<scp> <i>Porphyromonas gingivalis</i> </scp> Drives Trained Immunity via the Glycolysis– <scp>SIRT1</scp> Axis to Aggravate Colitis

ABSTRACT Aim To investigate whether Porphyromonas gingivalis aggravates colitis through trained immunity, and to elucidate the underlying metabolic and epigenetic mechanisms. Materials and Methods In vivo, bone marrow from P. gingivalis ‐infected mice was transplanted into recipient mice, followed by induction of colitis. In vitro, macrophages trained with P. gingivalis were subjected to lipopolysaccharide (LPS) re‐stimulation to assess inflammatory cytokine production. Histone acetylation and untargeted metabolomic analysis were examined in P. gingivalis ‐infected macrophages. Results Recipient mice transplanted with bone marrow from P. gingivalis ‐infected donors developed more severe colitis. Moreover, macrophages trained with P. gingivalis showed an enhanced inflammatory response upon LPS re‐stimulation. Mechanistically, histone H3 lysine 27 acetylation (H3K27ac) was markedly increased following P. gingivalis infection and remained elevated after its removal. Furthermore, P. gingivalis drives a metabolic shift towards glycolysis, which reduces nicotinamide adenine dinucleotide (NAD + ) levels and sirtuin 1 (SIRT1) activity, thereby attenuating SIRT1‐mediated deacetylation of H3K27ac. Inhibiting glycolysis or activating SIRT1 reversed P. gingivalis ‐induced trained immunity and alleviated the aggravated colitis phenotype. Conclusions P. gingivalis induces trained immunity via the glycolysis–SIRT1 axis and aggravates colitis. These findings provide a novel explanation for the persistent risk of colitis associated with periodontitis.