The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus.

Short-chain fatty acids (SCFAs) are the primary metabolites of dietary fiber fermented by intestinal flora. They play a systemic role in the immune regulation of type 2 diabetes mellitus (T2DM) by integrating receptor-mediated signaling and epigenetic regulatory mechanisms. At the receptor pathway level, SCFAs activate G protein-coupled receptors such as GPR41/43/109 A, initiate downstream signaling cascades including MAPK, NF-κB, and mTOR/STAT3, and thereby achieve rapid modulation of immune cell function; at the epigenetic regulatory level, SCFAs induce chromatin remodeling and gene expression reprogramming by inhibiting histone deacetylase (HDAC) activity, giving immune cells long-term functional memory. These two pathways act coordinately to broadly regulate the functional status of innate and adaptive immune cells. In innate immune cells, SCFAs influence macrophage polarization, neutrophil activation, dendritic cell antigen presentation, mast cell degranulation, and eosinophil-mediated immune homeostasis; in adaptive immune cells, SCFAs regulate the differentiation of CD4 + T cell subsets, CD8 + T cell effector function, regulatory T cell stability, B cell antibody production and cytokine secretion of congenital lymphocytes (ILCs). These immunomodulatory effects are integrated in multiple metabolic organs such as adipose tissue, liver, islet and intestine to collectively improve T2DM-related chronic inflammation and insulin resistance. Investigation of SCFAs reveals the molecular basis of the interaction between intestinal flora and host immune metabolism, and provides a theoretical foundation for the prevention and treatment of T2DM based on dietary intervention or microecological regulation.