Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis.
Metformin enhances protection in guinea pigs chronically infected with Mycobacterium tuberculosis.
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DOI：
10.1038/s41598-020-73212-y
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发表时间：
2020-10-01
影响因子：
4.6
通讯作者：
Basaraba RJ
中科院分区：
文献类型：
--
作者：
Frenkel JDH;Ackart DF;Todd AK;DiLisio JE;Hoffman S;Tanner S;Kiran D;Murray M;Chicco A;Obregón-Henao A;Podell BK;Basaraba RJ
结核病（TB）是一种慢性炎症性疾病，通常与全身和细胞代谢的改变有关，在成功的抗微生物药物治疗后消退。我们假设，结核分枝杆菌（Mtb）感染导致全身葡萄糖代谢改变，有助于TB发病机制，当使用降糖药物恢复正常时，将改善临床结局。为了检验这一假设，在暴露于Mtb H37 Rv菌株的气雾剂前4周或同时，每天用抗糖尿病药物二甲双胍治疗豚鼠。在感染的慢性阶段，Mtb感染的二甲双胍治疗的动物恢复了全身胰岛素敏感性，但仍保持葡萄糖不耐受，如通过口服葡萄糖耐量试验所确定的。尽管持续的葡萄糖耐受不良，二甲双胍治疗的豚鼠有2.8倍减少肺部病变的负担和0.7个单位的CFU下降。使用细胞外通量分析和流式细胞术检验了二甲双胍治疗通过对免疫细胞能量代谢产生直接影响而改善临床疾病的备择假设。在未处理的豚鼠中对Mtb感染的促炎免疫应答与外周血单核细胞（PBMC）的能量代谢（糖酵解和线粒体呼吸）的显著增加相关，这在二甲双胍处理的豚鼠中正常化。此外，来自Mtb感染的二甲双胍治疗动物的CD4+和CD8+ T淋巴细胞均保持更正常的线粒体膜电位，而从未治疗动物分离的那些具有持续的线粒体超极化。这些数据表明，二甲双胍通过在活动性TB疾病的慢性阶段维持免疫细胞代谢稳态和功能来促进宿主对Mtb感染的天然抗性。
Tuberculosis (TB) is a chronic inflammatory disease that is often associated with alterations in systemic and cellular metabolism that resolves following successful antimicrobial drug treatment. We hypothesized that altered systemic glucose metabolism as a consequence of Mycobacterium tuberculosis (Mtb) infection, contributes to TB pathogenesis, and when normalized with anti-glycemic drugs would improve clinical outcomes. To test this hypothesis, guinea pigs were treated daily with the anti-diabetic drug metformin starting 4 weeks prior or concurrent with aerosol exposure to the H37Rv strain of Mtb. In the chronic stages of infection, Mtb infected metformin-treated animals had restored systemic insulin sensitivity but remained glucose intolerant as determined by oral glucose tolerance testing. Despite persistent glucose intolerance, metformin-treated guinea pigs had a 2.8-fold reduction in lung lesion burden and a 0.7 log decrease in CFUs. An alternative hypothesis that metformin treatment improved clinical disease by having a direct effect on immune cell energy metabolism was tested using extracellular flux analysis and flow cytometry. The proinflammatory immune response to Mtb infection in untreated guinea pigs was associated with a marked increase in energy metabolism (glycolysis and mitochondrial respiration) of peripheral blood mononuclear cells (PBMCs), which was normalized in metformin-treated guinea pigs. Moreover, both CD4+ and CD8+ T lymphocytes from Mtb infected, metformin treated animals maintained a more normal mitochondrial membrane potential while those isolated from untreated animals had persistent mitochondrial hyperpolarization. These data suggest that metformin promotes natural host resistance to Mtb infection by maintaining immune cell metabolic homeostasis and function during the chronic stages of active TB disease.
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影响因子：
12.8
作者：
Kim EK;Lee SH;Lee SY;Kim JK;Jhun JY;Na HS;Kim SY;Choi JY;Yang CW;Park SH;Cho ML
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影响因子：
64.5
作者：
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