Lee Grace C, Moreira Alvaro G, Hinojosa Cecilia, Benavides Raymond, Winter Caitlyn, Anderson Audrey C, Chen Chang-Jui, Borsa Noemi, Hastings Gabrielyd, Black Cody A, Bandy Sarah M, Shaffer Alexander, Restrepo Marcos I, Ahuja Sunil K
College of Pharmacy, The University of Texas at Austin, Austin, TX, United States.
Pharmacotherapy Education and Research Center, School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
Front Aging. 2022 Apr 29;3:736835. doi: 10.3389/fragi.2022.736835. eCollection 2022.
Metformin may potentially reverse various age-related conditions; however, it is unclear whether metformin can also mitigate or delay the deterioration of immunological resilience that occurs in the context of infections that are commonly observed in older persons. We examined whether metformin promotes the preservation of immunological resilience in an acute (SPN) infection challenge in young adult mice. Mice were fed metformin (MET-alone) or standard chow (controls-alone) for 10 weeks prior to receiving intratracheal inoculation of SPN. A subset of each diet group received pneumococcal conjugate vaccine at week 6 (MET + PCV and control + PCV). Compared to controls-alone, MET-alone had significantly less infection-associated morbidity and attenuated inflammatory responses during acute SPN infection. Metformin lowered the expression of genes in the lungs related to inflammation as well as shorter lifespan in humans. This was accompanied by significantly lower levels of pro-inflammatory cytokines (e.g., IL6). MET + PCV vs. control + PCV manifested enhanced SPN anticapsular IgM and IgG levels. The levels of SPN IgM production negatively correlated with expression levels of genes linked to intestinal epithelial structure among MET + PCV vs. control + PCV groups. Correspondingly, the gut microbial composition of metformin-fed mice had a significantly higher abundance in the Verrucomicrobia, a species previously associated with beneficial effects on intestinal integrity and longevity. Together, these findings indicate metformin's immunoprotective potential to protect against infection-associated declines in immunologic resilience.
二甲双胍可能会逆转各种与年龄相关的状况；然而，目前尚不清楚二甲双胍是否也能减轻或延缓老年人常见感染情况下发生的免疫恢复力下降。我们研究了在年轻成年小鼠的急性（SPN）感染挑战中，二甲双胍是否能促进免疫恢复力的维持。在经气管接种SPN之前，小鼠分别喂食二甲双胍（仅MET组）或标准饲料（仅对照组）10周。每个饮食组的一个亚组在第6周接受肺炎球菌结合疫苗接种（MET + PCV组和对照组 + PCV组）。与仅对照组相比，仅MET组在急性SPN感染期间与感染相关的发病率显著降低，炎症反应减弱。二甲双胍降低了肺部与炎症相关基因的表达以及人类较短的寿命。这伴随着促炎细胞因子（如IL6）水平的显著降低。MET + PCV组与对照组 + PCV组相比，SPN抗荚膜IgM和IgG水平升高。在MET + PCV组与对照组 + PCV组中，SPN IgM产生水平与肠道上皮结构相关基因的表达水平呈负相关。相应地，喂食二甲双胍的小鼠肠道微生物组成中疣微菌门的丰度显著更高，该菌此前被认为对肠道完整性和寿命有有益影响。总之，这些发现表明二甲双胍具有免疫保护潜力，可防止感染相关的免疫恢复力下降。
