Butyrate Alleviates Diabetic Periodontitis by Suppressing Macrophage M1 Polarization and PANoptosis ‐Like Cell Death

Dysbiosis of the gut microbiota in diabetes is accompanied by reduced levels of short-chain fatty acids (SCFAs), including butyrate, a four-carbon SCFA with immunomodulatory activity. Inflammatory stimulation drives macrophage polarization toward an M1 phenotype and can induce concurrent activation of markers associated with pyroptosis, apoptosis, and necroptosis, consistent with a PANoptosis-like cell death phenotype that may exacerbate periodontal destruction. Here, we investigated whether butyrate attenuates diabetic periodontitis by restraining macrophage M1 polarization and reducing PANoptosis-like cell death. In a mouse model of diabetic periodontitis, oral butyrate treatment alleviated alveolar bone loss and reduced M1 polarization and PANoptosis-like death in periodontal tissues. In THP-1-derived macrophages, we assessed inflammatory polarization and PANoptosis-like cell death under inflammatory stimulation with or without butyrate pretreatment. Butyrate suppressed M1-associated programs and reduced PANoptosis-like cell death, accompanied by inhibition of histone deacetylase 3 (HDAC3) and attenuation of signal transducer and activator of transcription 1 (STAT1) signaling. Moreover, butyrate mitigated inflammatory responses in periodontal ligament stem cells (PDLSCs) and promoted osteogenic differentiation. Collectively, these findings suggest that butyrate mitigates diabetic periodontitis progression by suppressing macrophage inflammatory programs while supporting PDLSC osteogenesis, highlighting its potential as an adjunctive immunomodulatory approach.