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.

项目总结。衰老涉及多系统的生理退化。除了受影响的组织，