肠道菌群老化影响老龄小鼠溃疡性结肠炎易感性和恢复能力的研究

During host aging, gut microbiota undergo dramatic changes in composition and function, termed microbiota aging. Aging of the microbiota is closely related to health of the elderly and susceptibility of many age-related diseases. Ulcerative colitis is a disease that shows distinct phenotype and characteristics between elderly patients and patients of younger age, but whether microbiota aging contributed to these clinical differences has not been studied. In this project, we will establish a model of dextran sodium sulfate-induced ulcerative colitis in young and old mice. By following-up changes in gut microbiota from induction to recovery, we will study how gut microbiota aging affects ulcerative colitis susceptibility and recovery rate. To further explore whether gut microbiota can serve as a target for the regulation of ulcerative colitis, we plan to use two experiments to interfere with gut microbiota aging: 1) using co-housing of young and old mice to brought their gut microbiota to an intermediate state, and 2) using heterochronic fecal microbiota transplantation of young and aged mice to switch the aging state of their gut microbiota. Comparison of disease induction response in mice with and without treatment can clarify whether microbiota aging directly affects ulcerative colitis susceptibility and recovery ability in old mice. The findings of this project will promote understanding of the pathogenesis of ulcerative colitis in elderly patients, and provide potential therapeutic strategies of regulating gut microbiota to treat ulcerative colitis.

肠道菌群随宿主衰老进程发生的组成和功能变化称为“肠道菌群老化”，与老年健康和多种老年病密切相关。溃疡性结肠炎在老年人中的发病表现不同于其他年龄病人，但肠道菌群老化是否与其发病与恢复有关尚缺乏研究。本项目计划对年轻和老龄小鼠建立葡聚糖硫酸钠诱导溃疡性结肠炎模型，跟踪观察诱导和恢复过程中肠道菌群的变化，研究肠道菌群老化对宿主溃疡性结肠炎易感性和恢复能力的影响。为了进一步探索肠道菌群是否能作为靶点调节溃疡性结肠炎表现，我们计划使用两种方案干预肠道菌群的老化：1）利用年轻小鼠和老龄小鼠的混笼饲养使肠道菌群达到中间态，2）对年轻小鼠和老龄小鼠进行交叉的粪菌移植。通过对比菌群经过干预和未经干预的小鼠对疾病诱导的反应，可以阐明肠道菌群的老化是否决定了老龄小鼠溃疡性结肠炎的易感性和恢复能力。本项目的研究结果将增进对于老年病人溃疡性结肠炎的发病机制的理解，提供通过调节肠道菌群来治疗溃疡性结肠炎的科学依据。

本课题主要研究肠道菌群如何影响老龄宿主溃疡性结肠炎（Ulcerative Colitis，UC）的易感性和恢复能力。我们首先利用成熟且广泛应用于年轻小鼠的葡聚糖硫酸钠（Dextran sulphate sodium, DSS）诱导溃疡性结肠炎模型（DSS-UC），系统性地比较了年轻（2月龄）、中年（12月龄）和老龄（20月龄）小鼠在DSS-UC过程中疾病表现和肠道菌群变化的差异。进而，我们通过混笼饲养的方式调节不同年龄小鼠的肠道菌群，观察到了明显的肠道菌群趋同现象，并且发现这一处理改变了小鼠对DSS-UC的易感性和恢复能力。在进行对老龄小鼠进行年轻供体粪便菌群移植以改善肠道菌群老化的过程中，我们发现尽管来自年轻小鼠的菌群可以成功地在老龄宿主中定植，但是对于移植后的受体鼠进行化学诱导溃疡性结肠炎测试时，我们发现从年龄不匹配的供体移植的肠道菌群无法承受扰动，而是恢复为移植前的自身原始菌群状态。这一现象表明肠道菌群也受老龄宿主肠道环境的限制，仅靠单次菌群移植来逆转肠道菌群老化、改善溃疡性结肠炎表型有一定困难，仍需后续研究探索具体机制和更优的干预手段。综上所述，本项目研究了肠道菌群老化对老龄小鼠溃疡性结肠炎的影响，既具有揭示衰老过程中肠道菌群和宿主相互作用机制的科学意义，也具有阐明迟发型溃疡性结肠炎机制以制定更好的治疗方案的临床应用潜力。