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Colonic luminal pH is a fundamental feature of the gut environment, shaped largely by the composition and activity of the gut microbiota. Diets rich in fermentable fiber lower the colonic pH primarily through their microbial fermentation, which produces short-chain fatty acids (SCFAs) as metabolic by-products. While the local effects of colonic pH on microbiota composition and intestinal function are increasingly well defined, its systemic consequences remain poorly understood. This review explores the determinants of colonic pH and its dynamic interactions with the gut microbiota, with a particular focus on how these processes may influence and be influenced by host physiology beyond the gastrointestinal (GI) tract. Since dietary fiber and its acidic metabolites confer protection against hypertension, there is growing interest in whether fiber-induced colonic acidification contributes to blood pressure regulation. Notably, participants with hypertension exhibit a higher (more alkaline) colonic minimum pH compared to those with normal blood pressure, further supporting the potential link between luminal acidity and blood pressure control. Particular attention has been given to proton-sensing G protein-coupled receptors (GPCRs), namely, GPR4, GPR65 and GPR68, which are increasingly implicated in regulating immune and cardiovascular functions. Emerging evidence suggests that gene-environment interactions involving GPR65 and GPR68 may influence blood pressure regulation through pH-sensitive pathways; GPR65 primarily via immune modulation, and GPR68 through vascular mechanisms. Therefore, understanding how colonic pH impacts these pathways may uncover novel therapeutic targets for hypertension.