Gut microbial metabolites lower 24-hour systolic blood pressure in hypertensive patients

Background Fibres remain undigested until they reach the colon, where some are fermented by gut microbiota, producing metabolites called short-chain fatty acids (SCFAs). SCFAs lower blood pressure (BP) of experimental models, but their translational potential is unknown. We aimed to determine whether SCFAs lower 24-hour systolic BP (SBP) in untreated participants with essential hypertension. Methods We performed a phase II randomized placebo-controlled double-blind cross-over trial using SCFA-supplementation, delivered as acetylated and butyrylated high amylose maize starch (HAMSAB). Twenty treatment-naïve hypertensive participants were recruited from the community and randomised to 40g/day of HAMSAB or placebo. Participants completed each arm for three-weeks, with a three-week washout period between them. The primary endpoint was a 24-hour SBP decrease. Results Participants were on average 55.8±11.2-years old (mean±SD), had a body mass index (BMI) of 25.7±2.5km2/m, 30% were female, baseline 24-hour SBP 136±6mmHg. No adverse effects were reported. After the intervention, the placebo-subtracted reduction in 24-hour SBP was 6.1±9.9mmHg ( P = 0.027). This was independent of age, sex, BMI and study arm. There was no statistical significance in the placebo arm. Day and night SBP were reduced by 6.5±12.3mmHg ( P =0.01) and 5.7±9.8mmHg ( P =0.02), respectively, and 24-h central SBP by 7.2±14.7 mmHg ( P =0.005). HAMSAB increased levels of acetate and butyrate by 7.8-fold ( P =0.016), shifted the microbial ecosystem, and expanded the prevalence of SCFA-producers. Conclusions We observed a clinically relevant reduction in 24-hour SBP in participants with essential hypertension treated with the gut microbial-derived metabolites acetate and butyrate. These metabolites may represent a novel option for lowering BP. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Australian New Zealand Clinical Trials Registry ACTRN12619000916145 ### Funding Statement This work was supported by a National Heart Foundation Vanguard (102182) Grant, a National Health & Medical Research Council (NHMRC) of Australia Project Grant (GNT1159721), and NHMRC fellowships to D.M.K., G.A.H., J.M., and R.E.C. F.Z.M. is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation Fellowship, and by National Heart Foundation Future Leader Fellowships (101185, 105663). The Baker Heart & Diabetes Institute is supported in part by the Victorian Government's Operational Infrastructure Support Program. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human ethics approval was obtained from Monash University Human Research Ethics Committee (Study ID: 19203). The study was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12619000916145) and followed the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The microbiome data described in this article will be made available at the GenBank Nucleotide Database (under submission). The other data underlying this article will be shared upon reasonable request to the corresponding author.