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各不相同，可能会影响不同种族中肥胖相关癌症的患病率。该提案研究了多种族队列（MEC）中脂肪积累和分布，肠道微生物组以及与肥胖相关癌症风险相关的表型之间的关联。因此，肠道微生物组代表了一种可能影响癌症风险的潜在可改变的肥胖相关因素。肠道微生物组通过调节饮食中的能量摄取、与参与宿主脂肪酸代谢的信号分子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。亚慢性炎症可能通过微生物产生的饮食代谢物间接介导，也可能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）结合至Toll样受体（TLR），所述TLR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会改变宿主与肠道微生物组的相互作用，并改变与肥胖相关的癌症风险相关的炎症。这个创新项目将使用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因素。我们将：1）在本研究重新接触的2，000名MEC受试者中，鉴定与5个种族群体中的体脂量和分布相关的肠道微生物谱，并分析为项目2中的微生物组GWA研究收集的4，229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）; 3）使用嵌套在MEC内的病例对照研究并测量从1379个结肠直肠病例和1379个对照中在诊断前抽取的血浆中的LBP来检查循环LBP和结肠直肠癌之间的关联;以及4）参与分析，将肠道微生物组结果与其他项目中产生的结果相结合，以澄清数据维度中变量之间的关系，并构建身体脂肪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.