Gut Microbiota and Hypertension: Mechanisms, Drug Interactions, and Translational Directions for Individualized Therapy.

Hypertension remains a major global health challenge, with suboptimal treatment and blood pressure (BP) control rates and apparent or confirmed resistant hypertension (RHT) affecting approximately 10-20% of treated patients. Increasing evidence suggests that the gut microbiota may contribute to BP regulation through interconnected metabolic, immune-inflammatory, intestinal barrier, gut-brain, and gut-kidney pathways. Short-chain fatty acids (SCFAs) may support vasodilation, renal sodium handling, epithelial barrier integrity, and anti-inflammatory signaling through receptor- and tissue-specific mechanisms, whereas trimethylamine N-oxide (TMAO) has been associated with adverse vascular and cardio-renal phenotypes but may function either as a pathogenic mediator or as a biomarker of altered microbial-host metabolism or impaired renal clearance. Beyond the SCFA-TMAO axis, bile acid metabolism, tryptophan/indole derivatives, phenylacetylglutamine, uremic toxins, and the nitrate-nitrite-nitric oxide pathway provide additional mechanistic links between microbial ecology and BP phenotypes. This review synthesizes mechanistic, pharmacological, clinical, and translational evidence on microbiota-hypertension interactions, with particular emphasis on drug-microbiota bidirectionality. We propose a three-layer framework in which bacterial enzymatic transformation, host metabolic regulation, and epithelial transport/barrier functions jointly shape antihypertensive drug exposure and response. Human interventional evidence remains preliminary: colon-targeted acetylated and butyrylated high-amylose maize starch increased circulating SCFAs and reduced 24-hour systolic BP by approximately 5-6 mmHg in a small, short-duration trial of untreated essential hypertension, whereas probiotics and prebiotics generally show modest BP reductions of approximately 1-3 mmHg systolic and 1-2 mmHg diastolic in meta-analyses. These findings support microbiota-informed hypertension research and risk stratification, but clinical implementation, particularly in well-defined RHT populations, remains investigational.