Wang Xiaoxue, Luo Yilin, Huang Yanlan, Jin Zhiheng, Li Zhichao, Chen Junyu, Hu Fei, Zhang Xueyang, Rausch-Fan Xiaohui
Department of Stomatology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, China.
Stomatological Hospital, Southern Medical University, Guangzhou, China.
J Clin Periodontol. 2023 May;50(5):627-641. doi: 10.1111/jcpe.13759. Epub 2022 Dec 27.
To evaluate whether and how microbiota-derived metabolites associated with periodontitis aggravate colitis in mice.
A mouse model of periodontitis and colitis was constructed. Unbiased transcriptomic analyses of the colon were performed to explore important pathways through which periodontitis exacerbated colitis. Oral and gut bacteria were analysed using 16S rRNA sequencing. Gas chromatography-mass spectrometry was used to observe the alterations of oral and gut metabolites. Isolated intestinal lamina propria lymphocytes were analysed by flow cytometry. Inflammasome pathway was detected using qRT-PCR, Western blotting or ELISA.
Periodontitis activated the colonic inflammasome pathway and altered the gut microbial composition and metabolite profiles in mice with colitis. Notably, periodontitis induced increase of the faecal metabolite isoleucine (Ile) which was synthesized by microbiota and plants. Moreover, periodontitis upregulated the Ile levels in saliva, but not in serum, indicating that Ile might be an oral pathobiont-synthesizing metabolite that transited from the oral cavity to the gut. Ile triggered the inflammasome pathway, upregulated the number of inflammatory IL-1β MHCII Ly6C monocytes in colonic lamina propria, and exacerbated colitis. Further studies found that the Ile metabolite acetyl-coenzyme A positively regulated NLRP3 inflammasome by KAT5-mediated acetylation of NLRP3.
Our study revealed that alteration in periodontitis-induced microbial metabolites deteriorated colitis in a mouse model and that this was associated with Ile production.
评估与牙周炎相关的微生物群衍生代谢产物是否以及如何加重小鼠结肠炎。
构建牙周炎和结肠炎小鼠模型。对结肠进行无偏转录组分析，以探索牙周炎加重结肠炎的重要途径。使用16S rRNA测序分析口腔和肠道细菌。采用气相色谱-质谱法观察口腔和肠道代谢产物的变化。通过流式细胞术分析分离的肠固有层淋巴细胞。使用qRT-PCR、蛋白质免疫印迹法或酶联免疫吸附测定法检测炎性小体途径。
牙周炎激活了结肠炎小鼠的结肠炎性小体途径，并改变了肠道微生物组成和代谢产物谱。值得注意的是，牙周炎导致粪便中由微生物群和植物合成的代谢产物异亮氨酸（Ile）增加。此外，牙周炎上调了唾液中Ile的水平，但血清中未上调，这表明Ile可能是一种从口腔转移到肠道的口腔致病共生菌合成的代谢产物。Ile触发炎性小体途径，上调结肠固有层中炎性IL-1β MHCII Ly6C单核细胞的数量，并加重结肠炎。进一步研究发现，Ile代谢产物乙酰辅酶A通过KAT5介导的NLRP3乙酰化对NLRP3炎性小体起正向调节作用。
我们的研究表明，牙周炎诱导的微生物代谢产物改变会使小鼠模型中的结肠炎恶化，且这与Ile的产生有关。
