High-Salt Diet Links Gut Microbiota, Intestinal Barrier Function, and Macrophage Responses

The Global North is increasingly exposed to a Western diet characterized by high fat, sugar, and salt content. Excess dietary salt has been linked to cardiovascular disease and hypertension and can accumulate in multiple tissues, exerting local immunomodulatory effects. Beyond these systemic consequences, a high-salt diet (HSD) is associated with gut dysbiosis, which alters the production of microbial metabolites, such as short-chain fatty acids (SCFAs), and compromises intestinal barrier integrity, thereby facilitating bacterial translocation and contributing to liver and kidney injury. These alterations are associated with inflammatory responses, although their direction and magnitude depend on dietary duration, microbial baseline composition, and experimental models. While most studies have focused on HSD-induced modulation of T cell responses, emerging data highlight macrophages as underexplored mediators of HSD-driven immune and metabolic effects. In this review, we summarize current knowledge on HSD-induced alterations of the intestinal microbiota, microbial metabolites, gut barrier function and macrophage function, and discuss their potential interplay along the gut-liver axis. In addition, we highlight key gaps and challenges that must be addressed to improve translational relevance.