High FODMAP diet causes barrier loss via lipopolysaccharide-mediated mast cell activation.

Prashant Singh,Yawen Zhang,Jun Gao,Chung Owyang,Shi-Yi Zhou,Gintautas Grabauskas

doi:10.1172/jci.insight.146529

Prashant Singh, Yawen Zhang + Show 4 more

Open Access

https://doi.org/10.1172/jci.insight.146529

Copy DOI

Journal: JCI insight	Publication Date: Nov 22, 2021
Citations: 34	License type: CC BY 4.0

Abstract

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are carbohydrates thought to contribute to the symptoms of IBS. A diet in high in FODMAPs (HFM) induces gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), and a diet low in FODMAPs (LFM) improves symptoms in up to 60% of patients with IBS. However, the mechanism by which FODMAPs affect IBS symptoms is unclear. We showed that mice fed on a HFM diet have mast cell activation and colonic barrier loss. Using mast cell–deficient mice with and without mast cell reconstitution, we showed that HFM-mediated colonic barrier loss is dependent on TLR4-dependent mast cell activation. In in vitro studies, we demonstrated that IBS fecal supernatant stimulates mast cells significantly more compared with fecal supernatant from healthy controls. This effect of IBS fecal supernatant on mast cell stimulation is ameliorated in the absence of the TLR4 receptor and after a LFM diet. We found that a LFM diet improves colonic barrier function and reduces mast cell activation while decreasing fecal LPS levels. Our findings indicate that a HFM diet causes mast cell activation via LPS, which in turn leads to colonic barrier loss, and a LFM diet reverses these pathophysiologic mucosal changes.

Highlights

Irritable bowel syndrome (IBS) has a global prevalence of ~11% with significant negative impact on quality of life, work productivity, and economic burden on patients and healthcare[1,2,3]
Animal studies have shown that in the presence of bacterial dysbiosis and/or dietary manipulation, LPS can migrate across the colonic epithelium via a transcellular route.[37,38,39,40,41] Once LPS is on the basolateral side, it can activate TLR4 receptors on various immune cells including mast cells to release cytokines such as TNF-α, IL-1β, and IL-6 as well as proteases such as tryptase.[42,43,44] We previously showed that levels of fecal or luminal LPS is elevated in irritable bowel syndrome (IBS)-D which is consistent with findings of elevated serum LPS in these patients [33, 45]
Our study shows that a diet high in FODMAPs cause colonic mast cell activation and barrier dysfunction in rodent models and TLR4 dependent mast cell activation is critical for this FODMAP induced colonic barrier dysfunction

Summary

Introduction

Irritable bowel syndrome (IBS) has a global prevalence of ~11% with significant negative impact on quality of life, work productivity, and economic burden on patients and healthcare[1,2,3]. A diet low in FODMAPs (LFM) has been shown to improve IBS symptoms in several randomized controlled trials [12]. A recent meta -analysis pooled the data from six randomized controlled trials in which the majority of patients were of IBS-D subtype, showing an LFM diet was associated with significantly higher reduction in IBS symptom severity compared with control intervention [14]. Based on these observations, an LFM diet is often recommended as first-line therapy for IBS-D patients[15]. The mechanisms by which FODMAPs cause IBS-D symptoms are not well understood [16, 17]

Methods

Results

Conclusion