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

TitleMicrobial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.
Publication TypeJournal Article
Year of Publication2022
AuthorsZhang, 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, LS, Li, Z, Xiao, H, Borlandelli, V, Overkleeft, HS, Cloer, EW, Major, MB, Goldfarb, D, Cai, Z, Redinbo, MR, Zhang, G
JournalNat Commun
Date Published2022 01 10
KeywordsAnimals, Anti-Infective Agents, Local, Anticarcinogenic Agents, Bacterial Proteins, Binding Sites, Biotransformation, Carcinogenesis, Carcinogens, Colitis, Colon, Colorectal Neoplasms, Gastrointestinal Microbiome, Gene Expression, Glucuronidase, Glycoside Hydrolase Inhibitors, Humans, Mice, Mice, Inbred C57BL, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins, Triclosan

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.

Alternate JournalNat Commun
PubMed ID35013263
PubMed Central IDPMC8748916
Grant ListR01 GM137286 / GM / NIGMS NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States
R01 AT010229 / AT / NCCIH NIH HHS / United States
R21 ES023371 / ES / NIEHS NIH HHS / United States
T32 GM008570 / GM / NIGMS NIH HHS / United States
R01 GM135218 / GM / NIGMS NIH HHS / United States