1. Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.
- Author
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Zhang J, Walker ME, Sanidad KZ, Zhang H, Liang Y, Zhao E, Chacon-Vargas K, Yeliseyev V, Parsonnet J, Haggerty TD, Wang G, Simpson JB, Jariwala PB, Beaty VV, Yang J, Yang H, Panigrahy A, Minter LM, Kim D, Gibbons JG, Liu L, Li Z, Xiao H, Borlandelli V, Overkleeft HS, Cloer EW, Major MB, Goldfarb D, Cai Z, Redinbo MR, and Zhang G
- Subjects
- Animals, Anti-Infective Agents, Local chemistry, Anti-Infective Agents, Local metabolism, Anti-Infective Agents, Local toxicity, Anticarcinogenic Agents chemistry, Anticarcinogenic Agents pharmacology, Bacterial Proteins chemistry, Bacterial Proteins genetics, Bacterial Proteins metabolism, Binding Sites, Biotransformation, Carcinogenesis drug effects, Carcinogenesis metabolism, Carcinogens chemistry, Carcinogens metabolism, Carcinogens toxicity, Colitis chemically induced, Colitis enzymology, Colitis microbiology, Colon drug effects, Colon microbiology, Colon pathology, Colorectal Neoplasms chemically induced, Colorectal Neoplasms enzymology, Colorectal Neoplasms microbiology, Gastrointestinal Microbiome drug effects, Gene Expression, Glucuronidase chemistry, Glucuronidase genetics, Glucuronidase metabolism, Glycoside Hydrolase Inhibitors chemistry, Humans, Mice, Mice, Inbred C57BL, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Triclosan chemistry, Triclosan metabolism, Triclosan toxicity, Bacterial Proteins antagonists & inhibitors, Carcinogens antagonists & inhibitors, Colitis prevention & control, Colorectal Neoplasms prevention & control, Glucuronidase antagonists & inhibitors, Glycoside Hydrolase Inhibitors pharmacology, Triclosan antagonists & inhibitors
- 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., (© 2022. The Author(s).)
- Published
- 2022
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