p38 MAP kinase senses short-chain fatty acids to attenuate Toll-like receptor signaling and intestinal inflammation.

Toll-like receptor (TLR) signaling is critical for innate immune system. However, whether it is directly modulated by microbiota-derived metabolites remains unclear. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate suppress TLR signaling by directly binding p38α MAP kinase, promoting its interaction with TAB1, thereby activating p38α via autophosphorylation. Activated p38α then phosphorylates TRAF3 at serine 85, inhibiting K63-linked polyubiquitylation of TRAF3 and disrupting TBK1-IRF3 activation, leading to reduced macrophage activation and intestinal inflammation. In ulcerative colitis patients, fecal levels of propionate and butyrate positively correlate with p38α activity and TRAF3 S85 phosphorylation, but inversely correlate with TBK1 activation, and cytokine levels. Notably, oral administration of propionate in three patients with ulcerative colitis markedly improved intestinal inflammation and clinical symptoms. These findings reveal p38α as a direct sensor for microbiota-derived SCFAs that suppress TLR signaling through nonmetabolic functions of propionate and butyrate, providing the first clinical evidence that propionate supplementation represents a practical dietary strategy for ulcerative colitis management.