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

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 resultsmore » indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.« less

Authors:

Bhatt, Aadra P.  ^[1];

• Search DOE PAGES for author "Bhatt, Aadra P."
• Search DOE PAGES for ORCID "0000-0002-0134-6543"

Pellock, Samuel J.  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-7557-7985"

Biernat, Kristen A. ^[1]; Walton, William G. ^[1]; Wallace, Bret D. ^[1]; Creekmore, Benjamin C. ^[1]; Letertre, Marine M. ^[2]; Swann, Jonathan R. ^[2]; Wilson, Ian D. ^[2]; Roques, Jose R. ^[1]; Darr, David B. ^[1]; Bailey, Sean T. ^[1]; Montgomery, Stephanie A. ^[1]; Roach, Jeffrey M.  ^[1];

• Search DOE PAGES for author "Roach, Jeffrey M."
• Search DOE PAGES for ORCID "0000-0001-9817-5877"

Azcarate-Peril, M. Andrea  ^[1];

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• Search DOE PAGES for ORCID "0000-0003-0325-1289"

Sartor, R. Balfour  ^[1];

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• Search DOE PAGES for ORCID "0000-0002-7820-632X"

Gharaibeh, Raad Z. ^[3]; Bultman, Scott J. ^[1]; Redinbo, Matthew R.  ^[1]

• Search DOE PAGES for author "Redinbo, Matthew R."
• Search DOE PAGES for ORCID "0000-0003-0814-5346"

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+ Show Author Affiliations

1. Univ. of North Carolina, Chapel Hill, NC (United States)
2. Imperial College, London (United Kingdom)
3. Univ. of Florida, Gainesville, FL (United States)

Publication Date:

Fri Mar 13 00:00:00 EDT 2020

Research Org.:

Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:

USDOE; University of Florida Health Cancer Center; University Cancer Research Fund; Crohn’s and Colitis Foundation; USDA; National Institutes of Health (NIH)

OSTI Identifier:

1644107

Grant/Contract Number:  

055336; T32-DK007737; P30 DK034987; P40 OD010995; CA098468; CA207416

Resource Type:

Accepted Manuscript

Journal Name:

Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:

Journal Volume: 117; Journal Issue: 13; Journal ID: ISSN 0027-8424

Publisher:

National Academy of Sciences

Country of Publication:

United States

Language:

ENGLISH

Subject:

60 APPLIED LIFE SCIENCES; microbiome; chemotherapy; cancer; gastrointestinal toxicity