The intestinal microbiome contribution to colon cancer and senescence

项目摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 23-045. 结直肠癌(CRC)与年龄(不可改变的危险因素)有关，并与肠道有关。 微生物组(潜在的可改变的危险因素)。我们的初步数据表明，微生物群可能会驱动 与年龄相关的结肠变化，如衰老。因此，我们假设与年龄相关的变化 肠道微生物群在功能上改变了结肠的动态平衡及其微环境，从而促进了 肿瘤性病变的形成。我们进一步假设结肠间质中的细胞衰老增加 在功能上将微生物群与肿瘤的形成联系起来。在目标1中，我们将定植易患肿瘤的灵知生菌 Fabp1-Cre+mt/mg+PIK3CA*+ApcMin/+小鼠，来自年轻和老年人类供者的微生物群 确定“老年”微生物是否促进结肠肿瘤的形成。在目标2中，我们将殖民 无菌野生型小鼠与来自年轻和老年人类捐赠者的微生物群一起来确定是否“老年” 微生物可诱导结肠基质中的细胞衰老。我们的研究将为未来的发展奠定基础 基于微生物组的策略(具体表现为饮食修改或基于移植 干预措施)，用于预防结直肠癌和提高健康寿命。

Project Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Colorectal cancer (CRC) is correlated with age (unmodifiable risk factor) and has been linked to the gut microbiome (potentially modifiable risk factor). Our preliminary data suggest that the microbiome may drive age-related changes in the colon such as senescence. We therefore hypothesize that age-related changes in the intestinal microbiome functionally alter colon homeostasis and its microenvironment, thereby promoting the formation of neoplastic lesions. We further hypothesize that increased cellular senescence in the colon stroma functionally connects the microbiome with tumor formation. In Aim 1, we will colonize tumor-prone gnotobiotic Fabp1-Cre+ mT/mG+ Pik3ca*+ ApcMin/+ mice with microbiomes from young and old human donors to determine whether “geriatric” microbiomes promote the formation of colonic tumors. In Aim 2, we will colonize germ-free wild-type mice with microbiomes from young and old human donors to determine whether “geriatric” microbiomes induce cellular senescence in the colonic stroma. Our studies will lay the foundations to develop microbiome-based strategies (concretely manifesting as dietary modifications or transplant-based interventions) for colorectal cancer prevention and improvement of health span.