肠道菌群介导的胰腺慢性炎症缓解在袖状胃切除术后β细胞功能改善中的作用及其机制研究

Type 2 diabetes mellitus can be regarded as a chronic and non-specific low-grade inflammatory consequence, and β cell dysfunction is one of its important pathogenesis. Chronic inflammation of the pancreas may play an important role in β cell dysfunction. LPS can activate TLR4 on the surface of macrophages in pancreatic tissue then mediate the expression of inflammation cytokines such as TNF-α, IL and IFN-α, resulting in the impairment of β cell function. Sleeve gastrectomy (SG) can achieve rapid and lasting remission of type 2 diabetes and also the alleviation of β cell dysfunction. However, the underlying mechanism remains unknown. The previous study of our group found that the composition of gut microbiota changed significantly after SG, and the level of LPS decreased dramatically. Here we propose the following hypothesis: the alterations of gut microbiota after SG lead to a decrease in the level of LPS, resulting in the remission of pancreatic tissue inflammation mediated by TLR4 on the surface of macrophages, thereby promoting the improvement of islet β cell function. In the present study, we will perform SG surgery on GK rats. With the help of hyperglycemic clamp, flow cytometry sorting, flora limited rats, flora transplantation, injection of LPS and TLR4 inhibitors and 16S full-length rDNA high-throughput sequencing technology, we intend to verify the hypothesis mentioned above from three levels: gut microbiota, LPS and TLR4. This study will point out a new direction for the mechanism of glucose metabolism improvement after SG.

2型糖尿病可视为慢性非特异性低度炎症性疾病，β细胞功能障碍是其重要发病机制之一。胰腺慢性炎症可能在β细胞功能障碍中起重要作用。而LPS可激活巨噬细胞TLR4并介导TNF-α、IL、IFN-α等炎症因子的表达，从而导致β细胞功能受损。袖状胃切除术（SG）可迅速、持久地缓解2型糖尿病，且术后β细胞功能障碍得以改善，但机制不明。本课题组前期研究发现：SG术后肠道菌群构成发生显著变化，LPS水平显著降低，并提出如下假说：SG术后肠道菌群构成的改变导致LPS水平的降低，使巨噬细胞TLR4介导的胰腺慢性炎症缓解，进而促进胰岛β细胞功能的改善。本研究拟以GK大鼠建立SG手术模型，利用高葡萄糖钳夹、流式细胞分选、动物限菌及菌群移植、LPS和TLR4抑制剂的注射、16S全长rDNA高通量测序等技术，从肠道菌群、LPS和TLR4三个层次验证上述假说，以期为SG术后糖代谢改善机制的研究开辟新的方向。

2型糖尿病可视为慢性非特异性低度炎症性疾病，β细胞功能障碍是其重要发病机制之一。胰腺慢性炎症可能在β细胞功能障碍中起重要作用。而LPS可激活巨噬细胞TLR4并介导TNF-α、IL、IFN-α等炎症因子的表达，从而导致β细胞功能受损。袖状胃切除术（SG）可迅速、持久地缓解2型糖尿病，且术后β细胞功能障碍得以改善，但机制不明。本课题组建立了袖状胃切除术（SG）糖尿病大鼠模型。利用高葡萄糖钳夹、流式细胞分选、动物限菌及菌群移植、LPS和TLR4抑制剂的注射、16S全长rDNA高通量测序等技术，证实了袖状胃切除术有助于缓解胰腺慢性炎症并改善β细胞功能。通过对袖状胃术后糖尿病肾脏、脾脏、肝脏等器官并发症改善机制的探索，丰富了袖状胃手术改善代谢综合征的理论成果，为临床进一步推广和开展减重手术奠定了理论基础。