Chen Zhen, Zhong Yang, Chen Lu, Liu Weijia, Lin Chuyin, Chen Yannan, Wang Xinhong
School of Stomatology, Guangzhou Medical University, Guangzhou 510180, China.
Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510180, China.
Biology (Basel). 2025 May 2;14(5):496. doi: 10.3390/biology14050496.
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., ). Notably, HGF also increased the enrichment of the periodontitis-associated pathogens (e.g., and ) in the gut. Microbial functions, particularly metabolic pathways, were significantly altered by HGF when periodontitis occurred. Some microorganisms like 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.
虽然牙周炎通过口腔-肠道轴与全身疾病的关联日益增加，但驱动肠道微生物群失调和屏障破坏的分子介质仍不明确。肝细胞生长因子（HGF）是牙周炎中炎症性骨质流失的一种新型调节因子，可能是口腔感染与远端肠道病理之间的关键沟通者。本研究调查了HGF过表达如何在转基因牙周炎模型中调节肠道微生物生态系统和肠道屏障完整性。在本研究中，我们使用过表达HGF的转基因（HGF-Tg）牙周炎小鼠，将粪便微生物群的16S rRNA测序与全面的肠道屏障评估相结合，包括全身标志物（D-乳酸、LPS和DAO ELISA）、结构完整性（绒毛形态）和分子分析（ZO-1、闭合蛋白和NOD2免疫组织化学）。结果表明，与野生型（WT）小鼠相比，HGF在牙周炎情况下增加了肠道通透性，血清D-乳酸和LPS水平升高证明了这一点。此外，在患有牙周炎的HGF-Tg小鼠中观察到肠道绒毛形态紊乱。HGF还降低了牙周炎小鼠中闭合蛋白的蛋白水平，并上调了NOD2表达。此外，患有牙周炎的HGF-Tg小鼠表现出肠道微生物群的显著失调，益生菌水平降低（例如）。值得注意的是，HGF还增加了肠道中牙周炎相关病原体（例如和）的富集。当发生牙周炎时，HGF显著改变了微生物功能，特别是代谢途径。一些微生物如可能在患有牙周炎的HGF-Tg小鼠的肠道屏障紊乱中起作用。总体而言，我们的研究结果将HGF定位为口腔-肠道串扰的新型协调者，其过表达将肠道微生物生态重塑为“肠道渗漏”表型，损害肠道屏障完整性，进一步加深了我们对口腔-肠道轴的理解。
