Abstract

Background: Sex differences in the pathogenesis of hypertension exist. Whilst gut microbiota (GM) dysregulation is a novel risk factor of hypertension, studies using shotgun metagenomics sequencing and ambulatory 24-hour blood pressure (BP) monitoring to study the potential sex differences in the associations between the GM and BP are lacking. Methods: We recruited 241 asymptomatic Hong Kong Chinese (113 male, 128 female, mean age 54±6), who were not on anti-hypertensive agents, and studied their GM composition using shotgun sequencing. 24-hour ambulatory BP was recorded. GM-mediated short chain fatty acids (SCFAs) were quantified in stool and plasma by GC-MS. Statistical analysis was performed under covariate-adjusted models including age, sex, BMI, smoking, sodium-intake, fatty liver and menopause status. Results: Based on 24-hour BP, 36% (87 of 241) of the study population was hypertensive. Males had a higher mean BP than females (127±13/81±10mmHg vs. 117±12/71±8mmHg, p<0.001). GM β-diversity was significantly different in hypertensive vs. normotensive individuals, driven by females. A significant enrichment of Ruminococcus gnavus was observed in the hypertensive group whilst Oscillibacter sp. CAG:241 and Gemmiger formicilis was enriched in the normotensive group. These differences remained significant in females with no significant differential species found in males. Additionally, Dorea formicigenerans was negatively associated whilst Clostridium bolteae and Bacteroides ovatus were positively associated in female-specific hypertension. Repeated cross-validation machine-learning demonstrated microbial features were more predictive of hypertension in females than males, and the addition of microbial features to clinical features (age, BMI) improved the model’s prediction accuracy from 0.69 to 0.84 in females. Total plasma SCFAs and propionic acid were independent predictors of systolic and diastolic BP in females but not males. GM β-diversity was also significantly associated with total SCFAs and propionic acid levels. Conclusion: GM dysregulation appears to be more strongly associated with hypertension in females, which may be mediated through circulating plasma SCFAs.

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