Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study

Abstract

BackgroundHigh systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation.MethodsFifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, β-glucuronidase and β-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each loge estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences), high] and compared to loge estrogens, β-glucuronidase and β-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with α=0.05.ResultsIn men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R≥0.50, P≤0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57−0.70, P=0.03−0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal β-glucuronidase (R=0.36, P=0.04). In contrast, fecal β-glucuronidase correlated inversely with fecal total estrogens, both conjugated and deconjugated (R≤-0.47, P≤0.01). Premenopausal female estrogen levels, which were collected across menstrual cycles and thus highly variable, were completely unrelated to fecal microbiome and enzyme parameters (P≥0.6).ConclusionsIntestinal microbial richness and functions, including but not limited to β-glucuronidase, influence levels of non-ovarian estrogens via enterohepatic circulation. Thus, the gut microbial community likely affects the risk for estrogen-related conditions in older adults. Understanding how Clostridia taxa relate to systemic estrogens may identify targets for interventions.Trial registrationNot applicable.

The Changes of Fecal Steroid Hormones and Bacterial Composition in Different Gestation Stages of Meishan Sows

“…However, whether the increasing of steroid hormones throughout the pregnancy account to the change of the fecal bacteria composition in Meishan sows need to be elucidate in the future. However, present sequencing profile did not find obvious difference in the richness estimators (ACE and Chao), and the diversity indices (Shannon and Simpson) of fecal bacterial community between the different gestation time in Meishan pigs, this did not agree with the studies in men and postmenopausal women, in which, the urinary estrogens concentration were changed strongly and directly associated with all measures of fecal microbiome diversity and composition [23]. Numbers of studies have proved that, the dietary composition can modify the gut microbial profiles [24].…”

“…Numbers of studies have proved that, the dietary composition can modify the gut microbial profiles [24]. Flores et al [23] had excluded the dietary patterns effect by dietary restrictions (vegan or vegetarian, gluten, lactose, peanuts, pork or shellfish) [23], but it is difficult to make all volunteers refine their diet on one recipe throughout the investigation. Whereas, the research on pigs has the advantage of fixing feed composition through the experimental period.…”

Sex steroid deficiency–associated bone loss is microbiota dependent and prevented by probiotics

“…As a result, decreased diversity is regarded as an indicator of disease state, reflecting a deteriorating habitat and/or depleted resources (91). Interestingly, estrogen depletion has also been associated with decreased α-diversity in the gut microbiome (92,93), while microbial diversity in the gut transiently increases with administration of probiotics (94). Therefore, we hypothesize that sex steroid deficiency leads to decreased microbiota diversity and that LGG and VSL#3 probiotics restore a greater diversity.…”

Associations of the Fecal Microbiome With Urinary Estrogens and Estrogen Metabolites in Postmenopausal Women

“…Therefore, we and others have hypothesized that systemic levels of EMs may be modulated, in part, by the metabolic and other activities of gut microbiota (13,14). In a previous study that included 25 men and seven postmenopausal women, we observed that measures of fecal microbiome richness and ␣-diversity were directly associated with levels of urinary EMs and inversely associated with levels of fecal EMs (15). Here we present a study of the fecal microbiome in association with urinary EM profiles in a sample of 60 postmenopausal women.…”

“…Fecal DNA isolation, 454 Pyrosequencing of barcoded 16S rRNA genes, and filtering of reads through the Institute of Genome Sciences bioinformatics pipeline were performed as described previously by Flores et al (15). Four samples had extremely low numbers of reads, suggesting a problem with amplification steps; the extraction and amplification were repeated, but two samples were ultimately excluded from the analysis.…”