肠道菌群代谢产物L-天冬氨酸介导HRH1加重肺泡上皮细胞损伤在重症急性胰腺炎相关肺损伤中的机制研究

急性肺损伤（ALI）作为重症急性胰腺炎（SAP）最常见并发症，出现较早、治疗困难，其预后较差。SAP引起肠道菌群改变已被证实参与局部炎症进展，但尚无研究探讨其在ALI中的作用机制。肠道菌群主要依赖“肠道菌群——宿主共代谢轴”发挥功能，借助16srDNA测序及代谢组学技术，我们前期发现肠道菌群代谢产物L-天冬氨酸水平与SAP相关ALI严重程度密切相关；进一步对其靶基因功能学分析发现，肠道菌群代谢产物L-天冬氨酸破坏肠道粘膜屏障入血加重SAP相关ALI。有鉴于此，本项目借助微生物组学、代谢组学及转录组学研究技术，在临床样本、条件性敲除小鼠及原代细胞层面，着力探讨肠道菌群代谢产物L-天冬氨酸介导HRH1激活Ⅱ型肺泡上皮细胞MAPK与NF-κB通路促进ALI的关键机制，为寻找早期预测及评估SAP相关ALI严重程度的生物标志物，开发特异性靶向药物及推动粪菌移植在SAP病人中的临床应用提供崭新思路。

Acute lung injury (ALI) is the most common complication in severe acute pancreatitis (SAP). It has a poor prognosis because of the early occurrence and the treatment difficulties. The change of gut microbiome has been proved to be crucial indicators for the local inflammatory response in the progression of SAP. However, the mechanism of gut microbiome in processing ALI remains to be declared. It is known to all that gut microbiome exacerbate the incidence and development of diseases via host-microbe metabolic axis. By methods of 16srDNA sequencing and metabolomics technology, our study found that gut microbiome and its metabolite L-Aspartic acid increase the severity of SAP-induced ALI. Furthermore, our data found that the microbiome and its metabolite L-Aspartic acid facilitate the ALI through damaging the intestinal mucosal barrier. The functional enrichment analysis indicates that the serum L-Aspartic acid elevates the expression of HRH1 which results in the progression of ALI. In light of that, we aim to investigate the effects of gut microbiome and its metabolite L-Aspartic acid on the damage of pulmonary epithelial cell with the aid of microbiomics, metabolomics and transcriptomics technology in the layers of clinical samples, conditional knock-out mice and primary cells. The L-Aspartic acid produced by gut microbiome accelerates the injury of Type Ⅱ pulmonary epithelial cell via the HRH1-induced activation of MAPK and NF-κB signaling pathways. Our study highlights novel insights to identify the effective biomarkers for the early detection of SAP-induced ALI and the prediction of its severity. Besides, we aim to develop the specific drugs and to bring the fecal microbiota transplantation to the clinics.