5-aminosalicylic acid ameliorates colitis and checks dysbiotic escherichia coli expansion by activating PPAR-G signaling in the intestinal epithelium

Stephanie A. Cevallos, Jee Yon Lee, Eric M. Velazquez, Nora J. Foegeding, Catherine D. Shelton, Connor R. Tiffany, Beau H. Parry, Annica R. Stull-Lane, Erin E. Olsan, Hannah P. Savage, Henry Nguyen, Star S. Ghanaat, Austin J. Byndloss, Ilechukwu O. Agu, Renee M Tsolis, Mariana X. Byndloss, Andreas J. Bäumler

Research output: Contribution to journalArticlepeer-review

Abstract

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-g) 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-g signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of Escherichia coli, which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hy-poxia, or blunt an expansion of E. coli in DSS-treated mice that lacked Pparg expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-g signal-ing, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis. IMPORTANCE An expansion of Enterobacterales in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used Escherichia coli, a representative of the Enterobacterales, to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. Dextran sulfate sodium (DSS)-induced colitis reduced mito-chondrial activity in the colonic epithelium, thereby increasing the amount of oxygen available to fuel an E. coli expansion through aerobic respiration. Activation of epithelial peroxisome proliferator-activated receptor gamma (PPAR-g) signaling with 5-aminosali-cylic acid (5-ASA) was sufficient to restore mitochondrial activity and blunt a dysbiotic E. coli expansion. These data identify the host’s epithelial metabolism as a potential treatment target to remediate microbial signatures of dysbiosis, such as a dysbiotic E. coli expansion in the fecal microbiota.

Original languageEnglish (US)
Article numbere03227-20
Pages (from-to)1-10
Number of pages10
JournalmBio
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Dysbiosis
  • Escherichia coli
  • Gut inflammation
  • Inflammatory bowel disease
  • Microbial communities

ASJC Scopus subject areas

  • Microbiology
  • Virology

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