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

Authors: ZHANG, GUODONG - University Of Massachusetts, Amherst; REDINBO, MATTHEW - University Of North Carolina; CAI, ZONGWEI - Hong Kong Baptist University; XIAO, HANG - University Of Massachusetts, Amherst; Liu, Linshu; GIBBONS, JOHN - University Of Massachusetts, Amherst; KIM, DAEYOUNG - University Of Massachusetts, Amherst; MINTER, LISA - University Of Massachusetts, Amherst; PANIGRAHY, ANAND - University Of Massachusetts, Amherst; YANG, JUN - University Of California, Davis

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2021
Publication Date: 1/10/2022
Citation: Zhang, G., Redinbo, M., Cai, Z., Xiao, H., Liu, L.S., Gibbons, J., Kim, D., Minter, L., Panigrahy, A., Yang, J. 2022. Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Nature. https://doi.org/10.1038/s41467-021-27762-y.
DOI: https://doi.org/10.1038/s41467-021-27762-y

Interpretive Summary: Triclosan (TCS) is used as an antimicrobial agent in more than 2,000 consumer and industrial products. Upon entering to the body, TCS is metabolized by gut microbiome, the metabolites produced may increase the severity of colitis and exaggerate the development of colon cancer. However, it remains unclear which specific gut microbial enzyme(s) are involved in TCS metabolism. In the present study, a mouse model and fecal cultures were used to characterize the enzymes that mediated the metabolic activation of TCS in the colon, which contribute to its adverse effects. Additionally it was shown that oral administration of an enzyme inhibitor could prevent TCS metabolism. Results from this study could help to develop novel strategies for reducing the toxic effects of TCS.

Technical Abstract: Metabolic transformations play critical roles in toxicities of environmental pollutant and toxicants. While previous research has focused on metabolism by host tissues, the biotransformation of environmental compounds by the gut microbiome are understudied. Here we pinpoint the specific gut microbial enzymes that metabolize the environmental compound triclosan (TCS) and reveal the functional impact of microbial metabolism to TCS gut toxicity. After TCS exposure in both mice and humans, the intestines have a distinct metabolic profile of TCS compared to other tissues. Using in vitro, in fimo, and in vivo approaches, we show that the unique metabolic profile of TCS in the gut is mediated by actions of microbial ß-glucuronidase (GUS) enzymes, notably the Loop-1 GUS orthologs, present in the commensal microbiota. We determine crystal structures of the identified gut microbial GUS enzymes, and use site-directed mutagenesis to define structural motifs required by the GUS enzymes to metabolically activate TCS. Finally, we demonstrate that targeted inhibition of microbial GUS enzymes abolishes the colitis-enhancing and microbiome-altering effects of TCS in mice, a result that establishes the essential roles of specific bacterial proteins in TCS toxicity. Together, our results support the conclusion that gut microbial GUS enzymes, notably the Loop-1 GUS orthologs, mediate metabolic activation of TCS in the colon, contribute to the adverse effects of this environmental toxin, and could lead to therapeutic interventions for chronic gut diseases.