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Gluten-free Diet Reduces the Risk of Irritable Bowel Syndrome: A Mendelian Randomization Analysis.

ABSTRACT: Background: Whether a gluten-free diet (GFD) is a cause of irritable bowel syndrome (IBS) remains controversial. We aim at exploring the causal relationship between gluten intake and IBS within Mendelian randomization (MR) design. Methods: We conducted a two-sample MR and selected single-nucleotide polymorphisms (SNPs) associated with GFD as instrumental variables (IVs). SNPs and genetic associations with GFD and IBS were obtained from the latest genome-wide association studies (GWAS) in Europeans (GFD: cases: 1,376; controls: 63,573; IBS: cases:1,121; controls: 360,073). We performed inverse variance weighting (IVW) as the primary method with several sensitivity analyses like MR-Egger and MR-PRESSO for quality control. The above analyses were re-run using another large dataset of IBS, as well as changing the p-value threshold when screening IVs, to verify the stability of the results. Results: The final estimate indicated significant causal association [per one copy of effect allele predicted log odds ratio (OR) change in GFD intake: OR = 0.97, 95% confidence interval (CI) 0.96 to 0.99, p < 0.01] without heterogeneity statistically (Q = 2.48, p = 0.78) nor horizontal pleiotropy biasing the causality (p = 0.92). Consistent results were found in validation analyses. Results of MR Steiger directionality test indicated the accuracy of our estimate of the causal direction (Steiger p < 0.001). Conclusion: GFD might be a protective factor of IBS. Therefore, we suggest taking a diet of lower gluten intake into account in IBS prevention and clinical practice.

SUBMITTER: Sun Y

PROVIDER: S-EPMC8660079 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).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.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-? in response to gluten than rice (unrelated to HLA genotype).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.

Project description:Background and objectiveRecently, dietary restriction of fermentable carbohydrates (a low-FODMAP diet) in combination with a gluten-free diet (GFD) has been proposed to reduce the symptoms in irritable bowel syndrome (IBS) patients. Different studies reported that IBS has been associated with dysbiosis in the gut microbiota. Additionally, a few studies have reported inflammation in the gastrointestinal (GI) system of adults with IBS. In this study, we aimed to investigate the effects of low FODMAP-gluten free diet (LF-GFD) on clinical symptoms, intestinal microbiota diversity, and fecal calprotectin (FC) level in Iranian patients with IBS.DesignIn this clinical trial study, 42 patients with IBS (Rome IV criteria) underwent LF-GFD intervention for 6 weeks. Symptoms were assessed using the IBS symptom severity scoring (IBS-SSS), and fecal samples were collected at baseline and after intervention and analyzed by quantitative 16 S rRNA PCR assay. The diversity of gut microbiota compared before and after 6 weeks of dietary intervention. FC was also analyzed by the ELISA method.ResultsThirty patients (mean age 37.8 ± 10.7 years) completed the 6-week diet. The IBS-SSS was significantly (P = 0.001) reduced after LF-GFD intervention compared to the baseline. Significant microbial differences before and after intervention were noticed in fecal samples. A significant increase was found in Bacteroidetes, and the Firmicutes to Bacteroidetes (F/B) ratio was significantly (P = 0.001) decreased after the dietary intervention. The value of FC was significantly decreased after 6 weeks of dietary intervention (P = 0.001).ConclusionsOur study suggests that patients with IBS under an LF-GFD had a significant improvement in IBS symptoms severity, with reduced FC level following normalization of their gut microbiota composition. Further rigorous trials are needed to establish a long-term efficacy and safety of this dietary intervention for personalized nutrition in IBS. Clinical Trial Registry Number: IRCT20100524004010N26.

Project description:ObjectivePotential causal associations between psychiatric disorders and irritable bowel syndrome have been demonstrated in observational studies; however, these studies are susceptible to underlying confounding and reverse causation biases. We aimed to assess the causal effects of psychiatric disorders on irritable bowel syndrome (IBS) and the potential mediators from a genetic perspective by conducting a Mendelian randomization (MR) study with mediation analysis.MethodGenetic instruments associated with psychiatric disorders, potential mediators, and IBS were obtained from large-scale genome-wide association studies (GWAS). Three MR methods - the inverse-variance weighted (IVW) method, MR-Egger method, and weighted median method, were used to investigate causal association estimates. Heterogeneity among different genetic instrumental variables (IVs) was assessed using Q tests. Additionally, the MR-PRESSO and MR-Pleiotropy methods were used to verify horizontal pleiotropy and detect outliers that might bias the results, which were removed from further analysis. Consequently, we used MR mediation analysis to investigate potential mediators in the causal associations between psychiatric disorders and IBS.ResultsMR provided evidence of the causal effects of genetically predicted broad depression, major depressive disorder (MDD), anxiety disorder, post-traumatic stress disorder (PTSD), and schizophrenia on IBS. The results of MR mediation analysis demonstrated that the reduction in acetate levels mediated 12.6% of the effects of broad depression on IBS; insomnia mediated 16.00%, 16.20%, and 27.14% of the effects of broad depression, MDD, and PTSD on IBS, respectively; and the increase in blood β-hydroxybutyrate levels mediated 50.76% of the effects of schizophrenia on IBS.ConclusionOur study confirmed the brain-gut axis involvement and potential modulators in the pathophysiology of psychiatric disorder-induced IBS from a genetic perspective, and suggests potential therapeutic targets for the disrupted brain-gut axis.

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Gluten-free Diet Reduces the Risk of Irritable Bowel Syndrome: A Mendelian Randomization Analysis.

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