Short-chain fatty acids (SCFAs), produced by bacterial fermentation, are crucial for regulating immune cell function. These metabolites, including acetic, propionic, and butyric acids, are found in high concentrations in the intestinal tract and are taken up by intestinal epithelial cells (IECs). SCFAs serve as an energy source for IECs and modulate immune responses through G protein-coupled receptors (FFAR2, FFAR3, GPR109a, and Olfr78), as well as by influencing enzymes and transcription factors like histone acetyltransferases and deacetylases. They play a key role in maintaining intestinal homeostasis and are involved in various immune functions, including the regulation of epithelial barrier integrity, antimicrobial peptide production, and immune cell differentiation. SCFAs interact with innate immune mechanisms, such as epithelial cells, neutrophils, monocytes, macrophages, and dendritic cells (DCs). They modulate the production of cytokines and chemokines, influence immune cell proliferation and apoptosis, and affect the balance between pro- and anti-inflammatory responses. For example, SCFAs can enhance the production of antimicrobial peptides, reduce pro-inflammatory cytokines, and promote the differentiation of regulatory T cells (Tregs). However, their effects can vary depending on the cell type, the specific SCFA, and the inflammatory context. In adaptive immunity, SCFAs modulate T-cell activation and effector functions, promoting a tolerogenic profile and suppressing excessive immune responses. They can induce the generation of Tregs and influence Th1, Th2, and Th17 polarization. Despite these beneficial effects, SCFAs can also promote inflammatory responses under certain conditions, highlighting the complexity of their role in immune regulation. The interaction between SCFAs and the immune system is multifaceted, involving various molecular mechanisms and cellular targets. While much is known about their role in maintaining intestinal homeostasis, the exact mechanisms and their implications in disease remain areas of active research. Understanding these interactions could lead to new therapeutic strategies for inflammatory and infectious diseases.Short-chain fatty acids (SCFAs), produced by bacterial fermentation, are crucial for regulating immune cell function. These metabolites, including acetic, propionic, and butyric acids, are found in high concentrations in the intestinal tract and are taken up by intestinal epithelial cells (IECs). SCFAs serve as an energy source for IECs and modulate immune responses through G protein-coupled receptors (FFAR2, FFAR3, GPR109a, and Olfr78), as well as by influencing enzymes and transcription factors like histone acetyltransferases and deacetylases. They play a key role in maintaining intestinal homeostasis and are involved in various immune functions, including the regulation of epithelial barrier integrity, antimicrobial peptide production, and immune cell differentiation. SCFAs interact with innate immune mechanisms, such as epithelial cells, neutrophils, monocytes, macrophages, and dendritic cells (DCs). They modulate the production of cytokines and chemokines, influence immune cell proliferation and apoptosis, and affect the balance between pro- and anti-inflammatory responses. For example, SCFAs can enhance the production of antimicrobial peptides, reduce pro-inflammatory cytokines, and promote the differentiation of regulatory T cells (Tregs). However, their effects can vary depending on the cell type, the specific SCFA, and the inflammatory context. In adaptive immunity, SCFAs modulate T-cell activation and effector functions, promoting a tolerogenic profile and suppressing excessive immune responses. They can induce the generation of Tregs and influence Th1, Th2, and Th17 polarization. Despite these beneficial effects, SCFAs can also promote inflammatory responses under certain conditions, highlighting the complexity of their role in immune regulation. The interaction between SCFAs and the immune system is multifaceted, involving various molecular mechanisms and cellular targets. While much is known about their role in maintaining intestinal homeostasis, the exact mechanisms and their implications in disease remain areas of active research. Understanding these interactions could lead to new therapeutic strategies for inflammatory and infectious diseases.