The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer.

Yue Sui,Jianming Wu,Jianping Chen

doi:10.3389/fcell.2021.631552

Abstract

Over the past decade, the gut microbiota has received considerable attention for its interactions with the host. Microbial β-glucuronidase generated by this community has hence aroused concern for its biotransformation activity to a wide range of exogenous (foreign) and endogenous compounds. Lately, the role of gut microbial β-glucuronidase in the pathogenesis of breast cancer has been proposed for its estrogen reactivation activity. This is plausible considering that estrogen glucuronides are the primary products of estrogens’ hepatic phase II metabolism and are subject to β-glucuronidase-catalyzed hydrolysis in the gut via bile excretion. However, research in this field is still at its very preliminary stage. This review outlines the biology of microbial β-glucuronidase in the gastrointestinal tract and elaborates on the clues to the existence of microbial β-glucuronidase–estrogen metabolism–breast cancer axis. The research gaps in this field will be discussed and possible strategies to address these challenges are suggested.

Highlights

With the microbiota–host interactions being rapidly explored, the microbial metabolic products are considered as the significant mediators within this interplay that are gaining attention, among which, gut microbial β-glucuronidase is one of the most studied. β-glucuronidase (GUS) has been known to be present in mammalian feces since the early 1970s (Creekmore et al, 2019), and the crystal structure of gmGUS was first reported in 2010 (Wallace et al, 2010)
Since estrogen has critical physiological roles in human and the overexposure of estrogen has long been considered as a determinant for sex hormone-responsive diseases such as breast cancer (BCa) (Samavat and Kurzer, 2015), this reactivation process performed by gmGUS is currently hypothesized as an important mediator for microbiota–host interaction and is a potential link between gut microbiota (GM) and BCa (Plottel and Blaser, 2011)
Focusing on the gmGUS–estrogen metabolism–BCa axis, this review aims to incorporate the pieces of intricated clues, identify the remaining research gaps, and provide some recommendations for the prospective research

Summary

Introduction

With the microbiota–host interactions being rapidly explored, the microbial metabolic products are considered as the significant mediators within this interplay that are gaining attention, among which, gut microbial β-glucuronidase (gmGUS) is one of the most studied. β-glucuronidase (GUS) has been known to be present in mammalian feces since the early 1970s (Creekmore et al, 2019), and the crystal structure of gmGUS was first reported in 2010 (Wallace et al, 2010). A high frequency of GUS genes has been identified in the human gut-associated microbial genomes (Wallace et al, 2010; Gloux et al, 2011; Kwa et al, 2016; Pollet et al, 2017) For most mammals, such as the human and mouse, the conservation of gmGUS in the gastrointestinal (GI) tract covers the major GI bacterial phyla: Bacteroidetes, Firmicutes, Verrucomicrobia, and Proteobacteria. The formed glucuronide metabolites can be transferred into the GI tract and deconjugated by gmGUS in the periplasmic space or into microbial cells This saccharification process performed by gmGUS is a carbon source for maintaining gut microbiota (GM) growth and an essential pathway for chemical biotransformation. Since estrogen has critical physiological roles in human and the overexposure of estrogen has long been considered as a determinant for sex hormone-responsive diseases such as breast cancer (BCa) (Samavat and Kurzer, 2015), this reactivation process performed by gmGUS is currently hypothesized as an important mediator for microbiota–host interaction and is a potential link between GM and BCa (Plottel and Blaser, 2011)

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Discussion

Conclusion