Short-Chain Fatty Acids in Sepsis: Mechanisms of Action and Therapeutic Advances.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Its development and progression involve multiple interconnected mechanisms, including uncontrolled inflammation, immunosuppression, metabolic reprogramming, intestinal barrier disruption, and multi-organ injury. Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are important metabolites produced by the anaerobic fermentation of dietary fiber and indigestible carbohydrates by gut microbiota. During sepsis, antibiotic exposure, intestinal hypoperfusion, insufficient nutritional substrates, and microbial dysbiosis may deplete SCFA-producing bacteria and lower SCFA levels, thereby aggravating intestinal barrier dysfunction, endotoxin translocation, and systemic inflammatory responses. SCFAs can influence sepsis-associated intestinal, pulmonary, cardiac, hepatic, renal, and cerebral injury by activating receptors such as free fatty acid receptor 2 (FFAR2)/G protein-coupled receptor 43 (GPR43), free fatty acid receptor 3 (FFAR3)/G protein-coupled receptor 41 (GPR41), and G protein-coupled receptor 109A (GPR109A); inhibiting histone deacetylases; and regulating immune-cell metabolism, inflammasome activation, oxidative stress, mitochondrial function, and modes of cell death. In recent years, strategies such as direct SCFA supplementation, promotion of endogenous SCFA production, restoration of SCFA-producing microbial communities, and targeting of SCFA receptors and downstream signaling pathways have shown therapeutic potential. However, their clinical translation remains limited by uncertainties regarding dose, timing, route of administration, patient stratification, and safety. This review systematically summarizes the mechanisms of action and therapeutic advances of SCFAs in sepsis, aiming to provide a reference for microbiome-based interventions and metabolism-targeted therapies in sepsis.