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; Lin Shu Liu; Zhengze Li; Hang Xiao; Valentina Borlandelli; Hermen S. Overkleeft; Erica W. Cloer; Michael B. Major; Dennis Goldfarb; Zongwei Cai; Matthew R. Redinbo; Guodong Zhang

doi:10.1038/s41467-021-27762-y

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. GibbonsLin Shu Liu, Zhengze Li, Hang Xiao, Valentina Borlandelli, Hermen S. Overkleeft, Erica W. Cloer, Michael B. Major, Dennis Goldfarb, Zongwei Cai^*, Matthew R. Redinbo^*, Guodong Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

58 Citations (Scopus)

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.

Original language	English
Article number	136
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	10 Jan 2022
DOIs	https://doi.org/10.1038/s41467-021-27762-y
Publication status	Published - Dec 2022

Scopus Subject Areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-27762-y

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Zhang, J., Walker, M. E., Sanidad, K. Z., Zhang, H., Liang, Y., Zhao, E., Chacon-Vargas, K., Yeliseyev, V., Parsonnet, J., Haggerty, T. D., Wang, G., Simpson, J. B., Jariwala, P. B., Beaty, V. V., Yang, J., Yang, H., Panigrahy, A., Minter, L. M., Kim, D., ... Zhang, G. (2022). Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Nature Communications, 13(1), Article 136. https://doi.org/10.1038/s41467-021-27762-y

@article{c35c23c9ceef49cbbd6bdd04ca6bf156,

title = "Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract",

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.",

author = "Jianan Zhang and Walker, {Morgan E.} and Sanidad, {Katherine Z.} and Hongna Zhang and Yanshan Liang and Ermin Zhao and Katherine Chacon-Vargas and Vladimir Yeliseyev and Julie Parsonnet and Haggerty, {Thomas D.} and Guangqiang Wang and Simpson, {Joshua B.} and Jariwala, {Parth B.} and Beaty, {Violet V.} and Jun Yang and Haixia Yang and Anand Panigrahy and Minter, {Lisa M.} and Daeyoung Kim and Gibbons, {John G.} and Liu, {Lin Shu} and Zhengze Li and Hang Xiao and Valentina Borlandelli and Overkleeft, {Hermen S.} and Cloer, {Erica W.} and Major, {Michael B.} and Dennis Goldfarb and Zongwei Cai and Redinbo, {Matthew R.} and Guodong Zhang",

note = "We thank Prof. D. Joseph Jerry at the Department of Veterinary and Animal Sciences of the University of Massachusetts Amherst for recording histology images. This research is supported by interdisciplinary faculty research award from the University of Massachusetts Amherst, USDA NIFA 2019-67017-29248 and 2020-67017-30844, and USDA/ Hatch MAS00556 (to G.Z.), NIH/NIGMS R01s GM135218, GM137286 (to M.R.R.), General Research Fund (12303319) of Hong Kong Research Grants Council (to Z.C.), NIH/NIEHS R21 ES023371 (to J.P.), NIH/NCCIH R01 AT010229 (to H.X.), and NIH T32GM008570 and NSF DGE-1650116 (to M.E.W.). We acknowledge the NIH grant P30DK034854 and the use of the Harvard Digestive Disease Center{\textquoteright}s (HDDC{\textquoteright}s) core services, resources, technology, and expertise. M.R.R. is a Founder of Symberix, Inc., which is developing microbiome-targeted therapeutics. M.R.R. is also the recipient of research funding from Merck and Lilly, although those funds were not used in this project. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-021-27762-y",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, LS, Li, Z, Xiao, H, Borlandelli, V, Overkleeft, HS, Cloer, EW, Major, MB, Goldfarb, D, Cai, Z, Redinbo, MR & Zhang, G 2022, 'Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract', Nature Communications, vol. 13, no. 1, 136. https://doi.org/10.1038/s41467-021-27762-y

TY - JOUR

T1 - Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract

AU - Zhang, Jianan

AU - Walker, Morgan E.

AU - Sanidad, Katherine Z.

AU - Zhang, Hongna

AU - Liang, Yanshan

AU - Zhao, Ermin

AU - Chacon-Vargas, Katherine

AU - Yeliseyev, Vladimir

AU - Parsonnet, Julie

AU - Haggerty, Thomas D.

AU - Wang, Guangqiang

AU - Simpson, Joshua B.

AU - Jariwala, Parth B.

AU - Beaty, Violet V.

AU - Yang, Jun

AU - Yang, Haixia

AU - Panigrahy, Anand

AU - Minter, Lisa M.

AU - Kim, Daeyoung

AU - Gibbons, John G.

AU - Liu, Lin Shu

AU - Li, Zhengze

AU - Xiao, Hang

AU - Borlandelli, Valentina

AU - Overkleeft, Hermen S.

AU - Cloer, Erica W.

AU - Major, Michael B.

AU - Goldfarb, Dennis

AU - Cai, Zongwei

AU - Redinbo, Matthew R.

AU - Zhang, Guodong

N1 - We thank Prof. D. Joseph Jerry at the Department of Veterinary and Animal Sciences of the University of Massachusetts Amherst for recording histology images. This research is supported by interdisciplinary faculty research award from the University of Massachusetts Amherst, USDA NIFA 2019-67017-29248 and 2020-67017-30844, and USDA/ Hatch MAS00556 (to G.Z.), NIH/NIGMS R01s GM135218, GM137286 (to M.R.R.), General Research Fund (12303319) of Hong Kong Research Grants Council (to Z.C.), NIH/NIEHS R21 ES023371 (to J.P.), NIH/NCCIH R01 AT010229 (to H.X.), and NIH T32GM008570 and NSF DGE-1650116 (to M.E.W.). We acknowledge the NIH grant P30DK034854 and the use of the Harvard Digestive Disease Center’s (HDDC’s) core services, resources, technology, and expertise. M.R.R. is a Founder of Symberix, Inc., which is developing microbiome-targeted therapeutics. M.R.R. is also the recipient of research funding from Merck and Lilly, although those funds were not used in this project. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122884620&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-27762-y

DO - 10.1038/s41467-021-27762-y

M3 - Journal article

C2 - 35013263

AN - SCOPUS:85122884620

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 136

ER -

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

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