood state has been reported in untreated coeliac disease patients.[13] Interestingly, reversal of this effect was observed after 1 year on a GFD.[13] This observed change in temporary predisposition in coeliac patients following the removal of gluten may be similar in patients with NCGS.

Interestingly, the relationship between psychological health and NCGS has seldom been studied. One recent publication explored trait anxiety and depression in patients with NCGS where patients consumed four slices of gluten-containing white bread per day for 3 days.[17] Results revealed that patients had higher trait anxiety and depression scores at baseline compared to healthy controls but that these scores did not differ significantly following the consumption of gluten. Mood state was not explored, although mood change and other extra-intestinal symptoms including forgetfulness were common symptoms related to gluten intake reported by recently surveyed NCGS participants.[18] It may be that the reversal of mood state among this entity, not personality trait, contributes to why such patients feel better when following a GFD despite the continuation of gastrointestinal symptoms.

This concept was investigated in the current exploratory study of participants with IBS in whom coeliac disease had been excluded and a GFD had led to self-reported improvement in gastrointestinal symptoms. It was hypothesised that the ingestion of gluten by participants with NCGS would have a significant effect on mental state and not necessarily on gastrointestinal symptoms. The effects of gluten on gastrointestinal symptoms were reported in part together with those of a preceding study.[9]