Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor

Abstract

Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.

Strategies to Dissect Host-Microbial Immune Interactions That Determine Mucosal Homeostasis vs. Intestinal Inflammation in Gnotobiotic Mice

“…These biologic activities were PXR-dependent. Alexeev et al reported that IPA was decreased in the serum of UC patients, with levels negatively associated with disease activity, and also in the serum and colons of SPF mice following DSS-induced colonic injury (71). Likewise, IPA is decreased in feces of patients with CD (51).…”

“…Likewise, IPA is decreased in feces of patients with CD (51). Alexeev et al showed that E. coli metabolites of tryptophan induced expression of the IL-10 receptor subunit (IL10R 1 ) in colon cancer-derived T84 epithelial cells (71). GF mice monoassociated with E. coli WT K12 had elevated cecal levels of indoles and increased colonic epithelial IL10R 1 expression, while E. coli K12 deleted for the tryptophanase A gene had negligible cecal indole concentrations and no induction of colonic IL10R 1 gene expression over GF levels.…”

Protective effects of bifidobacteria against enteropathogens

“…Therefore, in order to maintain good health, controlling gut environment balance may be effective to maintain a good health status in humans. Recent studies have also found that the gut microbiota produces a large variety of metabolites such as short‐chain fatty acids (SCFAs) (Flint et al ., ; den Besten et al ., ), trimethylamine (Wang et al ., ), indole metabolites (Rothhammer et al ., ; Alexeev et al ., ), vitamins (LeBlanc et al ., ), polyamines (Kibe et al ., ) and secondary bile acids (Wahlström et al ., ). These molecules play important roles to maintain good health and suppress onset of various diseases in the host.…”

Old Friends, immunoregulation, and stress resilience

“…Mechanistically, microbiota can directly modify tryptophan metabolism via de novo synthesis of 5-HT [394]. The microbiota can also metabolize tryptophan into a number of bacterially derived indole metabolites that act at the aryl hydrocarbon receptor, resulting in immunoregulation and protection of the mucosa from damage [6, 217, 238]. Furthermore, microbial-derived SCFA is able to indirectly promote the production of 5-HT from epithelial cells in the gut [340].…”