Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract PMID: 35013263

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2022 Jan 10;13(1):136. doi: 10.1038/s41467-021-27762-y.

Jianan Zhang ^# ¹ , Morgan E Walker ^# ² , Katherine Z Sanidad ^# ¹ , Hongna Zhang ^# ³ ⁴ , Yanshan Liang ³ , Ermin Zhao ¹ , Katherine Chacon-Vargas ¹ , Vladimir Yeliseyev ⁵ , Julie Parsonnet ⁶ , Thomas D Haggerty ⁶ , Guangqiang Wang ¹ ⁷ , Joshua B Simpson ² , Parth B Jariwala ² , Violet V Beaty ² , Jun Yang ⁸ , Haixia Yang ¹ , Anand Panigrahy ¹ , Lisa M Minter ⁹ , Daeyoung Kim ¹⁰ , John G Gibbons ¹ , LinShu Liu ¹¹ , Zhengze Li ¹ , Hang Xiao ¹ , Valentina Borlandelli ¹² , Hermen S Overkleeft ¹² , Erica W Cloer ¹³ , Michael B Major ¹⁴ , Dennis Goldfarb ¹⁵ , Zongwei Cai ¹⁶ , Matthew R Redinbo ¹⁷ , Guodong Zhang ¹⁸ ¹⁹

Affiliations

1. Department of Food Science, University of Massachusetts, Amherst, MA, USA.
2. Departments of Chemistry, Biochemistry, Microbiology and Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3. State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, SAR, China.
4. Department of Occupational and Environmental Health, School of Public Health, Qingdao University, Qingdao, China.
5. Massachusetts Host-Microbiota Center, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
6. Department of Medicine and Department of Health Research and Policy, Stanford University, Stanford, CA, USA.
7. School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
8. Department of Entomology and Nematology, University of California, Davis, CA, USA.
9. Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, MA, USA.
10. Department of Mathematics and Statistics, University of Massachusetts, Amherst, MA, USA.
11. Eastern Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Wyndmoor, PA, USA.
12. Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
13. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
14. Department of Cell Biology and Physiology, and Department of Otolaryngology, Washington University, St. Louis, MO, USA.
15. Department of Cell Biology and Physiology, Institute for Informatics, Washington University, St. Louis, MO, USA.
16. State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, SAR, China. [email protected].
17. Departments of Chemistry, Biochemistry, Microbiology and Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
18. Department of Food Science, University of Massachusetts, Amherst, MA, USA. [email protected].
19. Department of Food Science and Technology, National University of Singapore, Singapore, Singapore. [email protected].
# Contributed equally.

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.