Menopause factors and alterations in gut microbiota and insulin homeostasis: A cross-sectional analysis of the Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Authors: MAFFEI, VINCENT - Wake Forest University School Of Medicine; BERTONI, ALAIN - Wake Forest University School Of Medicine; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); ROTTER, JEROME - Harbor-Ucla Medical Center; CRAGO, OSA - Wake Forest University School Of Medicine; CHEN, YII - Harbor-Ucla Medical Center; PETROSINO, JOSEPH - Baylor College Of Medicine; HOFFMAN, KRISTI - Baylor College Of Medicine; GOODARZI, MARK - Cedars-Sinai Medical Center; JENSEN, ELIZABETH - Wake Forest University School Of Medicine

Submitted to: Diabetes Obesity and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/19/2025
Publication Date: 7/30/2025
Citation: Maffei, V.J., Bertoni, A.G., Wood, A.C., Rotter, J.I., Crago, O., Chen, Y.D., Petrosino, J.F., Hoffman, K.L., Goodarzi, M.O., Jensen, E.T. 2025. Menopause factors and alterations in gut microbiota and insulin homeostasis: A cross-sectional analysis of the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Diabetes Obesity and Metabolism. https://doi.org/10.1111/dom.16578.
DOI: https://doi.org/10.1111/dom.16578

Interpretive Summary: This study looked at how menopause and gut bacteria might affect a woman's risk for problems with insulin, the hormone that controls blood sugar. Researchers studied 175 women who had gone through menopause but did not have diabetes. They found that women who went through menopause before age 50 or who used hormone replacement therapy (HRT) had lower insulin sensitivity, which could raise their risk for diabetes. Having surgery to remove reproductive organs before menopause was linked to changes in gut bacteria — more bacteria that may raise diabetes risk and fewer that protect against it. That surgery was also linked to changes in certain blood chemicals that affect insulin. While early menopause and HRT were more closely tied to insulin resistance, the gut changes after surgery could still play a role in future diabetes risk. These results help scientists understand how menopause and gut health may be connected to diabetes.

Technical Abstract: The aim of this study was to assess the risk for impaired insulin homeostasis as a function of menopause-related factors and gut microbiota dysbiosis in non-diabetic, post-menopausal women. Baseline data (n=175 women) from the Microbiome and Insulin Longitudinal Evaluation Study (MILES) were used, including insulin and dysglycaemia indices calculated from a 2-h oral glucose tolerance test, untargeted peripheral metabolomics, targeted peripheral short chain fatty-acid levels and faecal bacterial microbiota surveyed by whole-metagenomic sequencing. After adjustment for covariates, menopause age <50 years and use of hormone replacement therapy (HRT) were associated with lower Matsuda et al. insulin sensitivity index levels (Beta=-0.232, confidence interval (CI)=[-0.450, -0.014] and Beta=-0.275, CI=[-0.444, -0.107], respectively) but not pre-menopausal gynaecologic surgery. Pre-menopausal gynaecologic surgery was significantly associated with faecal microbiota beta diversity driven by a relative increase in diabetogenic Ruminococcus gnavus and Clostridium species and a decrease in protective Alistipes species and Akkermansia muciniphila relative abundances. A reduction in two glycerophospholipids in the plasmalogen class significantly statistically mediated an inverse association between gynaecologic surgery before menopause and insulin sensitivity. Menopause age and history of HRT are more strongly associated with insulin resistance than gynaecologic surgery before menopause. However, gynaecologic surgery is associated with shifts in gut microbial composition and plasma metabolite levels with a potential to contribute to future diabetes risk.