Acetate, a fibre-derived gut metabolite, is associated with reduced cardiovascular disease risk in females with early menopause

Abstract Background and Aims Estrogen deficiency and testosterone excess substantially increase cardiovascular disease risk in females. Dietary fibre and its microbial by-products, short-chain fatty acids, have cardioprotective effects. We aim to investigate whether plasma acetate – the most abundant short-chain fatty acid – is associated with improved cardiovascular outcomes in females with altered sex hormone profiles. Methods This cohort study included 105,563 female participants from the UK Biobank and Biobank Japan with up to 10 years of follow-up. The primary outcome was major adverse cardiovascular event (MACE) in relation to early menopause (surrogate for estrogen insufficiency) and plasma free testosterone. Proteomics profiling explored underlying molecular pathways. Results Higher plasma acetate was associated with lower 10-year MACE incidence (HR=0.887, p =0.002) in the UK Biobank. Acetate levels above the median attenuated the high MACE risk associated with early menopause (HR=1.155, p =0.075) compared with lower acetate levels (HR=1.431, p27.1g fibre/day) attenuated the early menopause-associated MACE risk. Proteomics implicated the underrepresentation of pro-inflammatory pathways. High acetate also attenuated MACE risk associated with elevated free testosterone, although the interaction term was not significant. Conclusions Higher plasma acetate mitigated cardiovascular risk in females, particularly in those with early menopause, potentially by modulating pro-inflammatory pathways. These findings support recommendations for higher dietary fibre intake as a CVD prevention strategy for females with early menopause. Translational Perspective Plasma acetate is the key product of gut microbial fermentation of fibre. Using two cohort studies, totalling 105,563 female participants followed for 10-years from two independent biobanks with different ethnicities, higher plasma acetate was significantly associated with lower cardiovascular disease risk, especially for those with early menopause. Higher microbial acetate protects against cardiovascular disease in females, with greater benefits in those with hormone related cardiovascular vulnerability. These findings may inform the design of clinical trials and guidelines, supporting a personalised nutrition strategy based on hormonal profile.