Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract

Jianan Zhang, Morgan E. Walker, Katherine Z. Sanidad, Hongna Zhang, Yanshan Liang, Ermin Zhao, Katherine Chacon-Vargas, Vladimir Yeliseyev, Julie Parsonnet, Thomas D. Haggerty, Guangqiang Wang, Joshua B. Simpson, Parth B. Jariwala, Violet V. Beaty, Jun Yang, Haixia Yang, Anand Panigrahy, Lisa M. Minter, Daeyoung Kim, John G. GibbonsLin Shu Liu, Zhengze Li, Hang Xiao, Valentina Borlandelli, Hermen S. Overkleeft, Erica W. Cloer, Michael B. Major, Dennis Goldfarb, Zongwei Cai*, Matthew R. Redinbo*, Guodong Zhang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

42 Citations (Scopus)

Abstract

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

Original languageEnglish
Article number136
JournalNature Communications
Volume13
Issue number1
Early online date10 Jan 2022
DOIs
Publication statusPublished - Dec 2022

Scopus Subject Areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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