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Eur J Immunol. 2018 Jul;48(7):1235-1247. doi: 10.1002/eji.201747122. Epub 2018 May 17.

Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice.

Author information

1
Department of Comparative Pathobiology and Purdue Research Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
2
Laboratory of Immunology and Hematopoiesis, Department of Pathology and Mary H Weiser Food Allergy Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
3
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

Abstract

The intestinal immune system is regulated by microbes and their metabolites. The roles of gut microbial metabolites in regulating intestinal inflammation and tumorigenesis are incompletely understood. We systematically studied the roles of short-chain fatty acids (SCFAs) and their receptors (GPR43 or GPR41) in regulating tissue bacterial load, acute versus chronic inflammatory responses, and intestinal cancer development. SCFA receptor-, particularly GPR43-, deficient mice were defective in mounting appropriate acute immune responses to promote barrier immunity, and developed uncontrolled chronic inflammatory responses following epithelial damage. Further, intestinal carcinogenesis was increased in GPR43-deficient mice. Dietary fiber and SCFA administration suppressed intestinal inflammation and cancer in both GPR43-dependent and independent manners. The beneficial effect of GPR43 was not mediated by altered microbiota but by host tissue cells and hematopoietic cells to a lesser degree. We found that inability to suppress commensal bacterial invasion into the colonic tissue is associated with the increased chronic Th17-driven inflammation and carcinogenesis in the intestine of GPR43-deficient mice. In sum, our results reveal the beneficial function of the SCFA-GPR43 axis in suppressing bacterial invasion and associated chronic inflammation and carcinogenesis in the colon.

KEYWORDS:

Colon cancer; Dietary fiber; Inflammation; Short-chain fatty acids

PMID:
29644622
PMCID:
PMC6310065
DOI:
10.1002/eji.201747122
[Indexed for MEDLINE]
Free PMC Article

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