College of Life and Environmental Science, Wenzhou University, Wenzhou, 325000, China.
State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325015, China.
Free Radic Biol Med. 2024 Nov 1;224:600-617. doi: 10.1016/j.freeradbiomed.2024.09.017. Epub 2024 Sep 15.
Fibroblast growth factor 21 (FGF21) is an important regulator of glycolipid metabolism. However, whether the gut microbiota is related to the anti-diabetic and obesity effects of FGF21 remains unclear.
Our research used KO/KO db/db male mice and streptozotocin (STZ)-induced to simulate the construction of two type II diabetic mellitus (T2DM) models, and detected impaired glucose tolerance in the model by using the ipGTT and ITT assays, and collected feces from the model mice for sequencing of the intestinal flora and the content of short-chain fatty acids. H＆E staining was used to detect changes in intestinal tissue, the serum levels of LPS and GLP-1 were detected by ELISA.
In this study, we found that FGF21 significantly improved insulin sensitivity, attenuated intestinal lesions, and decreased serum lipopolysaccharide (LPS) concentrations in T2DM mice. Moreover, FGF21 reshaped the gut microbiota and altered their metabolic pathways in T2DM mice, promoting the production of short-chain fatty acids (SCFAs) and the secretion of glucagon-like peptide 1 (GLP-1). Fecal transplantation experiments further confirmed that feces from FGF21-treated diabetic mice demonstrated similar effects as FGF21 in terms of anti-diabetic activity and regulation of gut microbiota dysbiosis. Additionally, the antibiotic depletion of gut microbiota abolished the beneficial effects of FGF21, including increased GLP-1 secretion and fecal SCFA concentration. Additionally, the FGF21 effects of ameliorating intestinal damage and suppressing plasma LPS secretion were suppressed. All these findings suggest that FGF21 prevents intestinal lesions by modifying the gut microbiota composition. Furthermore, FGF21 affected bile acid synthesis by inhibiting CYP7A1, the key enzyme of bile acid synthesis.
Therefore, FGF21 enriched beneficial bacteria by preventing bile acid synthesis and stimulating the secretion of the intestinal hormone GLP-1 via the increased production of gut microbiota metabolites, thereby exerting its anti-diabetic effects.
成纤维细胞生长因子 21（FGF21）是糖脂代谢的重要调节剂。然而，肠道微生物群是否与 FGF21 的抗糖尿病和肥胖作用有关尚不清楚。
本研究使用 KO/KO db/db 雄性小鼠和链脲佐菌素（STZ）诱导来模拟构建两种 2 型糖尿病（T2DM）模型，通过 ipGTT 和 ITT 检测模型的葡萄糖耐量受损，并从模型小鼠中收集粪便进行肠道菌群和短链脂肪酸含量测序。H＆E 染色用于检测肠道组织的变化，ELISA 用于检测血清脂多糖（LPS）和胰高血糖素样肽 1（GLP-1）的水平。
在这项研究中，我们发现 FGF21 可显著改善胰岛素敏感性，减轻 T2DM 小鼠的肠道损伤，并降低血清脂多糖（LPS）浓度。此外，FGF21 重塑了 T2DM 小鼠的肠道微生物群，并改变了它们的代谢途径，促进了短链脂肪酸（SCFA）的产生和胰高血糖素样肽 1（GLP-1）的分泌。粪便移植实验进一步证实，来自 FGF21 治疗的糖尿病小鼠的粪便在抗糖尿病活性和调节肠道微生物群失调方面表现出与 FGF21 相似的作用。此外，抗生素耗尽肠道微生物群会消除 FGF21 的有益作用，包括增加 GLP-1 分泌和粪便 SCFA 浓度。此外，FGF21 改善肠道损伤和抑制血浆 LPS 分泌的作用也被抑制。所有这些发现表明，FGF21 通过改变肠道微生物群组成来预防肠道损伤。此外，FGF21 通过抑制胆汁酸合成的关键酶 CYP7A1 来影响胆汁酸合成。
因此，FGF21 通过防止胆汁酸合成和通过增加肠道微生物群代谢产物的产生刺激肠激素 GLP-1 的分泌来富集有益细菌，从而发挥其抗糖尿病作用。
