Dendritic cells (DCs) are responsible for maintaining tolerance to harmless antigens in the gut
however, the mechanism by which bacterial metabolites induce DC tolerance remains to be studied. Here, we observed that gut commensal bacterium-derived L-lysine stimulated the serine, glycine, one-carbon (SGOC) metabolism through the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-coenzyme A (AcCoA)-mechanistic target of rapamycin (mTOR) axis in DCs. This activation led to an increase in S-adenosyl methionine (SAM) and disruptor of telomeric silencing 1-like (DOT1L) expression, resulting in enhanced dimethylation on H3 lysine 79 (H3K79me2) enrichment at Tgfb and signal transducers and activator of transcription 3 (Stat3) gene promoters, which promote immune tolerance characteristics in DCs. The lysine-induced DC tolerance in restoring homeostasis was demonstrated using mouse models of immune-inflammatory diseases and phosphoglycerate dehydrogenase (Phgdh) conditional knockout mice. The single-cell RNA sequencing (scRNA-seq) analysis revealed that L-lysine restored homeostasis during inflammatory disorders by switching DCs to a tolerance state in vivo. Moreover, the enzyme by which bacteria effectively produce L-lysine is identified. The study reveals an unknown mechanism for regulating immune homeostasis through the intricate interplay of bacterial L-lysine, SGOC metabolism, histone methylation, and DC tolerance.