二甲双胍通过增加肠道微生物群中的 Lactobacillus sp. MF-1 来缓解小鼠的肝纤维化。
Metformin alleviates liver fibrosis in mice by enriching Lactobacillus sp. MF-1 in the gut microbiota.
机构信息
The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China; National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China; Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China.
National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China; Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China.
出版信息
Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166664. doi: 10.1016/j.bbadis.2023.166664. Epub 2023 Mar 7.
BACKGROUND
Liver fibrosis is associated with gut dysbiosis. Metformin administration has emerged as a promising method for the treatment of organ fibrosis. We aimed to investigate whether metformin ameliorates liver fibrosis by enhancing the gut microbiota in mice with carbon tetrachloride (CCl)-induced liver fibrosis and the underlying mechanism.
MATERIALS AND METHODS
A liver fibrosis mouse model was established, and the therapeutic effects of metformin were observed. We administered antibiotic treatment and performed fecal microbiota transplantation (FMT), and 16S rRNA-based microbiome analysis to evaluate the effects of the gut microbiome on metformin-treated liver fibrosis. We isolated the bacterial strain preferably enriched by metformin and assessed its antifibrotic effects.
RESULTS
Metformin treatment repaired the gut integrity of the CCl-treated mice. It reduced the number of bacteria in colon tissues and reduced the portal vein lipopolysaccharide (LPS) levels. The FMT performed on the metformin-treated CCl mice alleviated their liver fibrosis and reduced their portal vein LPS levels. The markedly changed gut microbiota was screened out from the feces and named Lactobacillus sp. MF-1 (L. sp. MF-1). In the CCl-treated mice, daily gavage of L. sp. MF-1 maintained gut integrity, inhibited bacterial translocation, and reduced liver fibrosis. Mechanistically, metformin or L. sp. MF-1 inhibited the apoptosis of intestinal epithelial cells and restored CD3 intestinal intraepithelial lymphocytes in the ileum and CD4Foxp3 lamina propria lymphocytes in the colon.
CONCLUSIONS
Metformin and its enriched L. sp. MF-1 can reinforce the intestinal barrier to alleviate liver fibrosis by restoring immune function.
背景
肝纤维化与肠道菌群失调有关。二甲双胍的应用已成为治疗器官纤维化的一种有前途的方法。我们旨在研究二甲双胍是否通过增强四氯化碳（CCl）诱导的肝纤维化小鼠的肠道微生物群来改善肝纤维化，以及潜在的机制。
材料和方法
建立肝纤维化小鼠模型，观察二甲双胍的治疗效果。我们进行了抗生素治疗和粪便微生物群移植（FMT），并进行了 16S rRNA 微生物组分析，以评估肠道微生物群对二甲双胍治疗肝纤维化的影响。我们分离出被二甲双胍优选富集的细菌菌株，并评估其抗纤维化作用。
结果
二甲双胍治疗修复了 CCl 处理的小鼠的肠道完整性。它减少了结肠组织中的细菌数量，并降低了门静脉内毒素（LPS）水平。在接受二甲双胍治疗的 CCl 小鼠中进行的 FMT 减轻了其肝纤维化并降低了门静脉 LPS 水平。从粪便中筛选出明显改变的肠道微生物群，并将其命名为 Lactobacillus sp. MF-1（L. sp. MF-1）。在 CCl 处理的小鼠中，每日灌胃 L. sp. MF-1 可维持肠道完整性，抑制细菌易位，并减少肝纤维化。在机制上，二甲双胍或 L. sp. MF-1 抑制了肠上皮细胞的凋亡，并恢复了回肠中的 CD3 肠道上皮内淋巴细胞和结肠中的 CD4Foxp3 固有层淋巴细胞。
结论
二甲双胍及其富集的 L. sp. MF-1 可以通过恢复免疫功能来增强肠道屏障，从而缓解肝纤维化。
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