Cardiovascular

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

TL;DR

Sexually dimorphic gut microbiota and gut microbiota-related metabolites may contribute to sex disparities in cardiometabolic disease risk across the life course, with sex steroids playing a central role in driving these differences.

Key Findings

Women generally have a more favorable cardiometabolic risk profile than men during the reproductive stage, but their risk of cardiometabolic disease significantly increases after menopause.

  • This pattern is observed across major cardiometabolic diseases (CMD) including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease.
  • The shift in risk profile is specifically associated with the menopausal transition.
  • Sex differences in CMD have been 'increasingly recognized across the life course.'

Sexually dimorphic gut microbiota and gut microbiota-related metabolites (GMRMs) may contribute to sex disparities in cardiometabolic disease.

  • Existing findings on sex differences in the gut microbiome are described as 'heterogeneous' and 'underlying mechanisms remain incompletely understood.'
  • The review synthesizes evidence on sex differences in gut microbial diversity, overall composition, taxa abundances, and GMRM levels.
  • Evidence is examined across key life stages: pre-puberty, adolescence, and different phases of adulthood with emphasis on pre- and post-menopausal periods.

Sex steroids play a central role in driving sexual dimorphism in the gut microbiome and GMRMs, with additional contributions from immune function and other host and environmental factors.

  • The review emphasizes 'the central role of sex steroids' as a biological mechanism underlying gut microbiome sexual dimorphism.
  • Immune function is identified as a contributing factor alongside sex steroids.
  • Other host and environmental factors are also noted as contributors to sexually dimorphic microbiome patterns.

Specific sexually dimorphic microbial taxa are linked to key cardiometabolic pathways involving inflammation, glucose and lipid metabolism, and vascular function.

  • Key sexually dimorphic taxa identified include Akkermansia muciniphila, Eubacterium, Ruminococcus, and other Firmicutes taxa.
  • These taxa are linked to cardiometabolic pathways involving inflammation, glucose metabolism, lipid metabolism, and vascular function.
  • The evidence integrates sexually dimorphic microbial taxa with specific cardiometabolic mechanisms.

Sexually dimorphic gut microbiota-related metabolites implicated in cardiometabolic disease include microbiota-derived short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide (TMAO).

  • Short-chain fatty acids (SCFAs), secondary bile acids, and TMAO are specifically named as GMRMs with sexually dimorphic patterns.
  • These metabolites are linked to cardiometabolic pathways including inflammation, glucose and lipid metabolism, and vascular function.
  • TMAO is a microbiota-derived metabolite with established links to cardiovascular disease risk.

Critical knowledge gaps exist in the field, and future large longitudinal studies integrating repeated measurements of the gut microbiome, untargeted metabolomics, and sex steroid hormones across the life course are needed.

  • The review identifies the need for studies with 'repeated measurements of the gut microbiome, untargeted metabolomics, and sex steroid hormones across the life course.'
  • Such approaches are described as 'essential to clarify biological pathways and inform sex-specific microbiome-based interventions for CMD prevention and management.'
  • The emphasis is on large longitudinal study designs as a priority for future research.

What This Means

This research suggests that differences between men and women in the types and amounts of bacteria living in the gut — and the chemical compounds those bacteria produce — may help explain why men and women develop heart disease, diabetes, and liver disease at different rates and different times in life. Women tend to be somewhat protected from these diseases during their reproductive years, but their risk rises substantially after menopause. The gut microbiome and its related metabolites, shaped in part by sex hormones like estrogen and testosterone, appear to influence key biological processes such as inflammation, blood sugar control, fat metabolism, and blood vessel function in ways that differ between sexes. The review highlights specific bacteria (such as Akkermansia muciniphila, Eubacterium, and Ruminococcus) and metabolites (such as short-chain fatty acids, secondary bile acids, and TMAO) that show different patterns in men versus women and that are connected to cardiometabolic health. Sex hormones appear to be the primary driver of these differences, though the immune system and environmental factors also play a role. The authors note that findings across existing studies are inconsistent and that the biological mechanisms are not yet fully understood. This research suggests that developing treatments or preventive strategies targeting the gut microbiome will likely need to account for a person's sex and hormonal status to be effective. The authors call for large, long-term studies that track gut bacteria, metabolites, and hormone levels together over time — especially across major hormonal transitions like puberty and menopause — to better understand these relationships and eventually develop sex-specific interventions for cardiometabolic disease.

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Citation

Wang Y, Cheng E, Peters-Samuelson B. (2026). Sex differences in the gut microbiome and related metabolites: role in cardiometabolic disease.. Gut microbes. https://doi.org/10.1080/19490976.2026.2721752