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

项目摘要 新出现的数据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的早期病变。 结肠直肠癌（CRC）和结肠镜检查筛查期间的实际靶点。然而，我们知识的不足 肠道微生物组的基础科学和诱导腺瘤形成的特定驱动机制 进展阻碍了翻译我们假设微生物组是一种非自主性腺瘤 结肠直肠“引发”的诱导物，我们在本申请中使用的术语是指分子/细胞改变 对腺瘤的形成和发展至关重要。本建议的近期目标是确定 以及微生物组和启动的结肠如何协同作用以驱动腺瘤形成。长期 该提案的目的是开发基于微生物组的策略，用于精确预防腺瘤， 最终CRC。在目标1中，我们将确定微生物组和启动结肠的相互依赖性。我们将 利用来自新的、经过验证的宏基因组分析的见解。我们将使用知菌小鼠， 致敏结肠、致瘤肠道细菌和肿瘤发生之间的相互作用。我们使用分析方法 例如介导分析以量化微生物组和致敏结肠各自介导的程度 另一个的致瘤效应在目标2中，我们将确定腺瘤相关的肠道微生物组特征， 描述人类侵袭性腺瘤与惰性腺瘤的特征。我们将分析一个独特的队列纵向 通过深度测序、原位细菌成像、严格定义的遗传/分子生物学方法 项目1中生成的特征，以及机器学习来识别腺瘤相关的微生物组特征， 与引发的结肠属性相互作用以驱动腺瘤进展。在目标3中，我们将确定微生物组是否- 诱导的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。使用原代 结肠成纤维细胞来源于与CRC相关的细菌财团定殖的非细菌性小鼠，我们将 评估在离体类器官模型中对腺瘤进展行为的致癌作用。我们将确定 微生物组的致瘤作用是否通过诱导衰老的结肠引发 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 腺瘤细胞在离体人腺瘤类器官中的行为。我们的发现可以作为基础， 生物学支持的，可干预的，精确预防腺瘤和最终的CRC。

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.