HGF Aggravated Periodontitis-Associated Gut Barrier and Microbial Dysfunction: Implications for Oral–Gut Axis Regulation

While periodontitis is increasingly linked to systemic disorders through the oral-gut axis, the molecular mediators driving gut microbiota dysbiosis and barrier disruption remain elusive. Hepatocyte growth factor (HGF), a novel regulator of inflammatory bone loss in periodontitis, may serve as a critical communicator between oral infection and distal intestinal pathology. This study investigates how HGF overexpression modulates the gut microbial ecosystem and intestinal barrier integrity in a transgenic periodontitis model. In this study, we combined 16S rRNA sequencing of fecal microbiota with comprehensive gut barrier assessments, including systemic markers (D-lactate, LPS, and DAO ELISA), structural integrity (villous morphology), and molecular analysis (ZO-1, occludin, and NOD2 immunohistochemistry), using HGF-overexpressing transgenic (HGF-Tg) mice with periodontitis. The results demonstrated that HGF increased gut permeability in the context of periodontitis, as evidenced by elevated serum levels of D-lactate and LPS compared to wild type (WT) mice. In addition, gut villous morphology disorder was observed in HGF-Tg mice with periodontitis. HGF also diminished the protein level of occludin and upregulated NOD2 expression in mice with periodontitis. Moreover, HGF-Tg mice with periodontitis exhibited significant dysbiosis of gut microbiota, with reduced levels of probiotics (e.g., <i>Faecalibaculum</i>). Notably, HGF also increased the enrichment of the periodontitis-associated pathogens (e.g., <i>Desulfovibrio</i> and <i>Streptococcus</i>) in the gut. Microbial functions, particularly metabolic pathways, were significantly altered by HGF when periodontitis occurred. Some microorganisms like <i>g_Desulfovibrio</i> may play a role in gut barrier disorder in HGF-Tg mice with periodontitis. Overall, our findings position HGF as a novel orchestrator of oral-gut crosstalk, where its overexpression reshapes gut microbial ecology toward a "leaky gut" phenotype to compromise intestinal barrier integrity, further deepening our understanding of the oral-gut axis.