司美格鲁肽对MAFLD患者肠道菌群结构及功能的影响

Effect of Semaglutide on the Structure and Function of Intestinal Flora in Patients with MAFLD

摘要: 目的：探讨司美格鲁肽对代谢相关脂肪性肝病(MAFLD)患者生化指标和肠道菌群的影响。方法：选取2023年6月至2024年6月期间于内蒙古包钢医院内科住院的MAFLD合并2型糖尿病(T2DM)患者11例作为研究对象，收集入选患者治疗前及治疗3个月后的一般资料、空腹血糖(FPG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbAlc)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)等临床指标，ELISA法检测血清中LPS。16Sr DNA测序检测粪便肠道菌群，采用Alpha多样性分析、Beta多样性、物种组成分析及LEfSe分析等来评价治疗前后两组菌群群落差异。结果：(1) 入组患者治疗后的FPG、2 hPG、HbAlc、TG、TC、LDL-C、ALT、AST、LPS及BMI较治疗前均明显减低，差异具有统计学意义(均P < 0.05)，而HDL-C较治疗前升高，但差异无统计学意义(P > 0.05)。(2) 16S rDNA测序结果：① 多样性分析：Alpha多样性分析结果显示，治疗前后患者群落物种多样性无显著变化，但丰富度升高；Beta多样性提示治疗前后患者肠道群落结构存在差异。② 物种组成分析：门水平上，治疗后拟杆菌门、假单胞菌门、放线菌门的丰度下降，芽孢杆菌门丰度升高。属水平上，治疗后拟杆菌属、粪杆菌属、Alistipes的丰度上升，埃希氏菌属的丰度下降。③ LEfSe分析：假单胞菌门、肠杆菌目、巨单细胞菌属、埃希氏菌属在治疗前的相对丰度均高于治疗后(均P < 0.05)；芽孢杆菌门、拟杆菌属、粪杆菌属、乳酸杆菌属在治疗后的相对丰度均高于治疗前(均P < 0.05)。④ 菌群功能注释分析：治疗后肠道菌群在辅助因子和维生素代谢通路显著下调(P < 0.05)；脂质代谢及氨基酸代谢通路显著上调(均P > 0.05)、其他次生代谢物的生物合成上调(P < 0.05)。结论：(1) 司美格鲁肽可以降低空腹血糖、血脂、ALT、AST，改善肝功能，调节机体内的糖脂代谢紊乱；(2) 司美格鲁肽可以降低患者血清LPS，减轻炎症反应；(3) 司美格鲁肽可以影响肠道菌群变化，调节脂质代谢及氨基酸代谢；(4) 司美格鲁肽可以通过增加粪杆菌属、Alistipes属的丰度，增加短链脂肪酸的生成，提高肠道抗炎作用，提示司美格鲁肽可改善肠道菌群结构，改变丰度，修复肠道菌群紊乱。

Abstract: Objective: To investigate the effects on biochemical indices and intestinal flora in patients with metabolic associated fatty liver disease (MAFLD) treated with semaglutide. Method: Eleven patients with MAFLD combined with type 2 diabetes mellitus (T2DM) who were admitted to the Department of Internal Medicine of Baogang Hospital in Inner Mongolia between June 2023 and June 2024 were selected as the study subjects, and the general data, fasting blood glucose (FPG), 2 h postprandial glucose (2 hPG), glycosylated hemoglobin (HbAlc), alanine aminotransferase (ALT), glutamate aminotransferase (AST), triglycerides (TG) and other clinical indexes were collected from the enrolled patients before treatment and 3 months after treatment. ELISA method to detect LPS in serum. 16Sr DNA sequencing to detect fecal intestinal flora, Alpha diversity analysis, Beta diversity, species composition analysis and LEfSe analysis were used to evaluate the differences in the bacterial flora communities between the two groups before and after treatment. Results: (1) FPG, 2 hPG, HbAlc, TG, TC, LDL-C, ALT, AST and BMI of MAFLD patients were significantly reduced after treatment compared with the pre-treatment group, and the difference was statistically significant (all P < 0.05), while HDL-C was elevated compared with the pre-treatment group, but the difference was not statistically significant (P > 0.05). (2) the results of 16S rDNA sequencing showed that: (i) Alpha diversity analysis results showed that there was no significant change in the diversity of the community in patients before and after treatment, but the richness increased; Beta diversity suggested that there was a difference in the structure of the intestinal community before and after treatment; (ii) Species composition analysis: at the phylum level, the abundance of Bacteroidota, Pseudomonadota (formerly known as Proteobacteria), and Actinobacteriota decreased and the abundance of Bacillota (formerly known as Firmicutes) increased after treatment. At the genus level, the abundance of Bacteroides, Faecalibacterium, and Alistipes increased, and the abundance of Escherichia decreased after treatment; (iii) And the results of LEfSe analysis showed that the Pseudomnadota, Enterobacterales, Megamonas, and Escherichia were more common in the pre-treatment group were higher than those in the post-treatment group (all P < 0.05); the relative abundance of Bacillota, Bacteroides, Faecalibacterium and Lactobacillus in the post-treatment group were higher than those in the pre-treatment group (all P < 0.05); (iv) Colony function annotation analysis: the post-treatment group was down-regulated in cofactor and vitamin metabolism (P < 0.05); significantly up-regulated in lipid metabolism and amino acid metabolism pathways (all P > 0.05), and up-regulated in biosynthesis of other secondary metabolites (P < 0.05). Conclusions: (1) Simeglutide can reduce fasting blood glucose, blood lipids, ALT, AST, improve liver function, and regulate the disorders of glucose and lipid metabolism in the body; (2) Simeglutide can reduce the patient’s serum LPS, and reduce the inflammatory response; (3) Simeglutide can affect the change of intestinal flora, and regulate lipid metabolism and amino acid metabolism; (4) Simeglutide can increase the abundance of Faecalibacterium and Alistipes and increase the generation of short-chain fatty acids to improve the anti-inflammatory effect of the intestine, suggesting that simeglutide can improve the structure of the intestinal flora, change the abundance, and repair the disorders of the intestinal flora.