Low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols Diet Improves Colonic Barrier Function and Mast Cell Activation in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Mechanistic Trial.

BACKGROUND & AIMS: A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) is the most efficacious dietary therapy for irritable bowel syndrome (IBS). However, the mechanisms by which fermentable oligosaccharides, disaccharides, monosaccharides, and polyols drive IBS pathophysiology are unclear.

METHODS

Patients with Rome IV diarrhea-predominant IBS (IBS-D) underwent barrier function evaluation pre- and post-LFD along with assessment of mast cell number and activation profile. Finally, fecal supernatants (FS) were administered intracolonically to wild-type mice with and without pharmacologic inhibition, toll-like receptor 4 (tlr4)-/- mice, and mast cell-deficient mice with/without mast cell reconstitution.

RESULTS

Of 42 patients, 34 responded to the LFD and 8 did not. Patients with IBS-D had significant improvement in colonic barrier structure and function, mast cell number, and levels of mast cell mediators post-LFD. The magnitude of physiological changes did not correlate with the magnitude of clinical response. Humanization of germ-free mice with pre-LFD feces caused barrier dysfunction and post-LFD feces did not. Similarly, pre-LFD FS caused barrier dysfunction in wild-type mice, whereas post-LFD FS did not. Lipopolysaccharide removal and TLR4 antagonism reversed pre-LFD IBS FS-induced barrier dysfunction. Barrier dysfunction was absent in tlr4-/- mice treated with pre-LFD FS. Similarly, pre-LFD IBS FS did not cause barrier dysfunction in wild-type mice treated with mast cell stabilizer or in mast cell-deficient mice. However, barrier dysfunction was inducible in mast cell-deficient mice upon reconstitution with wild-type mast cells, but not tlr4-/- mast cells.

CONCLUSIONS

Patients with IBS-D exhibited improvement in colonic barrier dysfunction, mast cell recruitment, and activation post LFD. Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols-mediated barrier dysfunction in IBS-D is mediated by direct activation of the TLR4 receptor on colonic mast cells by fecal lipopolysaccharide.

CLINICALTRIALS: gov, Number: NCT04542018.