肠道菌群-SCFAs-巨噬细胞轴在慢性胰腺炎中的作用及机制研究

巨噬细胞浸润/极化是导致慢性胰腺炎（CP）进程的关键。申请人前期发现肠道菌群及其代谢产物短链脂肪酸（SCFA）在调控巨噬细胞功能并在CP发病进程中发挥积极作用，但其作用及机制尚未明确。本项目拟开展以下研究内容：1) 分析临床及实验性CP的肠道菌群、SCFA水平和胰腺巨噬细胞浸润，确定肠道菌群-SCFA-巨噬细胞与CP发病进程的相关性；2）明确肠道菌群-SCFA在CP发病进程中的作用；3）通过抗生素处理、同笼饲养、添加SCFA以及体内巨噬细胞耗竭，阐明肠道菌群-SCFA通过调控巨噬细胞浸润/极化在CP发挥积极作用；4）采用CP小鼠模型，结合Toll样受体4-/-小鼠、SCFA受体G蛋白偶联受体(GPR)41-/-小鼠、GRP109A-/-小鼠和慢病毒GRP43沉默，揭示肠道菌群-SCFA-巨噬细胞轴在调节CP发病进程中的分子机制；为防治CP提供新思路。

Macrophage infiltration/polarization is the key to the progression of chronic pancreatitis (CP). Our preliminary data have shown that intestinal flora and its metabolite short-chain fatty acid (SCFA) plays an active role in regulating macrophage function and in the pathogenesis of CP. However, their modulatory effects and underlying mechanisms have not been elucidated. The current study hypothesizes that intestinal flora-SCFA-macrophage axis plays a critical role in the pathogenesis of CP. To this end, 1) The intestinal flora, SCFA levels and macrophage infiltration of clinical and experimental samples from CP patients or mice will be analyzed to establish the correlation between intestinal flora-SCFA-macrophages and CP progression; 2) modulatory effects of intestinal flora-SCFA on CP will be investigated; 3) by antibiotic treatment or cohousing, SCFA supplementation and in vivo macrophage depletion, the role of intestinal flora-SCFA on macrophage infiltration / polarization in CP will be evaluated; 4) by using Toll-like receptor 4 deficient (TLR4-/-), SCFA receptor G protein coupled receptor (GPR) 41-/-mice, GRP109A-/- mice combined with lentiviral GRP43 silencing technology, the molecular mechanism of intestinal flora-SCFA on macrophage infiltration / activation in the pathogenesis of CP will be elucidated. The current study emphasizes that the role of intestinal flora-SCFA-macrophage axis in the development of CP