Item - Research Publications, Montana State University (MSU)

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

• Alexeev, Erica E.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Lanis, Jordi M.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Kao, Daniel J.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Campbell, Eric L.  [ Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom ]
• Kelly, Caleb J.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Battista, Kayla D.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Gerich, Mark E.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]
• Jenkins, Brittany R.  [ Montana State University: Microbiology & Cell Biology ]
• Walk, Seth T.  [ Montana State University: Microbiology & Cell Biology ]
• Kominsky, Douglas J.   [ Montana State University: Microbiology & Cell Biology ]
• Colgan, Sean P.  [ Mucosal Inflammation Program and Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado ]

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.

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