Short-Chain Fatty Acids at the Crossroads of Microbiota, Immunometabolism, and Inflammation

Abstract

The rising incidence of chronic autoimmune and autoinflammatory diseases has been increasingly associated with environmental and lifestyle factors, including Western dietary patterns, intestinal dysbiosis, and reduced production of short-chain fatty acids (SCFAs). Reduced production of acetate, propionate, and butyrate has been associated with impaired epithelial barrier function, altered peripheral immune tolerance, and low-grade systemic inflammation. This article integrates and systematizes current knowledge in the field of immunometabolism, focusing on the role of the microbiota–metabolism–immunity axis. The molecular mechanisms by which these bacterial metabolites modulate immune function—both through the activation of specific surface receptors and direct epigenetic regulation—are analyzed in detail. SCFAs have been shown to actively reprogram the metabolic and transcriptional profiles of effector cells, stimulating anti-inflammatory macrophage polarization, suppressing cellular inflammatory cascades, and inducing the differentiation of protective regulatory T cells. To address the pharmacokinetic limitations of natural fatty acids, this study critically evaluates modern translational strategies. The clinical potential of synthetic receptor agonists, selective epigenetic modulators, and advanced next-generation bacterial consortia is analyzed. The presented data synthesis not only organizes the pathophysiological foundations but, above all, points to promising new directions for personalized non-pharmacological immunomodulation in the treatment of inflammatory diseases.