Antihypertensive effects of rice peptides involve intestinal microbiome alterations and intestinal inflammation alleviation in spontaneously hypertensive rats

Gut dysbiosis serves as an underlying risk factor for the development of hypertension. The resolution of this dysbiosis has emerged as a promising strategy in improving hypertension. Food-derived bioactive protein peptides have become increasingly more attractive in ameliorating hypertension, primarily due to their anti-inflammatory and anti-oxidant activities. However, the regulatory mechanisms linking rice peptides (RP), gut dysbiosis, and hypertension remain to be fully elucidated. In our study, male spontaneously hypertensive rats (SHR) were fed with chow diet and concomitantly treated with ddH₂O (Ctrl) or varying doses of rice peptides (20, 100, or 500 mg (kg bw day)^-1 designated as low-dose RP, LRP; medium-dose RP, MRP; high-dose RP, HAP) or captopril (Cap) by intragastric administration. Wistar-Kyoto (WKY) rats served as the normotensive control group and were orally administered with ddH₂O. We observed beneficial effects of RP in lowering blood pressure and ameliorating cardiovascular risk profiles, as evidenced by improvements in glucolipid metabolic disorders, hepatic and renal damage, left ventricular hypertrophy and endothelial dysfunction in hypertensive rats. More importantly, we found that RP attenuated intestinal pathological damage, improved impaired intestinal barrier, and reduced intestinal inflammation by inhibiting the HMGB1-TLR4-NF-κB pathway. Notably, multi-omics integrative analyses have revealed that RP altered the composition and function of the gut microbiota. This is exemplified by the observed enrichment of beneficial bacterial constituents, such as <i>g_Lactobacillus</i>, <i>g_Lactococcus</i>, <i>s_Lactobacillus_intestinalis</i>, and <i>Lactococcus lactis</i>, and elevated production of microbiota-derived short-chain fatty acid metabolites. Collectively, these studies suggest that the hypotensive effects of RP may be associated with modulation of the gut microbiota and its short-chain fatty acids metabolites. This implicates the microbiota-gut-HMGB1-TLR4-NF-κB axis as a novel venue for the amelioration of hypertension and its complications.