Shi Ying, Xing Lin, Wu Shanyu, Yue Fangzhi, He Tianqiong, Zhang Jing, Ouyang Lingxuan, Gao Suisui, Zhang Dongmei, Zhou Zhijun
Department of Endocrinology, Xiangya Hospital, Central South University, Changsha 410008.
Department of Laboratory Animal Science, Xiangya School of Medicine, Central South University, Changsha 410013, China.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025 May 28;50(5):851-863. doi: 10.11817/j.issn.1672-7347.2025.250151.
Recent evidence suggests that the gut may be a primary site of metformin action. However, studies on the effects of metformin on gut microbiota remain limited, and its impact on gut microbial metabolites such as short-/medium-chain fatty acids is unclear. This study aims to investigate the effects of metformin on gut microbiota, short-/medium-chain fatty acids, and associated metabolic benefits in high-fat diet rats.
Twenty-four Sprague-Dawley rats were randomly divided into 3 groups: 1) Normal diet group (ND group), fed standard chow; 2) high-fat diet group (HFD group), fed a high-fat diet; 3) high-fat diet + metformin treatment group (HFD+Met group), fed a high-fat diet for 8 weeks, followed by daily intragastric administration of metformin solution (150 mg/kg body weight) starting in week 9. At the end of the experiment, all rats were sacrificed, and serum, liver, and colonic contents were collected for assessment of glucose and lipid metabolism, liver pathology, gut microbiota composition, and the concentrations of short-/medium-chain fatty acids.
Metformin significantly improved HFD-induced glucose and lipid metabolic disorders and liver injury. Compared with the HFD group, the HFD+Met group showed reduced abundance of , , , and s, while abundance significantly increased (all <0.05). Colonic contents of butyric acid, 2-methyl butyric acid, valeric acid, octanoic acid, and lauric acid were significantly elevated (all <0.05), whereas acetic acid, isoheptanoic acid, and nonanoic acid levels were significantly decreased (all <0.05). Spearman correlation analysis revealed that abundance was negatively correlated with body weight gain and insulin resistance, while butyrate and valerate levels were negatively correlated with insulin resistance and liver injury (all <0.05).
Metformin significantly increases the abundance of beneficial bacteria such as and promotes the production of short-/medium-chain fatty acids including butyric, valeric, and lauric acid in the colonic contents of HFD rats, suggesting that metformin may regulate host metabolism through modulation of the gut microbiota.
近期证据表明，肠道可能是二甲双胍发挥作用的主要部位。然而，关于二甲双胍对肠道微生物群影响的研究仍然有限，其对短链/中链脂肪酸等肠道微生物代谢产物的影响尚不清楚。本研究旨在探讨二甲双胍对高脂饮食大鼠肠道微生物群、短链/中链脂肪酸及相关代谢益处的影响。
将24只Sprague-Dawley大鼠随机分为3组：1）正常饮食组（ND组），喂食标准饲料；2）高脂饮食组（HFD组），喂食高脂饮食；3）高脂饮食+二甲双胍治疗组（HFD+Met组），先喂食高脂饮食8周，从第9周开始每日灌胃给予二甲双胍溶液（150mg/kg体重）。实验结束时，处死所有大鼠，收集血清、肝脏和结肠内容物，用于评估葡萄糖和脂质代谢、肝脏病理学、肠道微生物群组成以及短链/中链脂肪酸浓度。
二甲双胍显著改善了高脂饮食诱导的葡萄糖和脂质代谢紊乱以及肝损伤。与HFD组相比，HFD+Met组的[具体菌种1]、[具体菌种2]、[具体菌种3]和[具体菌种4]丰度降低，而[具体菌种5]丰度显著增加（均P<0.05）。结肠内容物中丁酸、2-甲基丁酸、戊酸、辛酸和月桂酸含量显著升高（均P<0.05），而乙酸、异庚酸和壬酸水平显著降低（均P<0.05）。Spearman相关性分析显示，[具体菌种5]丰度与体重增加和胰岛素抵抗呈负相关，而丁酸盐和戊酸盐水平与胰岛素抵抗和肝损伤呈负相关（均P<0.05）。
二甲双胍显著增加了HFD大鼠结肠内容物中[具体菌种5]等有益菌的丰度，并促进了包括丁酸、戊酸和月桂酸在内的短链/中链脂肪酸的产生，提示二甲双胍可能通过调节肠道微生物群来调节宿主代谢。
