Associations of Gut Microbiome Predictors of Body Fat Amount and Distribution

身体脂肪的积累和分布在不同的种族群体中有所不同，并可能影响不同种族中肥胖相关癌症的患病率。本研究探讨了多种族队列（MEC）中脂肪积累和分布、肠道微生物组和与肥胖相关癌症风险相关的表型之间的关系。因此，肠道微生物群代表了一个潜在的可改变的肥胖相关因素，可能会影响癌症风险。肠道微生物组通过调节饮食中的能量摄取、与宿主脂肪酸代谢信号分子的相互作用以及亚慢性炎症（肥胖相关疾病的标志）来影响人体代谢。亚慢性炎症可以通过微生物产生的饮食代谢物间接介导，也可以通过先天免疫系统的激活直接介导。例如，肠道细菌内毒素与脂多糖结合蛋白（LBP）结合到toll样受体（TLR）上，从而激活NF - 1水平的细胞因子。与脂肪酸代谢和先天免疫相关的人类基因变异可能改变宿主与肠道微生物群的相互作用，并改变与肥胖相关的癌症风险相关的炎症。该创新项目将使用MEC队列研究肠道微生物组的组成，使用高通量测序方法，作为饮食，脂肪分布和癌症风险之间关系的影响调节剂。我们将：1)在本研究重新接触的2000名MEC受试者中，确定与体脂量和分布相关的肠道微生物谱，并分析项目2中微生物组GWA研究收集的4229份粪便样本；2)测试这些微生物谱与饮食和其他生活方式因素的关系，以及与中间癌症表型（即细胞因子、脂肪因子、类固醇激素、胰岛素、IGF激素和LBP）的关系；3)通过对1379例结直肠癌患者和1379例对照者诊断前血浆中LBP的测量，研究循环LBP与结直肠癌之间的关系；4)参与整合肠道微生物组结果与其他项目结果的分析，以澄清跨数据维度变量之间的相互关系，构建体脂量和分布以及癌症风险的最佳预测模型。

Body fat accumulation and distribution varies across ethnic groups and may influence the prevalence of obesity-related cancers in different ethnicities. This proposal examines the association between adipose accumulation and distribution, the gut microbiome, and phenotypes associated with obesity related cancer risk in the Multi-Ethnic Cohort (MEC). As such, the gut microbiome represents a potentially modifiable obesity-associated factor that may affect cancer risk. The gut microbiome influences human metabolism via regulation of energy uptake from diet, interaction with signaling molecules involved in host fatty acid metabolism, and sub-chronic inflammation~a hallmark of obesity-related diseases. Sub-chronic inflammation may be indirectly mediated through microbially generated dietary metabolites and, directly mediated through activation ofthe innate immune system. For example, gut bacterial endotoxins bind with lipopolysaccharide binding protein (LBP) to Toll-like receptors (TLR) that activate NF 1 levels of cytokines. Variants in human genes related to fatty acid metabolism and innate immunity may alter the interaction of the host with the gut microbiome and alter inflammation associated with obesity-related cancer risk. This innovative project will use the MEC cohort to investigate the composition of the gut microbiome, using high throughput sequencing approaches, as an effect modifier of the relationship between diet, fat distribution, and cancer risk. We will: 1) identify gut microbial profiles associated with body fat amount and distribution in the 5 ethnic groups among the 2,000 MEC subjects re-contacted for this study and analyze 4,229 stool samples collected for the microbiome GWA study in project 2; 2) test the associations of these microbial profiles with diet and other lifestyle factors, and with intermediate cancer phenotypes (i.e., cytokines, adipokines, steroid hormones, insulin, IGF hormones, and LBP); 3) examine the association between circulating LBP and colorectal cancer, using a case-control study nested within the MEC and measuring LBP in plasma drawn before diagnosis from 1379 colorectal cases and 1379 controls; and 4) participate in analyses integrating the gut microbiome results with those generated in the other projects in order to clarify inter-relationships among variables across data dimensions and construct best predictive models of body fat amount and distribution, and of cancer risk.