Age-dependent changes in gut microbiota composition and their significance for host aging

肠道微生物群组成的年龄依赖性变化及其对宿主衰老的意义

• 批准号: 10350561
• 负责人: Michael Shapira
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350561
• 关键词: Address; Affect; Age; Aging; Animal Model; Animals; Bacteria; Caenorhabditis elegans; Characteristics; Communities; Compost; Coupled; Data; Dependence; Deterioration; Dropout; Elements; Enterobacter; Enterobacteriaceae; Environment; Exposure to; Family; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Germ-Free; Harvest; Human; Immunity; Individual; Knowledge; Label; Larva; Lead; Longevity; Microbe; Modeling; Mus; Outcome; Pathology; Pattern; Phenotype; Physiological; Play; Population; Probiotics; Process; Quantitative Reverse Transcriptase PCR; Reporting; Research; Ribosomal DNA; Role; Supplementation; System; Testing; Time; Tissues; Vertebrates; Work; age effect; age related; beneficial microorganism; cell motility; deep sequencing; digital; dysbiosis; experimental study; fly; functional decline; gut microbes; gut microbiota; inter-individual variation; men; microbial community; microbiome research; microbiota; mutant; opportunistic pathogen; prebiotics; proteostasis; success; transcriptome sequencing

Project summary. Aging involves a multi-system physiological deterioration. In addition to affected tissues, and likely as a consequence, aging also affects the gut microbiota, an extensive microbial community which contributes to diverse host functions. Imbalances in microbiota composition, or dysbiosis, are often associated with pathology, and recent reports indicate that aging-dependent dysbiosis exacerbates aging phenotypes. Potentially, microbiotas could be rebalanced to ameliorate aging; however, to achieve this, better understanding is required of the reciprocal interactions between host aging and the altered microbiota, and strategies should be devised to enable rebalancing. C. elegans is a valuable model for aging research thanks to its short lifespan. We have recently established it also as a model for microbiome research, offering advantages unmatched in vertebrate models, including the ability to work with genetically homogenous populations, averaging-out inter-individual variation to better discern shared patterns. Two experimental pipelines are used in the lab to raise worms: natural-like compost microcosms, coupled to 16S rDNA deep sequencing for microbiota characterization, or defined synthetic microbiotas consisting of 30 worm gut isolates, characterizing microbiotas size and composition with calibrated qPCR. Work with these models showed that C. elegans harbors a characteristic and persistent gut microbiota shaped (both structurally and functionally) by host genetics, and is capable of preferential endorsement of beneficial commensals from a diverse environment. We further demonstrated that worms undergo extensive remodeling of their microbiota during aging, including an Enterobacteriaceae bloom, reminiscent of the overgrowth seen in aging humans. We propose to take advantage of the C. elegans model to 1) establish causative relationships between host age-dependent gene expression (representing processes of aging) and microbiota composition, and test gene-microbe dependencies using monocultures of individual bacterial strains, drop-out bacterial mixes, and worm mutants; 2) determine functional significance of age-altered commensals to aging, examining effects on motility, immunity, proteostasis and lifespan, and further test the possibility of aging-dependent decline in host selectivity toward beneficial commensals as an underlying cause of dysbiosis; 3) test different strategies to rebalance the microbiota and ameliorate aging, including synbiotic supplementation, or the use of mutants susceptible to manipulation; the Enterobacteriaceae bloom will serve as the first target for rebalancing, as preliminary results suggest that it may be the outcome of declined control over beneficial commensals turning them into opportunistic pathogens. The proposed work will test the hypothesis that age-dependent dysbiosis exacerbates aging and identify the relevant elements in this dysbiosis. It will further serve as a proof of concept for the possibility and strategies required to use microbiota rebalancing to ameliorate aging.

项目总结。衰老涉及多系统的生理退化。除了受影响的组织外， 因此，衰老可能也会影响肠道微生物群，这是一个广泛的微生物群落， 有助于多种宿主功能。微生物群组成不平衡或生态失调通常是 与病理学相关，最近的报告表明，衰老依赖性生态失调会加剧衰老 表型。微生物群有可能通过重新平衡来改善衰老；然而，为了实现这一目标， 需要更好地理解宿主衰老和改变之间的相互作用 微生物群，并应制定策略以实现再平衡。线虫是一个有价值的模型 由于其寿命短，因此对其进行了老化研究。我们最近也将其建立为微生物组模型 研究，提供脊椎动物模型无可比拟的优势，包括利用基因进行工作的能力 同质群体，平均个体间差异以更好地辨别共同模式。二 实验室使用实验管道来饲养蠕虫：类似自然的堆肥微观世界，耦合到16S 用于微生物群表征的 rDNA 深度测序，或由 30 个组成的定义的合成微生物群 蠕虫肠道分离物，通过校准的 qPCR 表征微生物群的大小和组成。与这些一起工作 模型表明，线虫具有特征性且持久的肠道微生物群形状（两者 结构和功能上）由宿主遗传学决定，并且能够优先认可有益的 来自不同环境的共生体。我们进一步证明蠕虫经历了广泛的 衰老过程中微生物群的重塑，包括肠杆菌科细菌的大量繁殖，让人想起 老年人中出现的过度生长。我们建议利用线虫模型来 1）建立 宿主年龄依赖性基因表达之间的因果关系（代表衰老过程） 和微生物群组成，并使用单个细菌的单一培养物测试基因-微生物依赖性 菌株、脱落细菌混合物和蠕虫突变体； 2）确定年龄改变的功能意义 与衰老共生，检查对运动、免疫、蛋白质稳态和寿命的影响，并进一步测试 宿主对有益共生体的选择性随年龄增长而下降的可能性是潜在的 生态失调的原因； 3）测试不同的策略来重新平衡微生物群和改善衰老，包括 合生元补充，或使用易受操纵的突变体；肠杆菌科细菌大量繁殖 将作为再平衡的第一个目标，因为初步结果表明，这可能是 减少对有益共生体的控制，将它们变成机会性病原体。 拟议的工作将检验年龄依赖性生态失调加剧衰老的假设，并确定 这种生态失调的相关因素。它将进一步作为可能性和策略的概念证明 需要利用微生物群重新平衡来改善衰老。