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

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.