5-Aminosalicylic Acid Ameliorates Colitis and Checks Dysbiotic Escherichia coli Expansion by Activating PPAR-γ Signaling in the Intestinal Epithelium

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfa...

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Bibliographic Details
Published in:	mBio Vol. 12; no. 1
Main Authors:	Cevallos, Stephanie A, Lee, Jee-Yon, Velazquez, Eric M, Foegeding, Nora J, Shelton, Catherine D, Tiffany, Connor R, Parry, Beau H, Stull-Lane, Annica R, Olsan, Erin E, Savage, Hannah P, Nguyen, Henry, Ghanaat, Star S, Byndloss, Austin J, Agu, Ilechukwu O, Tsolis, Renée M, Byndloss, Mariana X, Bäumler, Andreas J
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 19-01-2021
Subjects:	Host-Microbe Biology Research Article gut inflammation microbial communities Escherichia coli inflammatory bowel disease dysbiosis
Online Access:	Get full text
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Summary:	5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of , which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hypoxia, or blunt an expansion of in DSS-treated mice that lacked expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-γ signaling, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis. An expansion of in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used , a representative of the , to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. Dextran sulfate sodium (DSS)-induced colitis reduced mitochondrial activity in the colonic epithelium, thereby increasing the amount of oxygen available to fuel an expansion through aerobic respiration. Activation of epithelial peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling with 5-aminosalicylic acid (5-ASA) was sufficient to restore mitochondrial activity and blunt a dysbiotic expansion. These data identify the host's epithelial metabolism as a potential treatment target to remediate microbial signatures of dysbiosis, such as a dysbiotic expansion in the fecal microbiota.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Mariana X. Byndloss and Andreas J. Bäumler contributed equally.
ISSN:	2161-2129 2150-7511
DOI:	10.1128/mBio.03227-20