A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function

Abstract

Background & aims: Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).

Methods: We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups.

Results: Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype).

Conclusions: Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041.

Figure 1

Trial flow according to the CONSORT guidelines and baseline demographics showing comparability of the two diet treatment groups.

Figure 2

A. Diet effect on stool frequency, (* p= 0.04) form and ease of passage; the effect on stool frequency was greater in HLA-DQ2 or 8 positive patients (p=0.019). B. Mean bowel movements per day during 14-day baseline and 28-day diet treatment periods in each patient randomized to gluten free and gluten containing diets. HLA-DQ2/8 negative patients are indicated by the open symbols.

Figure 3

Small intestinal and colonic permeability by the cumulative mannitol (A) and lactulose (B) excretion at 0–2h and 8–24h, respectively. There was increased small intestinal permeability with GCD, as shown by both cumulative mannitol excretion and lactulose to mannitol ratio (ITT analysis, # p=0.028 and p=0.0012). The effect on lactulose excretion was borderline significant (* p=0.097).

Figure 4

In vitro cytokine production by peripheral blood mononuclear cells in response to stimulation with either rice (control) or gluten. Note the increased production of IL-10 and GM-CSF, and the borderline increased TNF-α in response to gluten, compared to rice.