The Gut Microbiome, Lifestyle, and Colorectal Neoplasia

肠道微生物群、生活方式和结直肠肿瘤

• 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
• 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' 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

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.

项目总结/摘要 结直肠腺瘤是绝大多数结直肠癌（CRC）的先兆。我们和其他人已经 生活方式因素在结直肠腺瘤-癌序列中起重要作用。西方饮食 和肥胖与结直肠肿瘤的风险增加有关，而体力活动和 经常服用阿司匹林与降低风险有关。新出现的证据表明，肠道微生物 在整合环境线索与宿主生理和代谢以及肠道干扰方面起关键作用 微生物群与结直肠肿瘤和其他慢性疾病有关。虽然微生物在 在致癌作用中的作用越来越被接受，现有的人类数据大部分是横截面的， 他们自己询问微生物是否是内在致癌的（即“驱动程序”）或 肿瘤发生（即“乘客”）。因此，进行大型前瞻性研究的需求很高， 研究肠道微生物群及其相关代谢物、生活方式之间的相互作用网络 因素和不同人群中的结直肠肿瘤。我们建议描述肠道微生物群 利用目前从参加正在进行的护士健康计划的妇女和男子中收集的粪便样本， 研究（NHS）II（n= 25，000）和南方社区队列研究（SCCS）（n= 8，500）。参与者一直在 自1989年（NHSII）和2002年（SCCS）以来，提供了经过验证的最新饮食评估， 生活方式、药物使用和高随访率的慢性病诊断。收集粪便后，我们将 继续跟踪这些队列并记录腺瘤的发病率。我们将检验这个假设， 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， 允许的肠道微生物和防止肿瘤发生的微生物的消耗。反过来，这些肠道 微生物群模式及其相关代谢物将与随访时腺瘤的风险相关 结肠镜检查为了提供更多的因果关系证据，我们将检查基线时肠道微生物特征是否 与腺瘤相关的粪便样品在腺瘤发展后收集的粪便样品中是稳定的， 与肠道微生物特征和腺瘤组织中人类宿主基因和途径的表达相关。 通过利用以白色女性为主的队列中正在进行的、已经资助的粪便收集（NHS II） 和一个女性和男性的队列，非洲裔美国人的比例很高（65%）， 弱势群体（SCCS），我们的建议是高度成本效益，并将提供严格的和可重复的结果 与不同的人群有关。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， 不同的人群。这项研究将阐明CRC发病机制的重要见解， 通过肠道微生物靶向诊断和治疗，开展新的CRC预防研究。