Short-Chain Fatty Acids in Blood Pressure Management: A Systematic Review of Clinical Effects, Delivery Strategies, and Translational Barriers

Abstract

Short-chain fatty acids (SCFAs) have been proposed as mediators of the relationship between the intestinal microbiome and blood pressure (BP), but their therapeutic relevance in humans remains uncertain. This systematic review evaluated the effects of direct SCFA administration and interventions modifying endogenous fecal or circulating SCFAs on BP in adults. MEDLINE via PubMed, Scopus, and Web of Science Core Collection were searched for randomized controlled trials published from January 1, 2022, through May 31, 2026. The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, with study selection, data extraction, and risk-of-bias assessment performed independently by two reviewers. Six randomized controlled trials were included and synthesized narratively because of substantial clinical and methodological heterogeneity. Three trials evaluated direct butyrate administration, while three assessed exercise, plant-derived, dietary, prebiotic, or physical therapy interventions that modified endogenous SCFAs. Direct administration produced inconsistent effects. Conventional oral butyrate increased daytime systolic and diastolic BP relative to placebo in adults with hypertension, whereas acute colon-targeted delivery reduced daytime systolic BP relative to a lower concentration in a small crossover trial. A further oral trial in type 2 diabetes mellitus reported within-group BP reductions without a demonstrated between-group effect. Indirect interventions generally increased plasma or fecal SCFAs alongside improvements in selected BP outcomes, but their multicomponent effects and the absence of formal mediation analyses precluded attributing these responses specifically to SCFAs. Fecal and circulating measurements also showed different relationships with BP, indicating that these compartments are not biologically interchangeable. One study was judged at low risk of bias, two had some concerns, and three were at high risk. Current evidence does not demonstrate a uniform antihypertensive effect of increasing SCFA availability or a reproducible dose-response relationship. Future trials should compare oral and colon-targeted formulations, measure fecal and circulating SCFAs concurrently, use 24-hour ambulatory BP monitoring as the primary outcome, and evaluate whether treatment responses vary by exposure and cardiometabolic phenotype.