Unraveling the links between estrogen and gut microbiota in sex-hormone driven cancers

Abstract

Estrogens are a group of steroid hormones produced by ovary, placenta, and other organs. They have historically been associated with female reproduction, but according to current evidence estrogens regulate also male reproductive and nonreproductive organs. Estrogens play a crucial role in female reproductive development and maintenance either directly by increasing glycogen levels, epithelial thickness and mucus secretion or indirectly, by decreasing vaginal pH through the maintenance of lactobacilli dominance and lactic acid production. Several studies demonstrated that dysbiosis and/or specific bacteria could have impact on the development of sex-hormone driven cancers such as endometrial, cervical, ovarian, breast and prostate cancers, through mechanisms involving modulation of estrogen metabolism. This modulation is realized through secretion of β-glucuronidase which deconjugates estrogens into their active forms. When gut dysbiosis occurs, microbial diversity decreases and so the deconjugation diminishes leading to a decrease of circulating estrogens. Low levels of circulating estrogen may adversely affect a wide range of physiological factors, with clinical implications especially for gut health. In this review, we discuss the different aspects of the critical interplay between gut microbiome and estrogens in sex-hormone driven cancers and the potential outcomes on their clinical management.

Keywords: Diet; Prostate; Breast; Estrobolome; Cancer; Gut microbiome; Estrogen

Core Tip: The effect of the gut microbiome (GM) expands upon the intestine in altering the metabolism and inducing inflammation. Mutually, the host microenvironment impacts the GM through the variation of estrogen levels. The circulating estrogen itself is regulated through the β-glucuronidase enzyme which deconjugates estrogen to its biologically active form, allowing it to link to estrogen receptors and thus contributing to its physiological and pathological effects (e.g. cancers and specially sex-hormone driven cancers). In this review, the interaction between estrogen and microbiota in sex-hormone-mediated cancers as well as the potential health outcomes on their clinical management are emphasized.