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A Molecular Mechanism For Suppression Of Colonic Inflammation By Gut Bacteria
Author(s) -
Gurav Ashish,
Singh Nagendra,
Ganapathy Vadivel
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1156.6
Subject(s) - butyrate , azoxymethane , inflammation , immune system , propionate , colorectal cancer , cancer research , colitis , downregulation and upregulation , ulcerative colitis , immunology , cancer , chemistry , medicine , biochemistry , disease , fermentation , gene
Ulcerative colitis is associated with colonic inflammation and increases colon cancer risk. Short‐chain fatty acids (SCFAs; acetate, propionate, and butyrate) are produced in colon by bacterial fermentation of dietary fibers, which protect against inflammation and cancer in colon. Our aim was to determine the role of these bacterial metabolites in colonic inflammation and colon cancer at molecular level. Dendritic cells (DCs) in colon extend their cellular processes across epithelial tight junctions to sample the luminal contents for immunogens, consequently initiating appropriate T and B cell mediated immune response. We hypothesized that SCFAs induce tolerogenic immune response in colon. Our studies show that DCs, when exposed to butyrate and propionate, but not to acetate, upregulate indoleamine 2,3‐dioxygenase (IDO) and that the ability of these two SCFAs to inhibit HDACs is responsible for this action. This process is dependent on Slc5a8, a transporter for SCFAs. Pharmacological inhibition of IDO in mice subjected to azoxymethane/dextran sulfate‐mediated colorectal carcinoma enhances colon cancer incidence. We conclude that propionate and butyrate protect against colonic inflammation and colon cancer partly through DC‐mediated immunosuppression and that the mechanism involves Slc5a8‐mediated entry of these SCFAs into cells with subsequent inhibition of HDACs.