代谢手术术后IL-17对肠道NLRP3表达水平及肠道菌群分布的调控机制研究

Bariatric surgery is a new therapy for treating obesity by regulating intestinal immunity and gut microbiota. Abundant gut IL-17 plays an important role in gut immunity. Meanwhile, activation of NLRP3 could help restrain gut dysbacteriosis. However cross talk between IL-17 and NLRP3 and the effects of them in bariatric surgery remains largely unknown. Our preliminary data suggested that expression of IL-17 and NLRP3 both decreased in obesity condition and got recovered after bariatric surgery. In vitro experiments showed that IL-17 could induce activation of NLRP3. We proposed this hypothesis that bariatric surgery could induce higher secretion of IL-17 in the gut and then activate more NLRP3 in intraepithelial cells, resulting in better endocrine metabolism and decreased degree of obesity. This project tries to identify the sources of IL-17 after surgery in the gut and the mechanism of how IL-17 interferes with the NLRP3-Asc-Caspase1-gut microbiota pathway. Based on these findings this project tries to figure out how bariatric surgery functions on gut microbiota through the IL-17-NLRP3 pathway. Results of this project could also help improve the surgical procedures during the bariatric surgery.

代谢手术治疗肥胖的机制与其调节肠道内免疫状态及菌群分布关系密切。肠道内高度富集的IL-17可维持肠道正常免疫状态，而肠上皮细胞NLRP3通路有维持肠道菌群平衡的作用。肠道内IL-17与NLRP3间是否存在相互调控目前尚无报道。我们此前研究表明肥胖状态下肠道IL-17及NLRP3表达水平减低，而代谢手术后两者表达上调。预实验表明IL-17可促进肠上皮表达NLRP3。我们据此提出，代谢手术可诱导IL-17表达上调，从而活化NLRP3通路并纠正肠道菌群紊乱，改良机体糖脂代谢。本课题拟研究代谢手术后高表达的IL-17来源于何种免疫细胞，并探究肠上皮中IL-17如何介入NLRP3-Asc-Caspase1-肠道菌群通路。进而分析如何改良代谢手术术式进而调控IL-17及NLRP3表达。本研究的完成，可从肠道免疫角度，阐述代谢手术治疗肥胖的机制，寻找能达成最佳免疫状态的代谢手术术式。

本项目的研究背景为观察分析肠道手术后肠道菌群变化情况及其对肠道免疫系统的影响。本项目的主要研究内容包括评估代谢手术后炎症因子对于肠道菌群的分布，评估炎症因子如何通过肠上皮细胞NLRP通路调控下游免疫相关蛋白表达。最终评价这样的炎症波动对于手术疗效的影响。在本项目的研究中我们达成了以下的研究成果：1.摸索出成熟稳定的动物减重手术模型。2.确认了代谢手术后肠道免疫细胞的改变特点。3.明确NLRP6在代谢手术中对于肠道菌群分布的影响及初步机制。4.明确了肠道菌群下游代谢产物对于机体脂肪肝的影响。5.确认代谢手术中胃迷走神经离断对于机体的影响效应。6.积累了一批减重代谢手术患者的血清及大便样本并进行了代谢组学检测筛查。上述研究以手术为中心，揭示了手术对于肠道微环境，尤其是肠道菌群的独特影响，并以此为依据确认了与肠道菌群调控密切相关的受体蛋白及代谢产物。这些研究结果可以为进一步的代谢综合征治疗寻找新靶点，也能为手术的远期预后疗效评价提供新思路。