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

Guotong Sun,1,* Hongshuai Shen,2,* Zheng Xiao,3 Caiyun Yang1 1Department of Cardiology, Shouguang Hospital of T.C.M, Shouguang, Weifang, People’s Republic of China; 2Department of Geriatric Medicine, Zibo Central Hospital, Zibo, People’s Republic of China; 3Department of Pediatrics, Shouguang Hospital of T.C.M, Shouguang, Weifang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Caiyun Yang, Department of Cardiology, Shouguang Hospital of T.C.M, Shouguang, Weifang, 262700, People’s Republic of China, Email caiyundoctor@163.comAbstract: 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.