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: 10615757
• 负责人: Mingyang Song
• 金额: $ 64.39万
• 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/10615757
• 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; carcinogenicity; 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; permissiveness; 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.

项目摘要/摘要 结直肠腺瘤是绝大多数结直肠癌的先兆。我们和其他人有 表明生活方式因素在结直肠腺瘤-癌序列中起着重要作用。西式饮食 肥胖与结直肠癌风险的增加有关，而体力活动和 经常使用阿司匹林与较低的风险相关。新出现的证据表明，肠道微生物 在将环境线索与宿主生理和新陈代谢以及肠道紊乱相结合的过程中起关键作用 微生物区系与结直肠肿瘤和其他慢性疾病有关。尽管微生物区系扮演着一个角色 在致癌方面，现有的人类数据大多是横截面的，并不适用于 询问微生物是不是天生致癌的(即“驱动因素”)，还是 肿瘤发生(即“乘客”)。因此，有一种高度未得到满足的需求，需要进行一项大规模的前瞻性研究，以 检查肠道微生物区系及其相关代谢物、生活方式之间的相互作用网络 因素，以及不同人群中的结直肠癌。我们建议对肠道微生物区系进行描述 利用目前从参加持续护士健康计划的女性和男性收集的粪便样本 研究(NHS)II(n=25,000)和南方社区队列研究(SCCS)(n=8,500)。参与者已经被 自1989年(NHSII)和2002年(SCCS)以来一直跟踪，并提供了经过验证的、最新的饮食评估， 生活方式、用药情况、慢性病诊断及高随访率。在收集完粪便后，我们将 继续跟踪这些队列，记录腺瘤的发生率。我们将检验这一假设 与结直肠癌有关的生活方式因素与免疫调节和肿瘤的更高丰度相关- 允许肠道微生物和枯竭的微生物，以防止肿瘤发生。反过来，这些内脏 微生物组模式及其相关代谢产物将与随访中的腺瘤风险相关 结肠镜检查。为了提供更多因果关系的证据，我们将检查基线中的肠道微生物特征 与腺瘤有关的粪便样本在腺瘤发展后收集的粪便样本中将保持稳定，并且 与肠道微生物特征和人类宿主基因的表达以及腺瘤组织中的通路有关。 通过利用以白人为主的女性队列中持续的、已经获得资金的粪便收集(NHS II) 以及一群非洲裔美国人比例较高(65%)的女性和男性，他们的社会经济状况 对于弱势群体(SCCS)，我们的建议具有很高的成本效益，并将提供严谨和可重复的结果 与不同人群相关。我们成熟的多学科团队提出了下一个关键步骤 了解肠道微生物区系、生活方式因素与大肠肿瘤之间的复杂关系 不同的人群。这项研究将对结直肠癌和结直肠癌的发病机制有重要的启示。 通过针对肠道微生物区系的诊断和治疗，开展针对CRC预防的新研究。

项目成果

Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts.

根据 KRAS 和 BRAF 突变的维生素 C 摄入量和结直肠癌生存率：一项针对两个美国队列的前瞻性研究。

• DOI: 10.1038/s41416-023-02452-2
• 发表时间: 2023
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Shi,Shanshan;Wang,Kai;Ugai,Tomotaka;Giannakis,Marios;Cazaubiel,Jules;Chan,AndrewT;Giovannucci,EdwardL;Nowak,JonathanA;Meyerhardt,JeffreyA;Ogino,Shuji;Song,Mingyang
• 通讯作者: Song,Mingyang