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Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy
Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

Drug, Metabolomics, Microbiome, Microbiota, Xenobiotic, Gastrointestinal toxicity, Chemotherapy, Cancer
0027-8424
7374-7381
Bhatt, Aadra P
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Pellock, Samuel J.
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Biernat, Kristen A.
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Walton, William G.
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Wallace, Bret D.
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Creekmore, Benjamin C
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Letertre, Marine M.
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Swann, Jonathan R.
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Wilson, Ian D.
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Roques, Jose R.
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Darr, David B.
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Bailey, Sean T.
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Montgomery, Stephanie A.
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Roach, Jeffrey M.
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Azcarate-Peril, M. Andrea
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Sartor, R. Balfour
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Gharaibeh, Raad Z.
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Bultman, Scott J.
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Redinbo, Matthew R.
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Bhatt, Aadra P
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Pellock, Samuel J.
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Biernat, Kristen A.
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Walton, William G.
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Wallace, Bret D.
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Creekmore, Benjamin C
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Letertre, Marine M.
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Swann, Jonathan R.
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Wilson, Ian D.
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Roques, Jose R.
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Darr, David B.
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Bailey, Sean T.
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Montgomery, Stephanie A.
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Roach, Jeffrey M.
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Azcarate-Peril, M. Andrea
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Sartor, R. Balfour
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Gharaibeh, Raad Z.
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Bultman, Scott J.
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Redinbo, Matthew R.
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Bhatt, Aadra P, Pellock, Samuel J., Biernat, Kristen A., Walton, William G., Wallace, Bret D., Creekmore, Benjamin C, Letertre, Marine M., Swann, Jonathan R., Wilson, Ian D., Roques, Jose R., Darr, David B., Bailey, Sean T., Montgomery, Stephanie A., Roach, Jeffrey M., Azcarate-Peril, M. Andrea, Sartor, R. Balfour, Gharaibeh, Raad Z., Bultman, Scott J. and Redinbo, Matthew R. (2020) Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy. Proceedings of the National Academy of Sciences of the United States of America, 117 (13), 7374-7381. (doi:10.1073/pnas.1918095117).

Record type: Article

Abstract

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

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Accepted/In Press date: 17 February 2020
e-pub ahead of print date: 13 March 2020
Published date: 31 March 2020
Keywords: Drug, Metabolomics, Microbiome, Microbiota, Xenobiotic, Gastrointestinal toxicity, Chemotherapy, Cancer

Identifiers

Local EPrints ID: 439785
URI: http://eprints.soton.ac.uk/id/eprint/439785
ISSN: 0027-8424
PURE UUID: c018302e-0f5d-4104-ba5f-070ab96cbdac
ORCID for Jonathan R. Swann: ORCID iD orcid.org/0000-0002-6485-4529

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Date deposited: 04 May 2020 16:30
Last modified: 28 Apr 2022 02:29

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Contributors

Author: Aadra P Bhatt
Author: Samuel J. Pellock
Author: Kristen A. Biernat
Author: William G. Walton
Author: Bret D. Wallace
Author: Benjamin C Creekmore
Author: Marine M. Letertre
Author: Ian D. Wilson
Author: Jose R. Roques
Author: David B. Darr
Author: Sean T. Bailey
Author: Stephanie A. Montgomery
Author: Jeffrey M. Roach
Author: M. Andrea Azcarate-Peril
Author: R. Balfour Sartor
Author: Raad Z. Gharaibeh
Author: Scott J. Bultman
Author: Matthew R. Redinbo

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