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

项目总结。衰老涉及一种多系统的生理退化。除了受影响的组织外， 因此，衰老可能也会影响肠道微生物区系，这是一个广泛的微生物群落， 有助于实现不同的宿主功能。微生物区系组成的不平衡，或称生物失调，通常是 与病理学有关，最近的报告表明，依赖衰老的生物失调会加剧衰老 表型。潜在地，微生物群可以重新平衡以改善衰老；然而，要实现这一点， 需要更好地理解寄主老化和变态之间的相互作用 微生物区系，并应制定战略，以实现再平衡。线虫是一种有价值的模型 老龄化研究，这要归功于它的短寿命。我们最近也建立了它作为微生物组的模型 研究，在脊椎动物模型中提供了无与伦比的优势，包括利用基因工作的能力 同质种群，平均个体间的差异，以更好地识别共同的模式。二 实验室中使用实验管道饲养蠕虫：天然的堆肥微观世界，再加上16个 用于微生物区系鉴定的rDNA深度测序，或定义的合成微生物群，由30个 蠕虫肠道分离，用校准的定量聚合酶链式反应表征微生物群的大小和组成。使用这些工具 模型显示，线虫具有特征和持久的肠道微生物群形状(两者 在结构和功能上)，并能够优先认可有益的 来自不同环境的共生品。我们进一步证明了蠕虫经历了广泛的 他们的微生物群在老化过程中的重塑，包括肠杆菌科的开花，让人想起 在老龄化的人类中可见的过度生长。我们建议利用线虫模型1)建立 宿主年龄依赖的基因表达(代表衰老过程)之间的因果关系 和微生物区系组成，并使用单个细菌的单一培养来测试基因-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 衰老的共性，检查对运动性、免疫力、蛋白平衡和寿命的影响，并进一步测试 随着年龄的增长，宿主对有益共生体的选择性可能下降，这是一种潜在的 生物失调的原因；3)测试重新平衡微生物区系和改善衰老的不同策略，包括 合生体补充剂，或使用易受操纵的突变体；肠杆菌科开花 将作为再平衡的第一个目标，因为初步结果表明，这可能是 拒绝了对有益共生品的控制，将它们变成了机会主义的病原体。 这项拟议的工作将检验依赖年龄的生物失调会加剧衰老的假设，并确定 这种生物失调的相关因素。它将进一步作为对可能性和策略的概念证明 需要使用微生物区系再平衡来改善衰老。

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.