The Gut Microbiome, Lifestyle, and Colorectal Neoplasia

肠道微生物群、生活方式和结直肠肿瘤

基本信息

批准号：
10407848
负责人：
Mingyang Song
金额：
$ 66.18万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407848
关键词：
Address African American population Aspirin Bacteria Bile Acids Biochemical Biological Sciences Butyrates Cancer Etiology Carcinoma Caucasians Cell physiology Cessation of life Chronic Chronic Disease Cohort Studies Collection Colonoscopy Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Colorectal Polyp Communities Cues Deoxycholic Acid Development Diagnosis Diagnostic Diet Enrollment Enterobacteriaceae Environmental Risk Factor Etiology Eubacterium Exposure to Feces Female Firmicutes Funding Fusobacterium Gene Expression Genes Human Immune Incidence Inflammatory Investigation Life Style Link Lithocholic Acid Malignant Neoplasms Massachusetts Metabolic Metabolism Microbe Mucous Membrane Nurses Nurses&apos Health Study Obesity Oncogenic Participant Pathway interactions Pattern Pharmaceutical Preparations Physical activity Physiology Play Polypectomy Polyps Population Heterogeneity Prospective Studies Prospective cohort Reproducibility of Results Research Research Personnel Risk Risk Factors Role Taxonomy Testing Therapeutic Tissues Tumor-infiltrating immune cells Unhealthy Diet Update Volatile Fatty Acids Woman adenoma aged cancer prevention carcinogenesis cohort colorectal cancer prevention colorectal cancer risk cost efficient follow-up functional genomics genomic profiles gut microbes gut microbiome gut microbiota high risk human data immunoregulation insight intestinal tumorigenesis lifestyle factors low socioeconomic status men metabolome microbial microbial community microbial composition microbiota multidisciplinary neoplastic novel prospective recruit risk sharing socioeconomic disadvantage stool sample tumor tumorigenesis tumorigenic western diet

项目摘要

PROJECT SUMMARY / ABSTRACT Colorectal adenoma is the precursor for the vast majority of colorectal cancers (CRCs). We and others have shown that lifestyle factors play an important role in the colorectal adenoma-carcinoma sequence. Western diet and obesity have been associated with increased risk of colorectal neoplasia, whereas physical activity and regular use of aspirin has been associated with lower risk. Emerging evidence indicates that gut microbes are pivotal in integrating environmental cues with host physiology and metabolism, and disturbances in the gut microbiota have been linked to colorectal neoplasia and other chronic conditions. Although a role for microbiota in carcinogenesis is gaining acceptance, available human data are largely cross-sectional and do not lend themselves to interrogation of whether microbes are intrinsically oncogenic (i.e. “drivers”) or a consequence of tumorigenesis (i.e. “passengers”). Thus, there is a high unmet need to conduct a large, prospective study to examine the network of interactions between the gut microbiota and their associated metabolites, lifestyle factors, and colorectal neoplasia within diverse populations. We propose to characterize the gut microbiota leveraging stool samples currently being collected from women and men enrolled in the ongoing Nurses’ Health Study (NHS)II (n=25,000) and the Southern Community Cohort Study (SCCS) (n=8,500). Participants have been followed since 1989 (NHSII) and 2002 (SCCS) and have provided validated, updated assessments of diet, lifestyle, medication use, and diagnoses of chronic diseases with high follow-up. After stool collection, we will continue to follow these cohorts and document the incidence of adenoma. We will test the hypothesis that lifestyle factors linked with CRC are associated with a higher abundance of immunomodulatory and tumor- permissive gut microbes and a depletion of microbes that protect against tumorigenesis. In turn, these gut microbiome patterns and their associated metabolites will be associated with risk of adenoma on follow-up colonoscopy. To provide additional evidence of causality, we will examine if the gut microbial features in baseline stool samples linked to adenoma will be stable in stool samples collected after adenoma development and is associated with gut microbial features and expression of human host genes and pathways in adenoma tissue. By leveraging ongoing, already funded stool collections within a cohort of predominantly white women (NHS II) and a cohort of women and men with a high proportion of African-Americans (65%) and the socioeconomically disadvantaged (SCCS), our proposal is highly cost-efficient and will offer rigorous and reproducible results relevant to diverse populations. Our established multidisciplinary team proposes the next critical step in understanding the intricate relationship between the gut microbiota, lifestyle factors and colorectal neoplasia in diverse populations. This investigation will illuminate significant insights into the etiopathogenesis of CRC and launch novel research into CRC prevention through gut microbiota-targeted diagnostics and therapeutics.

项目概要/摘要结直肠腺瘤是绝大多数结直肠癌 (CRC) 的前兆。西方饮食表明，生活方式因素在结直肠腺瘤-癌序列中起着重要作用。和肥胖与结直肠肿瘤风险增加有关，而体力活动和新出现的证据表明，经常服用阿司匹林可以降低肠道微生物的风险。在将环境因素与宿主生理和代谢以及肠道紊乱相结合方面发挥着关键作用微生物群与结直肠肿瘤和其他慢性疾病有关，尽管微生物群也有一定作用。在致癌作用越来越被接受的过程中，现有的人类数据大多是横截面的，不能提供任何帮助他们自己询问微生物是否本质上是致癌的（即“驱动因素”）还是致癌的结果因此，开展大规模前瞻性研究的需求尚未得到满足。检查肠道微生物群与其相关代谢物、生活方式之间的相互作用网络我们建议表征不同人群中的肠道微生物群。利用目前从参加正在进行的护士健康项目的女性和男性身上收集的粪便样本研究 (NHS)II (n=25,000) 和南方社区队列研究 (SCCS) (n=8,500) 是参与者。自 1989 年 (NHSII) 和 2002 年 (SCCS) 以来一直遵循并提供了经过验证的、最新的饮食评估，粪便收集后，我们将进行高随访的生活方式、药物使用和慢性病诊断。我们将继续跟踪这些队列并记录腺瘤的发病率。与结直肠癌相关的生活方式因素与较高丰度的免疫调节和肿瘤相关因子有关。肠道微生物的许可和微生物的消耗反过来又可以防止肿瘤的发生。微生物组模式及其相关代谢物将与随访中腺瘤的风险相关为了提供因果关系的额外证据，我们将检查肠道微生物特征是否处于基线状态。与腺瘤相关的粪便样本在腺瘤发展后收集的粪便样本中将是稳定的，并且与肠道微生物特征以及腺瘤组织中人类宿主基因和途径的表达有关。通过利用以白人女性为主的队列中正在进行的、已经资助的粪便收集（NHS II）以及一群非裔美国人 (65%) 和社会经济地位较高的女性和男性群体弱势群体 (SCCS)，我们的建议具有极高的成本效益，并将提供严格且可重复的结果我们建立的多学科团队提出了下一个关键步骤。了解肠道微生物群、生活方式因素和结直肠肿瘤之间的复杂关系这项研究将阐明结直肠癌的发病机制和发病机制的重要见解。通过针对肠道微生物群的诊断和治疗来开展结直肠癌预防的新研究。