Sex differences in the gut microbiome and related metabolites: role in cardiometabolic disease

Sex differences in major cardiometabolic diseases (CMD), such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, have been increasingly recognized across the life course. During the reproductive stage, women generally have a more favorable cardiometabolic risk profile than men, but their risk of experiencing CMD significantly increases after menopause. Emerging evidence suggests that sexually dimorphic gut microbiota and gut microbiota-related metabolites (GMRMs) may contribute to such sex disparities. However, existing findings are heterogeneous and underlying mechanisms remain incompletely understood. In this review, we synthesize the evidence examining sex differences in gut microbial diversity, overall composition, taxa abundances, and levels of GMRMs across key life stages, including pre-puberty, adolescence, and different phases of adulthood (with emphasis on pre- and post-menopausal periods). We summarize potential biological mechanisms underlying sexual dimorphism in the gut microbiome and GMRMs, emphasizing the central role of sex steroids, along with contributions from immune function and other host and environmental factors. We further integrate evidence linking sexually dimorphic microbial taxa (e.g., Akkermansia muciniphila, Eubacterium, Ruminococcus, and other Firmicutes taxa) and GMRMs (e.g., microbiota-derived short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide) to key cardiometabolic pathways involving inflammation, glucose and lipid metabolism, and vascular function. Finally, we identify critical knowledge gaps and emphasize the need for future large longitudinal studies that would integrate repeated measurements of the gut microbiome, untargeted metabolomics, and sex steroid hormones across the life course. Such approaches are essential to clarify biological pathways and inform sex-specific microbiome-based interventions for CMD prevention and management.