Abstract
Conjugated estrogens (CE) and Bazedoxifene (BZA) combination is used to alleviate menopause-associated symptoms in women. CE+BZA undergo first-pass-metabolism in the liver and deconjugation by gut microbiome via β-glucuronidase (GUS) enzyme inside the distal gut. To date, the impact of long-term exposure to CE+BZA on the gut microbiome or GUS activity has not been examined. Our study using an ovariectomized mouse model showed that CE+BZA administration did not affect the overall cecal or fecal microbiome community except that it decreased the abundance of Akkermansia, which was identified as a fecal biomarker correlated with weight gain. The fecal GUS activity was reduced significantly and was positively correlated with the abundance of Lactobacillaceae in the fecal microbiome. We further confirmed in Escherichia coli K12 and Lactobacillus gasseri ADH that Tamoxifen-, 4-hydroxy-Tamoxifen- and Estradiol-Glucuronides competed for GUS activity. Our study for the first time demonstrated that long-term estrogen supplementation directly modulated gut microbial GUS activity. Our findings implicate that long-term estrogen supplementation impacts composition of gut microbiota and microbial activity, which affects estrogen metabolism in the gut. Thus, it is possible to manipulate such activity to improve the efficacy and safety of long-term administered estrogens for postmenopausal women or breast cancer patients.
Highlights
We reported that serum glucuronic acid – a product of deconjugation of estrogens- levels were decreased in mice, leading to our hypothesis that Conjugated estrogens (CE)+BZA may impact the metabolism of estrogens in the gut
To understand how estrogen administration modulated the community structure of the gut microbiome, we performed microbiome analysis using cecal and fecal samples from ovariectomized female mice that were supplemented with Vehicle (Veh as negative control) and various estrogens including E2 (5 μg. kg−1.day−1), Conjugated estrogens (CE, 2.5 mg.kg−1.day−1), Bazedoxifen (BZA, 3 mg.kg−1.day−1) and CE+BZA for six weeks
The 10 genera unique to Veh added up to less than 0.02% abundance and the one genus unique to CE+BZA added up to less than 0.03% abundance of the total bacterial abundance
Summary
The high ratio of circulating estrogen metabolites/ parent estrogens has been linked to increased risk for postmenopausal estrogen receptor positive (ER+) breast cancer[6]. One current ERT, Conjugated Estrogens and Bazedoxifene (CE+BZA), binds to estrogen receptors (ER) and has tissue selective effects. We reported that serum glucuronic acid – a product of deconjugation of estrogens- levels were decreased in mice, leading to our hypothesis that CE+BZA may impact the metabolism of estrogens in the gut. In the intestine, conjugated estrogens are deconjugated by the gut microbiome and are partially reabsorbed[19,20]. One study reported that both a diet rich in estrogenic isoflavones and the host estrogen receptor status affected the composition of gut microbiome in mice[24].
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