The gut microbiome, interactions with primed colon states, and effects on adenoma formation and progression

肠道微生物组、与结肠状态的相互作用以及对腺瘤形成和进展的影响

• 批准号: 10519076
• 负责人: Neelendu Dey
• 金额: $ 34.45万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519076
• 关键词: Architecture; Area; Automobile Driving; Back; Bacteria; Basic Science; Behavior; Biology; Cells; Collaborations; Colon; Colonic Adenoma; Colonoscopy; Colorectal; Colorectal Adenoma; Colorectal Cancer; Data; Fibroblasts; Fusobacterium nucleatum; Future; Genes; Gnotobiotic; Health; Human; Image; In Situ; Individual; Indolent; Intervention; Knowledge; Lesion; Link; Longitudinal cohort; Machine Learning; Mediating; Mediation; Metagenomics; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Mus; Natural History; Oncogenic; Organoids; Phenotype; Role; Testing; Tissues; Translations; Up-Regulation; adenoma; base; clinical care; colorectal cancer prevention; deep sequencing; design; experimental study; genomic signature; gut bacteria; gut microbes; gut microbiome; host microbiome; individualized prevention; insight; microbiome; novel; pathobiont; screening; senescence; tumor; tumorigenesis; tumorigenic

Project Summary Emerging data have linked the gut microbiome to colorectal adenomas, the established early lesions in colorectal cancer (CRC) and de facto targets during screening colonoscopy. However, deficit in our knowledge of the basic science of the gut microbiome and the specific driver mechanisms for inducing adenoma formation and progression has impeded translation. We hypothesize that the microbiome is an adenoma nonautonomous inducer of colorectal “priming,” the term we use in this application to refer to molecular/cellular alterations critical for adenoma formation and progression. The near-term objective of this proposal is to define whether and how the microbiome and the primed colon act in concert to drive adenoma formation. The long-term objective of this proposal is to develop microbiome-based strategies for precision prevention of adenomas and ultimately CRC. In Aim 1, we will identify interdependencies of the microbiome and the primed colon. We will leverage insights from a novel, validated metagenomic analysis. Using gnotobiotic mice, we will study interactions between a primed colon, tumorigenic gut bacteria, and tumorigenesis. We use analytic approaches such as mediation analysis to quantify the extent to which the microbiome and a primed colon each mediate the other’s tumorigenic effects. In Aim 2, we will identify the adenoma-associated gut microbiome features that characterize aggressive vs indolent adenomas in humans. We will analyze a unique cohort of longitudinally monitored adenomas through deep sequencing, in situ bacterial imaging, rigorously defined genetic/molecular profiles generated in Project 1, and machine learning to identify adenoma-associated microbiome features that interact with primed colon attributes to drive adenoma progression. In Aim 3, we will determine if microbiome- induced senescent fibroblasts drive progression behavior in adenoma cells in ex vivo adenoma organoids through specific CRC-associated senescence-associated secretory phenotype (SASP) factors. Using primary colon fibroblasts derived from gnotobiotic mice colonized with a CRC-associated bacterial consortium, we will assess oncogenic effects on adenoma progression behavior in an ex vivo organoid model. We will determine whether tumorigenic effects of the microbiome are mediated through induction of the senescent colon primed state, and we will mechanistically test roles for candidate CRC-associated SASP factors in driving progression behavior of adenoma cells in ex vivo human adenoma organoids. Our findings could serve as the basis for biology-backed, intervenable, precision prevention of adenomas and ultimately CRC.

项目概要 新出现的数据已将肠道微生物组与结直肠腺瘤联系起来，结直肠腺瘤是结直肠癌中已确定的早期病变。 结直肠癌（CRC）和筛查结肠镜检查过程中的实际目标然而，我们的知识不足。 肠道微生物组的基础科学和诱导腺瘤形成的具体驱动机制 我们认为微生物组是一种非自主的腺瘤。 结直肠“启动”的诱导剂，我们在本申请中使用的术语指分子/细胞改变 该提案的近期目标是确定是否对腺瘤形成和进展至关重要。 以及微生物组和引发的结肠如何协同作用来驱动腺瘤的长期形成。 该提案的目标是制定基于微生物组的策略来精确预防腺瘤和 最终 CRC 在目标 1 中，我们将确定微生物组和已启动的结肠之间的相互依赖性。 我们将利用新的、经过验证的宏基因组分析的见解，利用无菌小鼠进行研究。 我们使用分析方法来研究已启动的结肠、致瘤肠道细菌和肿瘤发生之间的相互作用。 例如介导分析，以量化微生物组和引发的结肠各自介导的程度 在目标 2 中，我们将确定与腺瘤相关的肠道微生物组特征。 我们将纵向分析一组独特的人类腺瘤的特征。 通过深度测序、原位细菌成像、严格定义的遗传/分子来监测腺瘤 项目 1 中生成的概况，以及机器学习来识别与腺瘤相关的微生物组特征 在目标 3 中，我们将确定微生物组是否与已启动的结肠属性相互作用以驱动腺瘤进展。 诱导衰老成纤维细胞驱动离体腺瘤类器官中腺瘤细胞的进展行为 通过特定的 CRC 相关衰老相关分泌表型 (SASP) 因子使用主要因子。 结肠成纤维细胞来源于定植有结直肠癌相关细菌群的无菌小鼠，我们将 我们将确定离体类器官模型中对腺瘤进展行为的致癌作用。 微生物组的致瘤作用是否是通过诱导衰老结肠介导的 状态，我们将机械地测试候选 CRC 相关 SASP 因素在推动进展中的作用 我们的研究结果可以作为离体人类腺瘤类器官中腺瘤细胞的行为的基础。 生物学支持的、可干预的、精确预防腺瘤并最终预防结直肠癌。