Linking macrophages to gut microbiota in obesity-enhanced colon cancer

 描述（由申请人提供）：新出现的证据将肠道微生物群与结肠癌（CoCA）的发展和进展联系起来。有趣的是，肥胖是肠道微生物群组成的重要驱动因素。然而，没有研究直接研究肠道微生物群对驱动肥胖增强的CoCA的影响。CoCA中微生物群的促肿瘤作用至少部分由改变的宿主-微生物相互作用引起。宿主衍生的免疫和炎症反应是塑造微生物群落组成的重要驱动力，当改变时，可能导致生态失调。巨噬细胞（MΦ）是肥胖相关炎症的主要来源，并且与CoCA的预后不良有关。然而，没有研究系统地检查了MΦ在改变肥胖增强的CoCA中的肠道微生物谱中的作用。长期目标是揭示肥胖与CoCA之间的联系机制。这项研究的目的是确定肥胖诱导的UT微生物群改变对CoCA进展的影响，并测试该过程是否受MΦs调节。核心假设是肥胖诱导的肠道微生物群变化是由MΦ介导的炎症过程驱动的，并导致CoCA的进展增强。该假设将通过追求两个特定目标进行测试：1）确定肥胖诱导的肠道微生物群改变对CoCA的影响; 2）评价MΦ在改变肥胖增强的CoCA中的肠道微生物谱中的作用。在第一个目标下，我们将测试肥胖可以通过改变肠道微生物群来增强CoCA的假设。我们将使用一个可诱导的结肠癌遗传小鼠模型，研究饮食诱导的肥胖对肠道微生物分布和随后的肿瘤发生进展的影响。此外，我们将把肠道微生物从肥胖小鼠转移到携带诱导型Apc突变的瘦小鼠，以测试肥胖诱导的肠道微生物群改变对CoCA进展的影响。最后，使用抗生素，我们将耗尽肥胖小鼠的肠道微生物群，以进一步证实肥胖诱导的肠道微生物群改变对CoCA的作用。在第二个目标中，我们将检验MΦ在肥胖增强的CoCA中改变肠道微生物群中发挥必要作用的假设。使用MΦ耗竭技术，我们将在肥胖增强的CoCA小鼠模型中检查MΦs在改变肠道微生物谱和随后促进肿瘤发生进展中的作用。此外，使用从肥胖小鼠到携带诱导型Apc突变的瘦小鼠的MΦ的过继转移，我们将直接确定它们对肠道微生物群和CoCA进展的影响。这项研究意义重大，因为它将揭示肥胖与CoCA之间的联系机制。了解肥胖引起的肠道细菌改变对CoCA的影响将使我们能够转化为识别CoCA风险个体的方法的发展。这将为预防肥胖个体中的CoCA提供巨大的潜力，通过开发个性化的饮食干预策略，旨在恢复肠道中更健康的微生物分布。

 DESCRIPTION (provided by applicant): Emerging evidence links gut microbiota to the development and progression of colon cancer (CoCA). Interestingly, obesity is a significant driver for the composition of gut microbiota. However, there are no studies that have directly examined the influence of gut microbiota on driving obesity-enhanced CoCA. The tumor- promoting effects of the microbiota in CoCA are caused, at least in part, by altered host-microbial interactions. Host-derived immune and inflammatory responses are important driving forces that shape microbial community composition and, when altered, may contribute to dysbiosis. Macrophages (MΦs) are a primary source of obesity-associated inflammation and have been linked to poor prognosis in CoCA. However, there are no studies that have systematically examined a role for MΦs in altering the gut microbial profile in obesity- enhanced CoCA. The long-term goal is to uncover the mechanisms linking obesity to CoCA. The objective in this particular investigation is to determine the influence of an obesity-induced alteration in ut microbiota on CoCA progression and to test whether this process is regulated by MΦs. The central hypothesis is that obesity-induced changes in gut microbiota are driven by MΦ-mediated inflammatory processes and lead to enhanced progression of CoCA. This hypothesis will be tested by pursuing two specific aims: 1) Determine the effects of an obesity-induced alteration in gut microbiota on CoCA; and 2) Evaluate the role of MΦs in altering the gut microbial profile in obesity-enhanced CoCA. Under the first aim, we will test the hypothesis that obesity can enhance CoCA by altering gut microbiota. Using an inducible genetic mouse model of colon cancer, we will examine the effects of diet-induced obesity on the gut microbial profile and subsequent progression of tumorigenesis. Further, we will transfer gut microbes from obese mice to lean mice carrying an inducible Apc mutation to test the influence of an obesity-induced alteration of gut microbiota on CoCA progression. Finally, using antibiotics we will deplete gut microflora from obese mice to further confirm the role of obesity-induced alterations in gut microbiota on CoCA. In the second aim, we will test the hypothesis that MΦs play a necessary role in altering gut microbiota in obesity-enhanced CoCA. Using MΦ depletion techniques, we will examine the role of MΦs in altering the gut microbial profile and subsequently promoting progression of tumorigenesis in a mouse model of obesity-enhanced CoCA. Further, using adoptive transfer of MΦs from obese mice to lean mice carrying an inducible Apc mutation, we will directly determine their effects on gut microbiota and CoCA progression. The proposed investigation is significant as it will uncover a mechanism that links obesity to CoCA. Understanding the impact of obesity-induced alterations in gut bacteria on CoCA will allow us to translate to the development of approaches that will identify individuals at risk for CoCA. This would present enormous potential for prevention of CoCA in obese individuals through development of personalized dietary intervention strategies designed to restore a more healthy microbial profile in the gut.