节食通过调节肠道菌群抵抗炎性衰老的作用机制研究

A low-grade, systemic, chronic inflammatory condition associated with obesity has been recognized as a crucial pathological process underlying metabolic deteriorations and accelerated aging (inflammaging). The health-promoting and lifespan-extending effects of calorie restriction have been demonstrated in many mammals including non-human primates and humans. Compelling evidence points to that CR may exert its beneficial actions through attenuating the inflammatory state associated with aging and age-related diseases, but the primary mediator through which CR directly alleviate inflammation remains unclear. Our previous publication showed that CR can significantly modulate gut microbiota and reduce endotoxin load in host serum, indicating that CR modulated gut microbiota may play a critical role in reducing inflammation and extending lifespan of the hosts. In this study, gut microbiota transplantation to germfree mice will be employed to evaluate the causative role of gut microbiota in CR mediated health benefits; Co-variation analysis between metagenomic data of the CR modulated gut microbiota and host transcriptomic data will be used to identify those key functional bacteria and their important genes; these functional bacteria will be isolated and inoculated into germfree mice to establish gnotobiotic model for further mechanistic studies. This project will generate new insights on anti-aging effects of CR and may shed light on how nutritional intervention for human beings should be formulated to target gut microbiota related inflammation and metabolic deterioration.

大量研究表明，节食可以通过减少炎性因子产生，来改善代谢稳态、延长寿命，但是能够作为节食的直接作用靶点，参与调节炎症反应的中介因子仍然不清楚。我们的前期工作表明，长期节食可以优化肠道菌群结构、减少内毒素入血，从而可能成为减轻炎性衰老的一个关键因素。本研究将通过菌群移植，评价节食改变的菌群对改善炎症、减轻代谢综合征从而延缓衰老的贡献；建立长期CR模型，通过菌群的元基因组学和宿主组织的转录组学数据的关联分析，寻找对改善宿主炎症反应和代谢稳态有贡献的关键肠道菌群成员及其重要基因；分离功能菌，在无菌动物中建立研究其与宿主的分子互作机制的模型，逐步揭示节食以菌群为中介的抗衰老作用机制，不仅完善对衰老机制的理解，而且可以为人群中建立和开展以使肠道菌群结构更加平衡及减少细菌产生的抗原总量为靶点的膳食干预提供理论依据，为延缓衰老、减少代谢性失调相关疾病的发病率提供新思路和新手段。

大量研究表明，节食可以通过减少炎性因子产生，来改善代谢稳态、延长寿命，但是能够作为节食的直接作用靶点，参与调节炎症反应的中介因子仍然不清楚。我们的前期工作表明，长期节食可以优化肠道菌群结构、减少内毒素入血，从而可能成为减轻炎性衰老的一个关键因素。在本课题的研究中，我们发现以Lactobacillus占绝对优势的肠道菌群能够在节食仅仅进行2周就建立起来，并且显著降低了宿主循环系统肠道细菌来源的抗原并改善宿主系统性炎症。分离自节食小鼠肠道且能代表节食最显著富集的肠道细菌菌株Lactobacillus murinus CR147，能够显著降低TNF-α刺激Caco-2细胞产生的炎症因子白介素8，能够显著增加线虫的产卵数量和延长其寿命，还能够显著改善老龄小鼠肠道菌群造成的肠屏障破坏和系统性炎症水平。但是另一株同样分离自节食小鼠肠道的Lactobacillus murinus CR141，虽然与前述菌株基因组有高度相似性，但却不具备对宿主的有益作用。这个结果充分说明了在研究肠道菌群与宿主健康之间的关系时，必须做到菌株水平，唯有如此才可能找到真正对维持宿主健康或者导致疾病的肠道菌群成员，并将机制研究清楚。不仅如此，我们还通过小鼠模型说明节食塑造一个健康的肠道菌群结构能够帮助小鼠抵抗化学试剂DSS诱导的肠炎和化疗药物造成的肠道损伤。本课题的研究证实了节食小鼠肠道中的优势Lactobacillus murinus对于节食给宿主提供的健康效应中起到了重要的贡献，这样的关键有益细菌很有潜力成为减缓衰老相关的炎症、延长宿主寿命的调控靶点。