肠道菌群及代谢产物SCFA/乳酰化修饰在慢阻肺肠-肺远端调控ILC2的作用机制研究

课题组发现2型固有淋巴细胞（ILC2）参与并调控Th2型免疫反应，在慢阻肺慢性炎症反应中起重要作用。研究报道，肠道菌群可以通过产生短链脂肪酸（SCFAs）抑制ILC2细胞GATA3表达、糖酵解通路，减轻肺部炎症反应。病理条件下，ILC2通过肠-肺轴从肠道远端转移至肺，但是我们对慢阻肺肠ILC2发生、分化及肺转移的调节还知之甚少。本课题通过16S rDNA、HPLC、流式等方法鉴定慢阻肺模型小鼠肠道菌群、SCFAs与肠、肺ILC2的相关关系；通过单细胞测序、ChIP-seq、多重核酸定量技术等检测肠、肺ILC2细胞糖酵解通路、组蛋白Kla的变化；结合临床病例数据揭示肠道菌群导致SCFAs变化、引起ILC2细胞GATA3及肺转移相关基因乳酰化修饰，从SCFAs-ILC2细胞表观遗传修饰角度揭示慢阻肺发生、发展过程中肺与大肠相表里的深层作用机制。

Our pilot studies showed that The type 2 innate lymphoid cells regulate Th2 type immune response, and played an important role in chronic inflammation of COPD.Studies have reported that under pathological conditions, ILC2 is transferred directly from the gut to the lungs via the gut-lung axis, and we know little about the development, differentiation and lung metastasis of ILC2 in COPD. The intestinal microbiota can reduce short-chain fatty acids (SCFAs) to inhibit GATA3 expression and glycolytic pathway in ILC2 cells, and reduce lung inflammation. However, the mechanism by which intestinal microbiota and SFCAs affect the glycolytic pathway to regulate ILC2 in COPD is unknown. In this subject, 16S rDNA, HPLC, and flow cytometry were used to identify the intestinal microbiota, SCFAs, and the correlation between intestinal and lung ILC2 in COPD model mice; single cell sequencing, ChIP-seq, and multiple nucleic acid quantitative techniques were used to detect changes of histone Kla and glycolytic pathway in lung ILC2 cells; Combined with clinical case data, it was revealed that the intestinal microbiota, SCFAs and caused lactylation of GATA3 and related factor genes in ILC2 cells. From the perspective of epigenetic modification of SCFAs-ILC2 cells, the underlying mechanism of the lung and the large intestine form an external-internal relationship during COPD development was revealed.