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. 2024 Nov 13;150(11):495.
doi: 10.1007/s00432-024-06028-2.

The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review

Lars E Hillege #  1   2 , Milou A M Stevens #  3   4 , Paulien A J Kristen  3   4 , Judith de Vos-Geelen  3   5 , John Penders  6   7 , Matthew R Redinbo  8 , Marjolein L Smidt  3   4
Affiliations

The role of gut microbial β-glucuronidases in carcinogenesis and cancer treatment: a scoping review

Lars E Hillege et al. J Cancer Res Clin Oncol. .

Abstract

Introduction: The human gut microbiota influence critical functions including the metabolism of nutrients, xenobiotics, and drugs. Gut microbial β-glucuronidases (GUS) enzymes facilitate the removal of glucuronic acid from various compounds, potentially affecting anti-cancer drug efficacy and reactivating carcinogens. This review aims to comprehensively analyze and summarize studies on the role of gut microbial GUS in cancer and its interaction with anti-cancer treatments. Its goal is to collate and present insights that are directly relevant to patient care and treatment strategies in oncology.

Methods: This scoping review followed PRISMA-ScR guidelines and focused on primary research exploring the role of GUS within the gut microbiota related to cancer etiology and anti-cancer treatment. Comprehensive literature searches were conducted in PubMed, Embase, and Web of Science.

Results: GUS activity was only investigated in colorectal cancer (CRC), revealing increased fecal GUS activity, variations in the gut microbial composition, and GUS-contributing bacterial taxa in CRC patients versus controls. Irinotecan affects gastrointestinal (GI) health by increasing GUS expression and shifting gut microbial composition, particularly by enhancing the presence of GUS-producing bacteria, correlating with irinotecan-induced GI toxicities. GUS inhibitors (GUSi) can mitigate irinotecan's adverse effects, protecting the intestinal barrier and reducing diarrhea.

Conclusion: To our knowledge, this is the first review to comprehensively analyze and summarize studies on the critical role of gut microbial GUS in cancer and anti-cancer treatment, particularly irinotecan. It underscores the potential of GUSi to reduce side effects and enhance treatment efficacy, highlighting the urgent need for further research to integrate GUS targeting into future anti-cancer treatment strategies.

Keywords: Carcinoma; Drug therapy; Glucuronidase; Microbiome; Neoplasm.

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Conflict of interest statement

Declarations Conflict of interest JVG has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier, all outside the submitted work. MRR has received funding grants from Merck & Co. Inc. and Eli Lilly and Company, and is a board member of Symberix, Inc., all outside the submitted work. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Examples of gut microbial GUS mechanisms associated with cancer. The active metabolite of irinotecan, SN-38, and estrogens are inactivated to SN-38G and estrogen-glucuronides (EG) in the liver by UGT (where the circled G represents glucuronic acid). SN-38G and EG are sent to the intestines via the bile duct. Gut microbial GUS enzymes remove glucuronides from inactivated compounds which leads to reactivation. Reactivated SN-38 generates gut toxicity and irinotecan’s dose-limiting side effect, diarrhea. Reactivated estrogens can be reabsorbed into the bloodstream and may contribute to the development and progression of breast cancer (Nagar & Blanchard ; Sui et al. 2021). Created with BioRender.com. E: estrogen; ER: estrogen receptor; G: glucuronic acid; GUS: beta-glucuronidases; UGT: UDP-glucuronosyltransferases.
Fig. 2
Fig. 2
PRISMA 2020 flow diagram for systematic reviews and meta-analyses of the literature search and selection process. GUS: beta-glucuronidases; GIT: gastro-intestinal tract
See this image and copyright information in PMC

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