Short-chain fatty acids (SCFAs), such as acetic, propionic, and butyric acids, are bacterial fermentation products found in high concentrations in the intestinal tract. These metabolites are taken up by intestinal epithelial cells (IECs) and act as a link between the microbiota and the immune system. SCFAs modulate various cellular processes, including gene expression, chemotaxis, differentiation, proliferation, and apoptosis, through the activation of G protein-coupled receptors (GPCRs) and the modulation of enzymes and transcription factors. They play a crucial role in maintaining intestinal homeostasis and are implicated in the development of inflammatory bowel disease, obesity, and other pathological conditions. SCFAs influence the immune system by affecting epithelial cells, neutrophils, monocytes, macrophages, and T lymphocytes. They can act as pro- or anti-inflammatory molecules depending on the cell type and conditions. For example, SCFAs can inhibit the growth of cancerous colonic cells and increase the production of antimicrobial peptides and cytokines by IECs. In neutrophils, SCFAs modulate their recruitment, effector function, and survival. In monocytes and macrophages, they can induce anti-inflammatory effects by regulating cytokine production and prostaglandin E2. In T lymphocytes, SCFAs can induce the generation of regulatory T cells (Tregs) and affect Th1, Th2, and Th17 polarization. The bidirectional interaction between the microbiota and the immune system, mediated by SCFAs, is essential for maintaining physiological and pathological homeostasis.Short-chain fatty acids (SCFAs), such as acetic, propionic, and butyric acids, are bacterial fermentation products found in high concentrations in the intestinal tract. These metabolites are taken up by intestinal epithelial cells (IECs) and act as a link between the microbiota and the immune system. SCFAs modulate various cellular processes, including gene expression, chemotaxis, differentiation, proliferation, and apoptosis, through the activation of G protein-coupled receptors (GPCRs) and the modulation of enzymes and transcription factors. They play a crucial role in maintaining intestinal homeostasis and are implicated in the development of inflammatory bowel disease, obesity, and other pathological conditions. SCFAs influence the immune system by affecting epithelial cells, neutrophils, monocytes, macrophages, and T lymphocytes. They can act as pro- or anti-inflammatory molecules depending on the cell type and conditions. For example, SCFAs can inhibit the growth of cancerous colonic cells and increase the production of antimicrobial peptides and cytokines by IECs. In neutrophils, SCFAs modulate their recruitment, effector function, and survival. In monocytes and macrophages, they can induce anti-inflammatory effects by regulating cytokine production and prostaglandin E2. In T lymphocytes, SCFAs can induce the generation of regulatory T cells (Tregs) and affect Th1, Th2, and Th17 polarization. The bidirectional interaction between the microbiota and the immune system, mediated by SCFAs, is essential for maintaining physiological and pathological homeostasis.