Elucidating the role of gut microbiota in colitis-associated colorectal cancer

摘要 溃疡性结肠炎(UC)是一种炎症性肠病(IBD)，患者发生溃疡性结肠炎的风险增加 结肠炎相关性结直肠癌(CAC)。人类肠道微生物群的组成最近被认为是 患有多种疾病，包括IBD和结直肠癌。研究表明，肠道微生物区系 可直接或间接影响结肠上皮细胞启动或促进结直肠癌的发生发展。 然而，对于CAC中微生物区系的结构和功能以及它们如何与 CAC在分子水平上的发展。在这项研究中，我们将调查微生物区系在 CAC的发展，以及微生物区系和宿主反应相互作用的分子事件。 该项目建立在我们之前研究基因组不稳定性和蛋白质组改变的基础上。 结肠上皮在IBD-CAC发病中的作用，并将重点放在其机制和功能上 微生物组及其组成部分参与(保护性细菌)的调节或激活 (由致癌细菌引起)CAC的发生。具体地说，我们将调查粘膜的含义- 通过使用三个模型系统的集成方法在CAC中关联微生物区系，包括临床 标本(AIM 1)、体外微生物培养和有机模型(AIM 2)和体内小鼠模型(AIM 3)。我们的综合，最先进的方法将表征组成，功能基因和途径 与CAC有关的微生物群，以及微生物区系对结肠粘膜的影响。通过研究肠道 使用新方法和尖端技术的微生物区系及其与结肠宿主的相互作用，我们的研究 具有显著的翻译潜力，可能导致建立肠道微生物组作为CAC的预测因子 开发IBD患者CAC预防和检测方法的风险和援助。

Abstract Patients with ulcerative colitis (UC), an inflammatory bowel disease (IBD), have an increased risk of developing colitis-associated colorectal cancer (CAC). Human gut microbiome composition has recently been associated with a wide array of diseases, including IBD and colorectal cancer. Studies have shown that gut microbiota could influence colon epithelium to initiate or promote colorectal cancer development directly or indirectly. However, little is known on the structure and function of the microbiota in CAC and how they implicate the development of CAC at the molecular level. In this study, we will investigate the role of microbiota in the development of CAC, as well as the molecular events underlying the interplay of microbiota and host response. The project builds upon our previous studies in examining the genomic instabilities and proteome alterations in the colon epithelium during the pathogenesis of IBD-CAC, and will focus on the mechanistic and functional involvement of the microbiome and their components in the modulation (by protective bacteria) or activation (by tumorigenic bacteria) of CAC development. Specifically, we will investigate the implication of mucosa- associated microbiota in CAC by an integrated approach using three model systems, including clinical specimens (Aim 1), in vitro microbial cultivation and organoid models (Aim 2), and in vivo mouse model (Aim 3). Our integrative, state-of-the-art approach will characterize the composition, functional genes and pathways of the microbiome implicated in CAC, and the impact of microbiota on colon mucosa. By studying the gut microbiota and its interplay with the colon host using novel approaches and cutting-edge technology, our study has significant translational potential that could lead to establishing the gut microbiome as predictors of CAC risk and aid in developing approaches for CAC prevention and detection in IBD patients.