Long-Term Administration of Conjugated Estrogen and Bazedoxifene Decreased Murine Fecal β-Glucuronidase Activity Without Impacting Overall Microbiome Community

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.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…Albeit, the high ratio of circulating estrogen metabolites and parent estrogen aided by bGLU deglucuronidation activity in the gut is considered a risk factor for postmenopausal estrogen receptor positive (ERþ) breast cancer. Accordingly, a study on the therapeutic utility of this combination drug in an ovariectomized mouse model showed significant reduction in faecal bGLU activity without altering faecal microbiota diversity [208]. The study articulated the significance of bacterial bGLU inhibition to improving the outcome of long-term administered estrogens for postmenopausal women or breast cancer patients.…”

Exploring the Potential of the Microbiome as a Marker of the Geographic Origin of Fresh Seafood

“…The sequence reads were processed in Mothur (v.1.42.3;Schloss et al, 2009) on the Niagara supercomputer at the SciNet HPC Consortium (Loken et al, 2010;Ponce et al, 2019). Operational taxonomic unit (OTU) picking was performed against SILVA ribosomal RNA database (132 release; Quast et al, 2013;Chen et al, 2018). Data interpretation, statistical analysis, and visualization were performed in MicrobiomeAnalyst (Dhariwal et al, 2017), including rarefaction to the minimum library size without scaling of data (Liu et al, 2017;Kaczmarek et al, 2019).…”

The Effect of Hops (Humulus lupulus L.) Extract Supplementation on Weight Gain, Adiposity and Intestinal Function in Ovariectomized Mice

“…The growth of this species may have been influenced by interactions between endogenous estrogen and HE supplementation, as this reduction was not observed in OVX HE animals. This idea is supported by Chen et al, who observed a decrease in A. muciniphila in OVX mice supplemented with combined conjugated estrogens plus Bazedoxifene (a selective estrogen receptor modulator), along with a decrease in deconjugation enzymes [55]. Akkermansia muciniphila utilizes intestinal mucin as its sole energy source [56] and the degradation of mucins stimulates the regeneration of new mucin by epithelial cells, and releases mucin metabolites that are utilized by other bacteria in the lumen.…”