Impact of gut microbiota and segmented filamentous bacteria on colitis-associated colorectal cancer

 描述（由申请人提供）：结直肠癌（CRC）是发达国家癌症相关死亡的第二大常见原因。慢性胃肠道（GI）炎症，如炎症性肠病（IBD）中发生的，是结直肠癌发展的主要危险因素之一。最近的证据表明，胃肠道中存在的复杂细菌群落（肠道微生物群; GM）对宿主健康有巨大影响，特别是在IBD和CRC等疾病中。此外，有证据表明，健康个体的GM可以聚集成有限数量的称为肠型的不同组合物。这些不同肠型对疾病风险的影响尚不清楚。一种特殊的细菌物种（分节丝状细菌; SFB）最近获得了相当大的关注，由于其对粘膜免疫系统的无数影响和与溃疡性结肠炎（IBD的一种形式）的明显相关性。然而，值得注意的是，充分表征转基因中存在的大部分不可培养的细菌所需的方法还没有存在足够长的时间来纵向跟踪人类从疾病发展之前到CRC被诊断的时间点。因此，关于全球机制在儿童权利公约中的作用的现有数据是相互关联的，并不表明因果关系。此外，GM在出生时就开始获得，并且直到儿童期或青春期早期的某个时候才正常化为其稳定的成人组成。目前尚不清楚在肠道的初始定植期间是否确定了以后生活中CRC的风险，或者疾病风险是否可以在以后生活中随着GM的变化而调节。拟议中的研究将通过使用与人类状况具有明显相似性的小鼠模型来回答这些问题。在该模型中，在携带影响与人CRC发展有关的途径的基因突变的小鼠中诱导CRC。疾病是通过实验接种弱机会病原体引发的，该病原体显示出诱导宿主对其他非致病性肠道细菌的免疫应答，从而模拟存在于CRC高风险个体中的环境，例如诊断为IBD的个体。该模型将允许通过疾病发展的所有阶段纵向跟踪疾病，并允许对实验治疗进行受控的前瞻性评估。虽然存在于人类和小鼠的GM中的特定微生物不同，但存在高等微生物分类群的高度保守的功能特性，例如，家庭或阶级。因此，在拟议的研究中产生的数据将可翻译给人类，并将指导后续实验的设计。此外，代谢组学分析将有助于确定个体之间的差异，无论是否进展为CRC，在GM的功能。值得注意的是，这些发现将为人类诊断和治疗方式的发展提供信息，并可能在肿瘤学和胃肠病学领域产生深远的影响。

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in developed countries. Chronic gastrointestinal (GI) inflammation, as occurs in inflammatory bowel disease (IBD), is one of the primary risk factors for the development of colorectal cancer. Recent evidence suggests that the complex community of bacteria present in the GI tract (gut microbiota; GM) has a tremendous impact on host health, particularly in diseases such as IBD and CRC. Additionally, there is evidence that the GM of healthy individuals can be clustered into a limited number of distinct compositions called enterotypes. The impact of these various enterotypes on disease risk is unknown. One particular bacterial species (segmented filamentous bacteria; SFB) has recently gained considerable attention due to its myriad effects on the mucosal immune system and an apparent correlation with ulcerative colitis, one form of IBD. Notably however, the methodologies needed to adequately characterize the largely uncultivable bacteria present in the GM have not existed long enough to track humans longitudinally from the time prior to disease development to the point at which CRC is diagnosed. Thus, existing data on the role of the GM in CRC are correlative and do not demonstrate a causal relationship. Additionally, the GM is acquired beginning at birth and does not normalize to its stable adult composition until some point in childhood or early adolescence. It is unknown whether the risk of CRC later in life is determined during the initial colonization of the gut, or if disease risk can be modulated later in life throuh changes in the GM. The proposed studies will answer these questions through the use of a mouse model with distinct similarities to the human condition. In this model, CRC is induced in mice carrying a genetic mutation affecting a pathway implicated in the development of human CRC. Disease is initiated via experimental inoculation with a weakly opportunistic pathogen shown to induce host immune responses to other non-pathogenic, commensal bacteria, thus mimicking the environment present in individuals at high risk of CRC such as those diagnosed with IBD. This model will allow disease to be tracked longitudinally through all stages of disease development, and will allow for the controlled, prospective assessment of experimental treatments. While the specific microbes present in the GM of humans and mice differ, there are highly conserved functional properties of higher microbial taxa, e.g., family or class. Thus, data generated in the proposed studies will be translatable to humans and will direct the design of subsequent experiments. Moreover, metabolomic profiling will serve to identify differences between individuals that do or do not progress to CRC, in the function of the GM. Of note, these findings will inform the development of both diagnostic and therapeutic modalities for use in humans and could have far-reaching consequences in the fields of oncology and gastroenterology.