Determining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk.

摘要：肥胖与13种癌症的风险增加有关。关键的问题是如何和什么 肥胖介导的慢性炎症增加的潜在机制可能会增加癌症风险 “保护性豁免”的失败。这种知识差距代表了一个尚未开发的机会，我们的多- ciplinary团队是唯一有资格探索与使命，以提高对癌症风险的理解。我们有 先前研究表明，肥胖改变了T细胞和巨噬细胞的功能，从而降低了抗肿瘤保护作用 并拥有人类研究方面的专业知识，这对跨学科的挑战至关重要。我们的目标是找出 人类受试者中的相关性和各种临床前模型中癌症风险介质的测试机制 沿着“肥胖-微生物-代谢物-保护性免疫”轴。我们的假设是肥胖改变 肠道微生物通过失调的保护性免疫增强癌症风险，从而增加启动。 目的1将定义肥胖介导的微生物衍生代谢产物的失调和对免疫phe的影响， 通过检查不同的受试者， 1a）不同年龄和肥胖症;和1b）减肥手术前后的肥胖患者。捐赠者将被 来自孟菲斯地区，该地区人口高度多样化，非洲裔美国人占65%， 肥胖的证据。患者分析将为补充临床前模型中的研究提供信息， nistic调查，以确定癌前微环境中的保守机制。目标2将阻止- 通过检查自发免疫细胞，挖掘微生物衍生代谢物对癌症风险的影响。 乳腺癌转基因模型，在潜伏期、对高脂肪的致肥胖反应方面具有已确立的异质性 饮食循环胆汁酸和肠道微生物目标3将测试饮食管理的一个特定的微生物-de- 衍生代谢物或微生物对互补致癌和同源模型中保护性免疫的影响 肥胖介导的乳腺癌。人受试者和鼠模型研究，补充了ex 体内和体外研究将测试潜在的机制，以确定微生物修饰的代谢物如何 可能会影响免疫癌细胞的串扰。为跨集团活动预留了合作资金， 在异质性瘦和肥胖人群中进行风险评估， 通过NCI的代谢失调和癌症风险计划对我们的研究结果产生影响。总之，结果将 定义有益的微生物衍生的代谢物，影响保护性免疫，以减少癌症的发生。 因此，这一建议的战略是在概念上的原创性，创新性，并有意义的定义保守的非- 抑制癌症风险的机制。所产生的结果将产生很大的影响，因为肥胖- 相关病因对风险的影响是异质性的，本研究旨在调查这些 不同的机制转化为更好的风险管理，以改善患者的结局。

SUMMARY: Obesity is associated with increased risk for 13 cancers. Critical questions are how and to what extent underlying mechanisms of obesity-mediated increases in chronic inflammation may increase cancer risk in a failure of “protective immunity”. This knowledge gap represents an untapped opportunity that our multidis- ciplinary team is uniquely qualified to explore with a mission to improve understanding of cancer risk. We have previously shown obesity alters T cell and macrophage functions that could decrease anti-tumor protections and have expertise in human studies essential for this interdisciplinary challenge. Our objective is to identify associations in human subjects and test mechanisms of mediators of cancer risk in various pre-clinical models along an “obesitymicrobes metabolites protective immunity” axis. Our hypothesis is that obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity that allows increased initiation. Aim 1 will define obesity-mediated dysregulation of microbial-derived metabolites and impacts on immune phe- notypes and protective immunity in human subjects at greater risk for cancer by examining diverse subjects 1a) of varied age and adiposity; and 1b) obese patients pre- and post- bariatric surgery. Donors will be drawn from the Memphis area, which offers a highly diverse population with 65% African Americans with a high inci- dence of obesity. Patient analyses will inform studies in complementary pre-clinical models to allow for mecha- nistic investigation to identify conserved mechanisms in the pre-cancer microenvironment. Aim 2 will deter- mine the impact of microbially-derived metabolites on cancer risk by examining immune cells in spontaneous transgenic models of breast cancer with established heterogeneity in latency, obesogenic response to high fat diet, circulating bile acids, and gut microbes. Aim 3 will test dietary administration of a specific microbially-de- rived metabolite or microbe on protective immunity in complementary carcinogenic and syngeneic models of obesity-mediated breast cancer, respectively. Human subject and murine model studies complemented by ex vivo and in vitro studies will test underlying mechanisms to determine how microbially-modified metabolites may impact immune-cancer cell crosstalk. Collaborative funds for cross-consortium activities are reserved for risk assessment across heterogenous lean and obese populations and models across aims to add synergistic impact to our findings through NCI’s Metabolic Dysregulation and Cancer Risk Program. In sum, outcomes will define beneficial microbially-derived metabolites that impact protective immunity to reduce cancer initiation. Thus, the strategy of this proposal is conceptually original, innovative, and significant to define conserved un- derlying mechanisms that suppress cancer risk. Findings generated will have high impact because the obesity- associated etiological impacts on risk will be heterogeneous and this study is designed to investigate those varied mechanisms to translate to better risk management to improve patient outcomes.