Linking macrophages to gut microbiota in obesity-enhanced colon cancer

将巨噬细胞与肥胖增强的结肠癌中的肠道微生物群联系起来

• 批准号: 9024980
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9024980
• 关键词: Adoptive Transfer; Affect; Antibiotics; Automobile Driving; Bacteria; Biota; Cancer Etiology; Carcinogens; Colon; Colon Carcinoma; DNA; Data; Development; Diet; Dietary Intervention; Epithelial Cells; Figs - dietary; Genetic; Goals; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; Laboratories; Lead; Link; Malignant Neoplasms; Mediating; Microbe; Modeling; Mus; Mutation; Obese Mice; Obesity; Play; Prevention; Process; Regulation; Reporting; Research; Risk; Role; Sampling; Shapes; Source; Techniques; Testing; Toxin; Translating; colon tumorigenesis; design; driving force; gut microbiota; macrophage; metaplastic cell transformation; microbial; microbial community; microbiota; microorganism interaction; mouse model; outcome forecast; public health relevance; response; tumor; tumor progression; tumorigenesis

 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.

 描述（由适用提供）：新兴证据将肠道菌群与结肠癌的发育和进展联系起来（COCA）。有趣的是，肥胖是肠道菌群组成的重要驱动力。但是，尚无研究直接研究肠道菌群对驱动肥胖增强的可口可乐的影响。微生物群在可口可乐中的肿瘤促进作用至少部分是由于宿主微生物相互作用改变引起的。宿主衍生的免疫反应和炎症反应是塑造微生物群落组成的重要驱动力，并且在改变时可能导致营养不良。巨噬细胞（MφS）是肥胖相关注射的主要来源，与可口可乐的预后不良有关。但是，尚无系统地检查Mφ在改变肥胖增强的oca中的肠道微生物剖面中的作用。长期目标是发现将肥胖与可口可乐联系起来的机制。这项特定研究的目的是确定肥胖诱导的UT微生物群改变对可口可乐进程的影响，并测试该过程是否受M或调节。中心假设是肥胖诱导的肠道菌群变化是由Mφ介导的炎症过程驱动的，并导致可口可乐的进展增强。该假设将通过追求两个具体目的来检验：1）确定肠道菌群中对象诱导的改变对可口的影响； 2）评估MφS在肥胖增强的可口可乐中改变肠道微生物的作用。在第一个目标下，我们将检验以下假设：肥胖可以通过改变肠道菌群来增强可口。使用诱导的结肠癌遗传小鼠模型，我们将检查饮食诱导的肥胖症对肠道微生物谱和随后肿瘤发生进展的影响。此外，我们将从肥胖小鼠中将肠道微生物转移到携带诱导APC突变的瘦小小鼠中，以测试肥胖诱导的肠道微生物群对可口可乐进展的影响。最后，使用抗生素，我们将从肥胖小鼠中巧妙地肠道菌群，以进一步证实肥胖诱导的肠道微生物群改变可口可乐的作用。在第二个目标中，我们将检验以下假设：Mφs在改变肥胖增强的可口可乐中肠道菌群中起必要的作用。使用Mφ耗竭技术，我们将研究MφS在改变肠道微生物剖面的作用，并随后在肥胖增强可口的小鼠模型中促进肿瘤发生的进展。此外，利用从肥胖小鼠到携带可诱导APC突变的瘦小鼠的MφS的自适应转移，我们将直接确定它们对肠道菌群和可口可乐进展的影响。拟议的研究很重要，因为它将发现将肥胖与可口可乐联系起来的机制。了解肥胖诱导的肠道细菌对可口可乐的改变的影响将使我们能够转化为可以识别有可口可口的人的方法的发展。通过制定旨在恢复肠道中更健康的微生物概况的个性化饮食干预策略，这将具有预防肥胖个体可口可乐的巨大潜力。