Probiotic fermented milk can lower the incidence rate of hypertension and is beneficial to the regulation of the intestinal microecology. However, the underlying molecular mechanism remains elusive. Here, we evaluated the role of the gut microbiota and its metabolites in the antihypertensive effect of milk fermented by the Lactiplantibacillus plantarum strains SR37-3 (PFM-SR37-3) and SR61-2 (PFM-SR61-2) in Ng-nitro-L-arginine methyl ester induced hypertensive rats. The results showed that PFM-SR37-3 and PFM-SR61-2 intervention significantly lowered the blood pressure (BP) of NG-nitro-L-arginine methyl ester induced hypertensive rats and attenuated renal injury. In particular, long-term administration of PFM inhibited a progressive elevation in SBP (170.22 ± 8.40 and 133.28 ± 6.09 by model group and PFM-SR37-3 treated model group, respectively, at the end of the 4 weeks; p < 0.01 PFM-SR37-3 treated model group versus model group) and DBP (133.83 ± 5.91 and 103.00 ± 6.41 by model group and PFM-SR37-3 treated model group, respectively, at the end of the 4 weeks; p < 0.01 PFM-SR37-3 treated model group versus model group). PFM-SR37-3 and PFM-SR61-2 reshaped the gut microbiome and metabolome, and especially regulated the metabolic levels of L-phenylalanine, L-methionine and L-valine in the intestine and blood circulation. The analysis of the target organ’s aortic transcriptome indicated that the protective effects of PFM-SR37-3 and PFM-SR61-2 were accompanied by the modulation of the BP circadian rhythm pathway, which was conducive to cardiovascular function. Vascular transcriptomic analysis showed that circadian rhythm and AMPK might be potential targets of hypertension. In addition, the ACE inhibition rates of Lactiplantibacillus plantarum SR37-3 and Lactiplantibacillus plantarum SR61-2 in vitro were 70.5% and 68.9%, respectively. Our research provides new insights into novel and safe options for hypertension treatment.

Cardiometabolic disease (CMD) encompasses a range of diseases such as hypertension, atherosclerosis, heart failure, obesity, and type 2 diabetes. Recent findings about CMD’s interaction with gut microbiota have broadened our understanding of how diet and nutrition drive microbes to influence CMD. However, the translation of basic research into the clinic has not been smooth, and dietary nutrition and probiotic supplementation have yet to show significant evidence of the therapeutic benefits of CMD. In addition, the published reviews do not suggest the core microbiota or metabolite classes that influence CMD, and systematically elucidate the causal relationship between host disease phenotypes-microbiome. The aim of this review is to highlight the complex interaction of the gut microbiota and their metabolites with CMD progression and to further centralize and conceptualize the mechanisms of action between microbial and host disease phenotypes. We also discuss the potential of targeting modulations of gut microbes and metabolites as new targets for prevention and treatment of CMD, including the use of emerging technologies such as fecal microbiota transplantation and nanomedicine. Key points: • To highlight the complex interaction of the gut microbiota and their metabolites with CMD progression and to further centralize and conceptualize the mechanisms of action between microbial and host disease phenotypes. • We also discuss the potential of targeting modulations of gut microbes and metabolites as new targets for prevention and treatment of CMD, including the use of emerging technologies such as FMT and nanomedicine. • Our study provides insight into identification-specific microbiomes and metabolites involved in CMD, and microbial-host changes and physiological factors as disease phenotypes develop, which will help to map the microbiome individually and capture pathogenic mechanisms as a whole. Graphical