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. Gibbons, LinShu Liu, Zhengze Li, Hang Xiao, Valentina Borlandelli, Hermen S. Overkleeft, Erica W. Cloer, Michael B. Major, Dennis Goldfarb, Zongwei Cai (), Matthew R. Redinbo () and Guodong Zhang ()
Additional contact information
Jianan Zhang: University of Massachusetts
Morgan E. Walker: University of North Carolina at Chapel Hill
Katherine Z. Sanidad: University of Massachusetts
Hongna Zhang: Hong Kong Baptist University
Yanshan Liang: Hong Kong Baptist University
Ermin Zhao: University of Massachusetts
Katherine Chacon-Vargas: University of Massachusetts
Vladimir Yeliseyev: Brigham and Women’s Hospital
Julie Parsonnet: Stanford University
Thomas D. Haggerty: Stanford University
Guangqiang Wang: University of Massachusetts
Joshua B. Simpson: University of North Carolina at Chapel Hill
Parth B. Jariwala: University of North Carolina at Chapel Hill
Violet V. Beaty: University of North Carolina at Chapel Hill
Jun Yang: University of California
Haixia Yang: University of Massachusetts
Anand Panigrahy: University of Massachusetts
Lisa M. Minter: University of Massachusetts
Daeyoung Kim: University of Massachusetts
John G. Gibbons: University of Massachusetts
LinShu Liu: Agricultural Research Service, United States Department of Agriculture
Zhengze Li: University of Massachusetts
Hang Xiao: University of Massachusetts
Valentina Borlandelli: Leiden University
Hermen S. Overkleeft: Leiden University
Erica W. Cloer: University of North Carolina at Chapel Hill
Michael B. Major: Washington University
Dennis Goldfarb: Washington University
Zongwei Cai: Hong Kong Baptist University
Matthew R. Redinbo: University of North Carolina at Chapel Hill
Guodong Zhang: University of Massachusetts

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27762-y

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