Table2_Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis.docx

The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.

本研究旨在探究二甲双胍是否通过调节肠道菌群发挥抗炎和黏液保护作用。二甲双胍具有广泛的益处，其中包括抗炎作用。既往研究表明，二甲双胍能够改变肠道菌群的组成，并增加杯状细胞的数量。肠道菌群失调和杯状细胞耗竭是溃疡性结肠炎（UC）的重要特征。二甲双胍改善UC患者黏液屏障的潜在机制尚不明确。本研究将二甲双胍（400 mg/kg/天）给予由硫酸葡聚糖钠（DSS）诱导的UC小鼠，连续使用2周，以研究二甲双胍对肠道黏液屏障的影响。通过抗生素处理降低肠道菌群，以探究其在二甲双胍黏液保护作用中的作用。将富含于二甲双胍处理小鼠中的阿克曼氏菌（A. muciniphila）给予小鼠，以研究该细菌对UC和黏液屏障的影响。结果显示，二甲双胍减轻了DSS诱导的UC小鼠的腹泻、血便症状，并降低了体重。与DSS处理组相比，二甲双胍处理组中黏液屏障蛋白mucin2的表达增加。16S rRNA粪便分析显示，二甲双胍治疗通过增加乳酸杆菌和阿克曼氏菌的相对丰度，同时降低梭菌属中链球菌属的丰度，改变了肠道菌群的组成。抗生素处理部分消除了二甲双胍的抗炎和黏液保护作用。A. muciniphila的给予缓解了结肠炎症和黏液屏障的破坏。二甲双胍通过影响肠道菌群减轻了DSS诱导的UC小鼠的病变，并保护细胞免受损伤，从而为二甲双胍在UC患者中的治疗作用提供了新的机制。本研究还提供了阿克曼氏菌作为一种益生菌，在UC中具有潜在益处的证据。