Marine octapeptide DLTAGLLE lowers blood pressure via endothelium-RAS-microbiota axis

The development of functional foods for hypertension requires more than in vitro ACE inhibition, it demands oral efficacy and a plausible mechanism linking vascular regulation to gut-host interactions. This study characterizes DLTAGLLE (Asp-Leu-Thr-Ala-Gly-Leu-Leu-Glu), a novel octapeptide from Lepidotrigla microptera, and elucidates its antihypertensive activity via an integrated “endothelium-renin-angiotensin system (RAS)-microbiota” pathway. In Ang II-challenged HUVECs, DLTAGLLE (1.2 mg/mL) reduced ROS by 43.5%, increased SOD activity by 1.43-fold, elevated NO levels 3.4-fold, and decreased endothelin-1, alongside modulating ACE and ACE2 expression, suggesting endothelial protection. Orally administered at 100 mg/kg, DLTAGLLE produced both rapid (0-5 h) and sustained (28-day) antihypertensive effects in spontaneously hypertensive rats, while mitigating cardiac and renal injury. It significantly decreased serum ACE activity, reduced plasma Ang II by ∼50%, and increased bradykinin by 1.4-fold. Furthermore, DLTAGLLE reshaped the gut microbiota composition by lowering the Firmicutes/Bacteroidetes (F/B) ratio and enriching SCFA-associated taxa such as Lactobacillus, Bifidobacterium, and Corynebacteriaceae_UCG-002. These findings position DLTAGLLE as a promising marine-derived, orally active antihypertensive peptide that restores endothelial redox homeostasis, modulates the RAS-kinin axis, and beneficially reshapes the gut microbiome, supporting its potential as a functional dietary ingredient for blood pressure regulation.