袖状胃切除术后肠道菌群介导的“肠-脑-肝”对话对肝脏葡萄糖输出的调节

Our previous clinical and animal researches confirmed that bariatric surgery could induce rapid and durable remission of diabetes, which is associated with reduced hepatic glucose production. The gut palys an important role in the mechanisms. However, the mechanisms remain ambiguous. The colonization of gut microbiota changes rapidly after bariatric surgeries. Short-chain fatty acids, which are produced by gut microbiota, are reported to modulate hepatic glucose production through gut-brain-liver crosstalk. Based on the above, we speculate that, after bariatric surgery, the rapidly adapted gut microbiota regulates the hepatic glucose production through a gut-brain-liver crosstalk mechanism which is mediated by short-chain fatty acids. In this study, we intend to perform sleeve gastrectomy on diabetic mice and figure out changes of gut microbiota colonization and the gene function, the effect of gut microbiota on hepatic glucose production and short-chain fatty acids after sleeve gastrectomy and the related mechanisms, by using 16S rDNA high throughput sequencing, metagenomics, target metabolomics, fecal microbiota transplantation to germ-free mice and basal insulin-euglycemic clamp tests. This study aims to further reveal the mechanisms of diabetes remission after bariatric surgery, and provide more theoretical evidences for the surgical treatment of diabetes mellitus.

本课题组前期临床和基础研究发现，减重手术能迅速、持久地缓解糖尿病，且糖尿病的迅速缓解与肝脏葡萄糖输出减少密切相关，肠道在其中发挥重要作用，但具体机制尚不明确。鉴于减重手术后肠道菌群的体内定植迅速发生变化，由肠道菌群产生的短链脂肪酸可通过“肠-脑-肝”对话调节肝脏葡萄糖输出，本课题组推测：减重手术后，迅速变化的肠道菌群通过短链脂肪酸介导“肠-脑-肝”对话调节术后肝脏葡萄糖输出的变化。本课题拟建立袖状胃切除术（SG）糖尿病小鼠模型，通过16S rDNA高通量测序、宏基因组学、靶标代谢组学、无菌小鼠粪便移植、葡萄糖钳夹等技术进行如下研究：SG术后肠道菌群体内定植和基因功能的变化；SG术后肠道菌群变化对肝脏葡萄糖输出和短链脂肪酸的影响；SG术后短链脂肪酸调节肝脏葡萄糖输出的作用和机制。本研究旨在从“肠道菌群”这一新视点上深入阐明减重手术改善糖代谢的机制，为手术治疗糖尿病提供理论基础。

本项目前期临床和基础研究发现，减重手术能迅速、持久地缓解糖尿病，且糖尿病的迅速缓解与肝脏葡萄糖输出减少密切相关，肠道在其中发挥重要作用，但具体机制尚不明确。鉴于减重手术后肠道菌群的体内定植迅速发生变化，由肠道菌群产生的短链脂肪酸可通过“肠-脑-肝”对话调节肝脏葡萄糖输出，本课题建立袖状胃切除术（SG）糖尿病大鼠模型，通过16S rDNA高通量测序、宏基因组学、靶标代谢组学、无菌小鼠粪便移植、葡萄糖钳夹等技术进行了相关研究：证实了中枢GLP-1有助于改善肥胖合并糖尿病大鼠十二指肠空肠旁路术后认知功能和脑葡萄糖摄取，并且对肝脏等器官的糖脂代谢具有改善作用；在炎症、凋亡等多方面进行探索和研究，充实了减重手术缓解代谢紊乱综合征的理论；并且本研究对于减重手术对糖尿病引发的肾脏、脾脏、心脏等器官的并发症的缓解作用也进行了初步探索，进一步加深了对减重手术的认识和了解，为临床广泛开展减重手术奠定了理论基础。