Microbial Genetic Composition Tunes Host Longevity
Microbial Genetic Composition Tunes Host Longevity
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DOI：
10.1016/j.cell.2017.05.036
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发表时间：
2017-06-15
期刊：
影响因子：
64.5
通讯作者：
Wang, Meng C.
中科院分区：
文献类型：
--
作者：
Han, Bing;Sivaramakrishnan, Priya;Wang, Meng C.
肠道微生物群的稳态严重影响宿主的健康和衰老。开发基因工程益生菌作为促进健康老龄化的新治疗范式具有很大的希望。在这里，通过筛选3,983个大肠杆菌突变体，我们发现29个细菌基因，当删除时，增加宿主秀丽隐杆线虫的寿命。这些细菌突变体中的十几种还保护宿主免受与年龄相关的肿瘤生长和淀粉样蛋白β积累的进展。从机制上讲，我们发现五种细菌突变体通过增加多糖可乐酸（CA）的分泌来促进长寿，CA调节宿主中的线粒体动力学和未折叠蛋白反应（UPRmt）。纯化的CA聚合物足以通过ATFS-1（宿主UPRmt响应性转录因子）促进长寿。此外，CA诱导的线粒体变化和寿命效应在不同物种中是保守的。我们的研究结果共同确定了开发促长寿微生物的分子靶点和作用于宿主线粒体以促进长寿的细菌代谢产物。
Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity.