Abstract
Menopause in human females and subsequent ovarian hormone deficiency, particularly concerning 17β-estradiol (E2), increase the risk for metabolic dysfunctions associated with obesity, diabetes type 2, cardiovascular diseases, and dementia. Several studies indicate that these disorders are also strongly associated with compositional changes in the intestinal microbiota; however, how E2 deficiency and hormone therapy affect the gut microbial community is not well understood. Using a rat model, we aimed to evaluate how ovariectomy (OVX) and subsequent E2 administration drive changes in metabolic health and the gut microbial community, as well as potential associations with learning and memory. Findings indicated that OVX-induced ovarian hormone deficiency and E2 treatment had significant impacts on several health-affecting parameters, including (a) the abundance of some intestinal bacterial taxa (e.g., Bifidobacteriaceae and Porphyromonadaceae), (b) the abundance of microbial short-chain fatty acids (SCFAs) (e.g., isobutyrate), (c) weight/BMI, and (d) high-demand spatial working memory following surgical menopause. Furthermore, exploratory correlations among intestinal bacteria abundance, cognition, and BMI underscored the putative influence of surgical menopause and E2 administration on gut-brain interactions. Collectively, this study showed that surgical menopause is associated with physiological and behavioral changes, and that E2-linked compositional changes in the intestinal microbiota might contribute to some of its related negative health consequences. Overall, this study provides novel insights into interactions among endocrine and gastrointestinal systems in the post-menopausal life stage that collectively alter the risk for the development and progression of cardiovascular, metabolic, and dementia-related diseases.
Highlights
From sexual maturity at puberty until reproductive senescence in mid- to late- life, female mammals experience predictable fluctuations in sex steroid hormones that control reproductive capacity (Melmed et al, 2015)
Based on studies that illustrated potential interactions between gut microbiota and body weight as well as cognitive function (John et al, 2018; Mohajeri et al, 2018; Sun et al, 2020), we evaluated exploratory Spearman r correlations for each treatment group individually between intestinal microbial families that were significantly affected by OVX and E2 treatments (Figure 1) and either (a) BMI based on body weight at the end of the experiment or (b) error scores at the highest working memory load trial, trial 4 (Total Maximum Load [Total Max Load (TML)] trial) during the Learning Phase as well as the Asymptotic Phase of water radial-arm maze (WRAM) testing (Figure 6)
It is important to note that menopause typically occurs in parallel with aging, age alone does not account for the significantly increased risk of developing these negative health outcomes in post-menopausal women, indicating that the loss of ovarian hormones plays a unique role in the risk, development, and progression of cardiovascular, neurodegenerative, and other diseases (Parker et al, 2009; Faubion et al, 2015; Hale and Shufelt, 2015; Riedel et al, 2016; Benjamin et al, 2017; El Khoudary and Thurston, 2018; El Khoudary et al, 2018; El Khoudary et al, 2019; El Khoudary et al, 2020)
Summary
From sexual maturity at puberty until reproductive senescence in mid- to late- life, female mammals experience predictable fluctuations in sex steroid hormones that control reproductive capacity (Melmed et al, 2015). Unless oophorectomy (surgical intervention to remove the ovaries; in rodents, ovariectomy [OVX]) takes place earlier, menopause (a natural end in reproductive capacity in females) occurs around age 51-52 (NAMS, 2014). Because growing ovarian follicles are the primary steroidogenesis site for estrogens and progesterone, the eventual natural exhaustion of the follicle reserve or the surgical removal of the ovaries coincides with a significant decrease in circulating ovarian hormone levels in the postmenopausal life stage. Menopause-related symptoms, including, but not limited to, changes in visceral body fat distribution, baseline body weight, metabolism, and memory function can have a significant impact on quality of life (Mitchell and Woods, 2001; Hoffman et al, 2012; Weber et al, 2013; Al-Safi and Santoro, 2014; NAMS, 2014; Leeners et al, 2017)
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