Periodontitis has been emphasized as a risk factor of insulin resistance–related systemic diseases. Accumulating evidence has suggested a possible “oral–gut axis” linking oral infection and extraoral diseases, but it remains unclear whether periodontal pathogens can survive the barriers of the digestive tract and how they play their pathogenic roles. The present study established a periodontitis mouse model through oral ligature plus Porphyromonas gingivalis inoculation and demonstrated that periodontitis aggravated diet-induced obesity and insulin resistance, while also causing P. gingivalis enrichment in the intestine. Metabolic labeling strategy validated that P. gingivalis could translocate to the gastrointestinal tract in a viable state. Oral administration of living P. gingivalis elicited insulin resistance, while administration of pasteurized P. gingivalis had no such effect. Combination analysis of metagenome sequencing and nontargeted metabolomics suggested that the tryptophan metabolism pathway, specifically indole and its derivatives, was involved in the pathogenesis of insulin resistance caused by oral administration of living P. gingivalis. Moreover, liquid chromatography–high-resolution mass spectrometry analysis confirmed that the aryl hydrocarbon receptor (AhR) ligands, mainly indole acetic acid, tryptamine, and indole-3-aldehyde, were reduced in diet-induced obese mice with periodontitis, leading to inactivation of AhR signaling. Supplementation with Ficz (6-formylindolo (3,2-b) carbazole), an AhR agonist, alleviated periodontitis-associated insulin resistance, in which the restoration of gut barrier function might play an important role. Collectively, these findings reveal that the oral–gut translocation of viable P. gingivalis works as a fuel linking periodontitis and insulin resistance, in which reduction of AhR ligands and inactivation of AhR signaling are involved. This study provides novel insight into the role of the oral–gut axis in the pathogenesis of periodontitis-associated comorbidities.

中文翻译：

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活牙龈卟啉单胞菌的肠道移位导致胰岛素抵抗

牙周炎被认为是胰岛素抵抗相关全身性疾病的危险因素。越来越多的证据表明，口腔感染和口外疾病之间可能存在一条“口肠轴”，但牙周病原体是否能够在消化道屏障中存活以及它们如何发挥致病作用仍不清楚。本研究通过口腔结扎加接种牙龈卟啉单胞菌建立了牙周炎小鼠模型，并证明牙周炎加剧了饮食引起的肥胖和胰岛素抵抗，同时也导致牙龈卟啉单胞菌在肠道内富集。代谢标记策略验证了牙龈卟啉单胞菌可以以存活状态转移到胃肠道。口服活的牙龈卟啉单胞菌会引起胰岛素抵抗，而施用巴氏灭菌的牙龈卟啉单胞菌则没有这种作用。宏基因组测序和非靶向代谢组学的组合分析表明，色氨酸代谢途径，特别是吲哚及其衍生物，参与了口服活体牙龈卟啉单胞菌引起的胰岛素抵抗的发病机制。此外，液相色谱-高分辨率质谱分析证实，饮食诱导的肥胖牙周炎小鼠中，芳基烃受体（AhR）配体（主要是吲哚乙酸、色胺和吲哚-3-醛）减少，导致失活。 AhR 信号传导。补充 Ficz（6-甲酰基吲哚 (3,2-b) 咔唑）（一种 AhR 激动剂）可减轻牙周炎相关的胰岛素抵抗，其中肠道屏障功能的恢复可能发挥重要作用。总的来说，这些研究结果表明，活牙龈卟啉单胞菌的口腔-肠道易位是牙周炎和胰岛素抵抗之间的一种推动因素，其中涉及 AhR 配体的减少和 AhR 信号传导的失活。这项研究为口肠轴在牙周炎相关合并症发病机制中的作用提供了新的见解。