Indole-3-propionic acid protects medium-diversity colitic mice via barrier enhancement preferentially over anti-inflammatory effects

Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate intestinal mucosal homeostasis in specific pathogen-free (SPF)-colonized animals through distinct receptor-mediated events. Interestingly, IPA levels are reduced in patients with inflammatory bowel disease (IBD). In the current study, we assessed whether IPA could improve colitis outcomes in the absence of its production by the microbiota. To do this, colitis was induced by dextran sulfate sodium (DSS) in gnotobiotic mice colonized with the 12-member stable defined moderately diverse microbiota mouse 2 (sDMDMm2) microbial consortium, which lacks the genes required for IPA generation. We found that these mice were exquisitely sensitive to DSS compared with SPF-colonized mice. However, IPA treatment significantly increased survival. Infiltrating immune cells in the colon were not altered by IPA treatment nor were there any remarkable changes in local and systemic inflammatory mediator levels. Nevertheless, IPA treatment changed the composition of the fecal microbiota and enhanced intestinal barrier function, demonstrated by a reduction in FITC-dextran flux and retainment of a bioluminescent <i>Escherichia coli</i> within the lumen of colitic mice. Together, our data suggest that IPA treatment in the context of its systemic depletion enhances barrier function and enhances survival in the presence of established inflammation. These data support continued assessment of IPA as a potential treatment for IBD.<b>NEW & NOTEWORTHY</b> Indole-3-propionic acid (IPA) is a metabolite produced by the intestinal microbiota that has been shown to elicit beneficial effects in the gastrointestinal (GI) tract that include regulating intestinal barrier function, reducing inflammation, and controlling immune responses that lead to fibrosis. In patients with inflammatory bowel disease (IBD), IPA levels are reduced. In the current study, we found that treating mice with IPA at the peak of intestinal inflammation improved clinical outcomes and disease.