Signaling Through SCFA Receptors Gpr43 and Gpr109a Drives Pro‐Inflammatory M1 Macrophage Polarization in Periodontitis

BACKGROUND: This study investigated the link between an imbalance in microbiota-derived short-chain fatty acids (SCFAs) and dysregulated host immunity in periodontitis, focusing on the metabolic reprograming of inflammatory macrophages. METHODS: We conducted a systematic review and meta-analysis of SCFA levels. Bulk RNA sequencing (RNA-seq) data from human gingival tissue (n = 24) were analyzed for differential expression and pathway enrichment, with immune cell composition estimated by Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT). Mouse single-cell RNA-seq (scRNA-seq) data were integrated, and myeloid cells (MCs) were subset for detailed clustering, differential analysis, and pseudotime trajectory reconstruction. RESULTS: Meta-analysis indicated a decreasing, though nonsignificant, trend in butyrate levels in periodontitis. Bulk RNA-seq identified 692 differentially expressed genes (DEGs) enriched in immune and cytokine signaling pathways. Immune deconvolution revealed an increased proportion of M1 macrophages and Tregs, alongside a decrease in M2 macrophages. Single-cell analysis confirmed the significant expansion of M1-like macrophages, which highly expressed SCFA receptors (Gpr43 and Gpr109a), inflammatory transcription factors (Nfkb1 and Hif1a), and effector molecules (Il1b). The pseudotime trajectory demonstrated a continuous M2-to-M1 polarization, marked by a decline in M2 markers and a rise in M1 markers. CONCLUSION: Periodontitis is characterized by SCFA metabolic imbalance and a shift in MCs toward a pro-inflammatory M1 state. The upregulation of SCFA receptors and the NF-κB/HIF-1 axis in M1 macrophages suggests an "SCFA receptor-metabolic sensing-inflammatory transcription" mechanism drives disease progression, providing a rationale for therapeutic strategies targeting this pathway.