Cross talk between obesogenic diet and estrogen drives distinct microbiota profiles in ovariectomized mice

The menopausal transition is associated with an increased risk of obesity, which can be ameliorated by hormone replacement therapy. However, the independent and interactive effects of obesity and menopause on the gut microbiota, along with the influence of hormone therapy, remain poorly understood. To address this, this study used a mouse model using sham-operated and ovariectomized mice, with or without high-fat diet-induced obesity, to disentangle the roles of menopause and obesity. Ovariectomized mice on a high-fat diet were further treated with estradiol to assess the regulatory effects of hormone supplementation on the gut microbiota. The results showed that obesity and ovariectomy altered the relative abundances of 29 and 7 genera, and 243 and 99 amplicon sequence variants, respectively, indicating a stronger impact of obesity on gut microbial composition. Notably, ovariectomy increased the abundance of <i>Faecalibaculum</i> and enriched microbial taxa capable of producing estrogen-metabolizing enzymes, including <i>Bifidobacterium</i> and <i>Dubosiella</i> species, as well as the predicted abundance of the estrobolome enzyme β-glucuronidase. Estradiol supplementation increased the relative abundance of <i>Bacteroides</i> and decreased <i>Akkermansia</i>, both of which possess distinct β-glucuronidase subtypes. It also reduced the species <i>Faecalibaculum rodentium</i>, that positively associated with adiposity. Together, these findings highlight the distinct and significant impacts of obesity and menopause on the gut microbiota and suggest that estrogen supplementation modulates microbial features linked to metabolic health. These results further implicate the potential of modulating the gut microbiota to improve postmenopausal health outcomes.<b>NEW & NOTEWORTHY</b> This study investigates how obesity, menopause, and estrogen supplementation influence the gut microbiota. The findings highlight the distinct and significant effects of obesity and menopause in shaping microbial composition and suggest that estrogen supplementation modulates microbial features associated with metabolic health.