Gut microbiota-derived metabolite isovalerylcarnitine modulates salt sensitivity of blood pressure and incident hypertension: a multicenter dietary salt intervention trial

This study aims to investigate the roles of gut microbiota and plasma metabolites in salt sensitivity (SS) of blood pressure (SSBP) and hypertension. A 23-day, multicenter, dietary salt intervention trial (the MetaSalt study) recruited 528 participants who underwent a baseline observation, low-salt, and high-salt interventions. SSBP was assessed and used as the primary outcome, and fecal shotgun metagenome and plasma targeted metabolome were measured. We found that high salt significantly altered 85 gut-microbial species (p < 9.42 × 10−5) and 70 metabolites (p < 2.26 × 10−4). Among them, the changes in 22 species and 8 metabolites were associated with SSBP (p < 0.05), and a gut microbiota-acylcarnitine network implicated in SSBP was identified, with a gut microbiota-derived metabolite, isovalerylcarnitine, as the core metabolite. Isovalerylcarnitine was also inversely associated with SSBP in the GenSalt study (p = 0.0102). Importantly, increased isovalerylcarnitine attenuated SS hypertension and improved endothelial function in rats, and was associated with reduced risk (ranging from 13% to 19%) of BP progression and incident hypertension in a prospective cohort (n = 3907, median follow-up = 5.5 years). This study demonstrated that the gut-acylcarnitine axis may play roles in the development of SS hypertension. Trial number: ChiCTR1900025171. Here, combining data from a clinical trial and animal models, the authors show a role for a gut-acylcarnitine axis in the development of salt-sensitive hypertension, and identify isovalerylcarnitine as a key microbiota-derived modulator and potential target for the precision prevention of hypertension.