Aging-related illnesses are increasing and effective strategies to prevent and/or treat them are lacking. This is because of a poor understanding of therapeutic targets. Low-grade inflammation is often higher in older adults and remains a key risk factor of aging-related morbidities and mortalities. Emerging evidence indicates that abnormal (dysbiotic) gut microbiome and dysfunctional gut permeability (leaky gut) are linked with increased inflammation in older adults. However, currently available drugs do not treat aging-related microbiome dysbiosis and leaky gut, and little is known about the cellular and molecular processes that can be targeted to reduce leaky gut in older adults. Here, we demonstrated that metformin, a safe Food and Drug Administration-approved antidiabetic drug, decreased leaky gut and inflammation in high-fat diet-fed older obese mice, by beneficially modulating the gut microbiota. In addition, metformin increased goblet cell mass and mucin production in the obese older gut, thereby decreasing leaky gut and inflammation. Mechanistically, metformin increased the goblet cell differentiation markers by suppressing Wnt signaling. Our results suggest that metformin can be used as a regimen to prevent and treat aging-related leaky gut and inflammation, especially in obese individuals and people with western-style high-fat dietary lifestyle, by beneficially modulating gut microbiome/goblet cell/mucin biology.

中文翻译：

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二甲双胍通过有益地调节肠道微生物组/杯状细胞/粘蛋白轴来减少与衰老相关的肠漏症并改善认知功能。

与衰老相关的疾病正在增加，但缺乏有效的预防和/或治疗策略。这是因为对治疗靶点了解不足。低度炎症在老年人中通常较高，并且仍然是与衰老相关的发病率和死亡率的关键危险因素。新的证据表明，异常（生态失调）肠道微生物组和肠道通透性功能障碍（肠漏）与老年人炎症增加有关。然而，目前可用的药物不能治疗与衰老相关的微生物群失调和肠漏，并且对于可减少老年人肠漏的细胞和分子过程知之甚少。在这里，我们证明二甲双胍是一种经美国食品和药物管理局批准的安全抗糖尿病药物，通过有益地调节肠道微生物群，减少高脂肪饮食喂养的老年肥胖小鼠的肠漏和炎症。此外，二甲双胍增加了肥胖老年肠道中杯状细胞质量和粘蛋白的产生，从而减少肠漏和炎症。从机制上讲，二甲双胍通过抑制 Wnt 信号传导来增加杯状细胞分化标记物。我们的研究结果表明，二甲双胍可以通过有益地调节肠道微生物组/杯状细胞/粘蛋白生物学来用作预防和治疗与衰老相关的肠漏和炎症的方案，特别是对于肥胖个体和具有西式高脂肪饮食生活方式的人。