肠道神经胶质细胞在代谢性炎症中的作用和机制研究

Obesity and its associated metabolic diseases, including insulin resistance (IR) and type 2 diabetes (T2D), have become global diseases that carry considerable morbidity and mortality. The cellular and molecular pathways that lead to the pathogenesis of obesity remain incompletely understood. Current dogma is that metabolic diseases are not simply metabolic disorders but rather a systemic inflammatory diseases caused by a special type of chronic inflammation called meta-inflammation. Recent evidence has pointed to the gut as a key site in regulating obesity. The gut has large number of nerve cells that can potentially regulate mucosal integrity, however whether the enteric nervous system can regulate meta-inflammation during obesity is not known. In the diet-induced obese mouse model, we found an increase expression of glial cell-derived neurotrophic factor family ligand artemin gene in the gut during early phase of high-fat diet feeding. We hypothesize that the enteric nervous system, especially the enteric glial cells, might play important roles in regulating meta-inflammation by orchestrating the cross-talk among the mucosal epithelium, the enteric nerve system and the gut immune systems. We will use cell type-specific gene knockout mouse model in combination with in vitro cellular and molecular technologies to test our hypothesis. This proposal will further improve our understanding of the pathogenesis of obesity and its related metabolic diseases and could potentially lead to novel obesity-related therapies by controlling gut local inflammation.

肥胖不仅仅是代谢性疾病，也是系统性慢性代谢炎症，免疫系统参与调控其病理进程。肠道局部免疫是肥胖等代谢炎症的重要调控环节。肠道本身的神经系统对肠道的粘膜屏障功能有重要的调控作用，然而它们在代谢性疾病中的作用常期以来并不清楚。我们课题组在小鼠高脂饮食诱导的肥胖模型中发现，早期在未见明显的脂肪和肠道炎症的情况下，肠道就已开始高表达神经营养因子artemin 基因，我们推测肠道自身的神经系统，特别是肠道胶质细胞作为肠道粘膜上皮细胞和免疫细胞之间的桥梁，在代谢炎症中可能起到重要作用。本研究将通过细胞特异性基因敲除小鼠模型，结合体外细胞培养和分子生物学手段系统研究肠道神经胶质细胞在肠道免疫活化以及肥胖及其相关的胰岛素抵抗中的作用及可能的细胞和分子机制。本项研究的完成可从一个新的角度阐述肥胖及代谢疾病的发病机理，并为临床通过干预肠道局部炎症来治疗系统性代谢疾病的新模式提供有力的理论依据和可能的靶标。

肠道是调节肥胖发生发展的重要器官，它不但调控营养物的消化与吸收，肠道炎症还与肥胖的发生发展密切相关，但其机理并不清楚。我们的原始假说认为肥胖过程中会造成肠道微生态紊乱，微生态的紊乱可能会导致肠道胶质细胞的活化，肠道胶质细胞的活化可能会影响肥胖的进程。在课题探索的过程中，我们发现诱发肥胖的高脂饮食的确可以引起肠道菌群的改变，但是这种改变并不像我们推测的那样仅仅只是影响肠道神经胶质细胞，它还能引起肠道粘膜屏障的改变。粘膜屏障功能损伤所导致的肠道微生物成分入血会引起代谢性内毒素血症，这是导致肥胖等代谢性炎性疾病的重要启动因素。我们发现高脂饮食可以降低肠道菌群代谢产物脱氨基酪氨酸DAT的产生。在高脂饮食中添加DAT可以抑制高脂饮食诱导的小鼠肥胖。DAT的粘膜保护作用与其抑制炎症的功能有关。因此，我们的研究结果提示肠道菌群紊乱是导致肥胖的重要因素。另外，与我们预期的相符，我们发现高脂饮食的确可以刺激肠道神经胶质细胞的应答。具体表现是肠道粘膜层有GFAP阳性的胶质细胞的聚集并分泌神经营养因子。这种现象依赖于胶质细胞表达的MyD88分子，提示高脂饮食诱导发肠道胶质细胞的应答可能与肠道菌群的紊乱有关。但是关于肠道胶质细胞在肥胖中的作用与机制还有待于进一步地研究。本项目的研究进一步阐述了肠道在代谢性疾病中的作用与机制，并为临床通过干预肠道炎症来治疗代谢性疾病的提供有力的理论依据。