Butyrate epigenetically licenses sustained epithelial-T cell crosstalk for intestinal immune tolerance.

Intestinal epithelial cells (IEC) are the primary cell type in direct contact with stimuli from the luminal microbiota, playing a critical role in host-microbe interactions. However, how IECs communicate with underlying immune cells to maintain homeostasis remains poorly understood. In addition, the mechanisms by which IECs sense microbiota-derived stimuli to initiate this crosstalk are not yet fully understood. Here, we demonstrate that oral administration of the gut microbiota metabolite butyrate induces sustained IL-10 production in CD4⁺ T cells, conferring long-lasting protection against intestinal inflammation even after treatment withdrawal. This persistent immunoregulatory effect is also observed in germ-free mice, indicating the establishment of a butyrate-conditioned intestinal environment. By metabolomic profiling, we identify N1-acetylspermidine as a metabolite contributing to the IL-10-inducing activity of butyrate-treated IEC-conditioned medium. Mechanistically, butyrate induces sustained transcriptional and epigenetic activation of the acetylpolyamine biosynthetic enzyme Sat1 in IECs, which catalyzes the acetylation of spermidine to generate N1-acetylspermidine, and this activation persists after butyrate withdrawal. Together, our findings reveal a mechanism by which butyrate sensing establishes persistent crosstalk between IECs and T cells, thereby maintaining intestinal immune tolerance through epigenetic regulation and reprogramming of epithelial metabolism.