Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 32, Pages 19376-19387Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2000047117
Keywords
gut microbiome; intestinal epithelium; colitis; inflammatory bowel disease
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Funding
- Arnold and Mabel Beckman Foundation
- President's Council for Cornell Women Affinito-Stewart Grant
- NIH [R35GM133501]
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Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites-indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde-which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.
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