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

项目摘要。衰老涉及多系统生理退化。除了受影响的组织， 因此，衰老也会影响肠道微生物群，这是一个广泛的微生物群落， 有助于实现不同的宿主功能。微生物群组成的不平衡，或生态失调，往往是 与病理学相关，最近的报告表明，衰老依赖性生态失调加剧了衰老 表型潜在地，微生物量可以重新平衡以改善衰老;然而，为了实现这一点， 需要更好地理解宿主衰老和改变的 微生物群，并应制定战略，使再平衡。C.秀丽线虫是一个很有价值的模型， 因为它的寿命很短我们最近也将其建立为微生物组的模型 研究，提供脊椎动物模型中无与伦比的优势，包括基因工程的能力， 同质群体，平均个体间的差异，以更好地辨别共享模式。两 在实验室中使用实验管道来饲养蠕虫：类似自然的堆肥微观世界，与16 S相结合 rDNA深度测序，用于微生物群表征，或由30个 蠕虫肠道分离物，用校准的qPCR表征微生物的大小和组成。使用这些 模型表明，C.秀丽线虫具有特征性的和持久的肠道微生物群形状（两者都是 结构上和功能上），并能够优先认可有益的 来自不同环境的学生。我们进一步证明了蠕虫经历了广泛的 他们的微生物群在衰老过程中重塑，包括肠杆菌科的水华，让人想起 在老年人中看到的过度生长。我们建议利用C。elegans模型1）建立 宿主年龄依赖性基因表达（代表衰老过程）之间的因果关系 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 研究衰老，检查对运动性，免疫力，蛋白质稳定性和寿命的影响，并进一步测试 可能性的老化依赖性下降的主机选择性对有益的药物作为一个潜在的 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 合生素补充剂，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 减少对有益病原体的控制，将它们转化为机会性病原体。 拟议的工作将测试年龄依赖性生态失调加剧衰老的假设，并确定 相关的因素它将进一步作为可能性和战略的概念证明 需要使用微生物群重新平衡来改善衰老。

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.