The intestinal microbiome contribution to colon cancer and senescence

项目摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-045. 结直肠癌（CRC）与年龄（不可改变的风险因素）相关，并与肠道有关 微生物组（潜在可改变的风险因素）。我们的初步数据表明，微生物组可能会驱动 与年龄相关的结肠变化，如衰老。因此，我们假设，年龄相关的变化， 肠道微生物组在功能上改变结肠内稳态及其微环境，从而促进 形成肿瘤性病变。我们进一步假设结肠间质细胞衰老的增加 在功能上将微生物组与肿瘤形成联系起来。在目标1中，我们将定植肿瘤倾向的gnotobiotic Fabp 1-Cre+ mT/mG+ Pik 3ca *+ ApcMin/+小鼠，其微生物组来自年轻和老年人供体， 确定“老年”微生物组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供体的微生物组，以确定是否“老年” 微生物组诱导结肠基质中的细胞衰老。我们的研究将奠定基础， 基于微生物组的策略（具体表现为饮食调整或基于移植的策略） 干预），以预防结直肠癌和改善健康寿命。

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.