Plasma Metabolites Mediate the Associations of Gut Microbial Diversity with Ambulatory Blood Pressure and Its...

Evidence suggests that depleted gut microbial α-diversity is associated with hypertension; however, whether metabolic markers affect this relationship remains unknown. We aimed to determine the potential metabolites mediating the associations of α-diversity with blood pressure (BP) and BP variability (BPV).

Metagenomics and plasma targeted metabolomics were conducted on 523 Chinese participants from the MetaSalt study. The 24-hour, daytime, and nighttime BP and BPV were calculated based on ambulatory BP measurements. Linear mixed models were used to characterize the relationships between α-diversity (Shannon and Chao1 index) and BP indices. Mediation analyses were performed to assess the contribution of metabolites to the observed associations. The influence of key metabolites on hypertension was further evaluated in a prospective cohort of 2,169 participants.

Gut microbial richness (Chao1) was negatively associated with 24-hour systolic BP, daytime systolic BP, daytime diastolic BP, 24-hour systolic BPV, and nighttime systolic BPV ( P < 0.05). Moreover, 26 metabolites were strongly associated with richness (Bonferroni P < 0.05). Among them, four key metabolites (imidazole propionate, 2-hydroxy-3-methylbutyric acid, homovanillic acid, and hydrocinnamic acid) mediated the associations between richness and BP indices (proportions of mediating effects: 14.1%-67.4%). These key metabolites were also associated with hypertension in the prospective cohort. For example, each 1-standard deviation unit increase in hydrocinnamic acid significantly reduced the risk of prevalent ( OR [95% CI] = 0.90 [0.82, 0.99]; P = 0.03) and incident hypertension ( HR [95% CI] = 0.83 [0.71, 0.96]; P = 0.01).

Our results suggest that gut microbial richness correlates with lower BP and BPV, and that certain metabolites mediate these associations. These findings provide novel insights into the pathogenesis and prevention of hypertension.