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: 10063937
• 负责人: Michael Shapira
• 金额: $ 29.24万
• 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/10063937
• 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; Recombinant DNA; Reporting; Research; Role; Structure; 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.

项目摘要。衰老涉及多系统生理恶化。除了受影响的组织外 因此，衰老也可能影响肠道微生物群，这是一个广泛的微生物群落， 有助于各种主机功能。菌群组成或营养不良的失衡通常是 与病理学相关，最近的报告表明，依赖衰老的营养不良加剧了衰老 表型。潜在地，微生物可以重新平衡以改善衰老。但是，为了实现这一目标， 需要更好地理解宿主衰老与变化之间的相互互动 微生物群和应设计策略以实现重新平衡。秀丽隐杆线虫是一个宝贵的模型 衰老研究的寿命短。我们最近还建立了它作为微生物组的模型 研究，提供脊椎动物模型中无与伦比的优势，包括具有基因工作的能力 同质种群，平均分散的人间变化，以更好地辨别共享模式。二 实验管道在实验室中用于饲养蠕虫：天然样堆肥缩影，耦合至16S rDNA深度测序，用于微生物群表征或定义的合成微生物群，由30个组成 蠕虫肠分离株，表征了微生物群的大小和用校准的QPCR组成。与这些一起工作 模型表明，秀丽隐杆线虫具有特征性和持久的肠道菌群形状（均 通过宿主遗传学在结构和功能上），能够优先认可有益 来自多样化环境的份子。我们进一步证明蠕虫经历了广泛的 在衰老过程中重塑其菌群，包括肠杆菌开花，让人联想到 在衰老的人类中看到过度生长。我们建议利用秀丽隐杆线虫模型到1）建立 宿主依赖年龄的基因表达（表示衰老的过程）之间的致病关系 和微生物群的组成，以及使用单个细菌的单一培养物测试基因微叶依赖性 菌株，辍学的细菌混合物和蠕虫突变体； 2）确定改变年龄的功能意义 与衰老的统计，检查对运动的影响，免疫力，蛋白质量和寿命，并进一步测试 宿主对有益份额的选择性依赖衰老的可能性作为基础 营养不良的原因； 3）测试不同策略以重新平衡微生物群和改善衰老，包括 补充合成剂，或使用易于操纵的突变体；肠杆菌开花 将作为重新平衡的第一个目标，因为初步结果表明这可能是 对有益的共生的控制下降，将其转变为机会性病原体。 拟议的工作将检验以下假设，即年龄依赖性的营养不良加剧了老化的衰老 这种营养不良的相关元素。它将进一步作为可能性和策略的概念证明 需要使用微生物群的重新平衡来改善衰老。