The Emerging Role of Butyrate in Immune Tolerance

The intestine is the largest peripheral lymphoid organ in humans and interacts with a vast intestinal microbiota. There is a growing awareness that the intestinal microbiota plays a crucial role in training, functioning, and inducing the host immune system, affecting the overall health of the host. However, the composition of the intestinal microbiota varies with factors such as ethnicity, geographical location, and diet, making it difficult to form a universal pattern. Microbial metabolites are regarded as messengers of the intestinal microbiota, capable of generating unique molecules that humans cannot produce. Many cells of the immune system also express receptors for these molecules, playing a key role in guiding the differentiation of immune cells. Short-chain fatty acids (SCFAs) produced through the fermentation of dietary fiber, particularly butyrate, serve as key mediators linking gut microbial metabolism to host immune regulation. Accumulating evidence indicates that butyrate contributes to the maintenance of immune homeostasis by modulating immune cell metabolism, differentiation, cytokine production, and intercellular communication. The immunological effects of butyrate cannot be simply categorized as immunosuppressive or tolerance-inducing. Instead, its functional outcomes are shaped by multiple factors, including immune cell type, local concentration, tissue microenvironment, route of administration, and disease context. This context-dependent nature highlights the complexity of butyrate-mediated immune regulation and underscores the need for a more comprehensive understanding of its mechanisms of action. This review summarizes the effects of butyrate on macrophages, dendritic cells (DCs), lymphocytes, and neutrophils with respect to cellular metabolism, differentiation, cytokine secretion, and intercellular communication. In addition, common underlying mechanisms, including histone deacetylase (HDAC) inhibition, metabolic reprogramming, and G protein-coupled receptor (GPCR) signaling, together with current controversies and knowledge gaps, are discussed to provide new insights into the role of butyrate in maintaining immune homeostasis.