Coffee and metabolites modulating the gut microbiome for improved colorectal cancer survival

咖啡和代谢物调节肠道微生物组以提高结直肠癌的生存率

• 批准号: 10409225
• 负责人: Mingyang Song
• 金额: $ 67.61万
• 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: 2022-06-02 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409225
• 关键词: Address; Adjuvant; Adult; Aging; American; Antioxidants; Bacteria; Beverages; Bile Acids; Biological Markers; Biological Products; Caffeine; Cancer Prognosis; Cancer Survivor; Cancer Survivorship; Cessation of life; Chlorogenic Acid; Choline; Clinical Data; Clinical Research; Coffee; Colorectal Cancer; Complex Mixtures; Consumption; Data; Diet; Diet Modification; Dietary Intervention; Encapsulated; Enzymes; Epidemiology; Escherichia coli; Etiology; Eubacterium; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Freeze Drying; Fusobacterium nucleatum; Genes; Goals; Hepatology; Inflammation; Intake; Intervention; Knowledge; Lead; Link; Liver; Liver Fibrosis; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Microbe; Natural Products; Oncology; Outcome; Pathogenesis; Pathway interactions; Patients; Placebos; Plasma; Prospective cohort; Protons; Randomized Controlled Trials; Recommendation; Recurrence; Regulation; Research; Research Personnel; Risk; Role; Strategic Planning; Testing; Therapeutic Agents; Therapeutic Intervention; Tumor Cell Invasion; United States National Institutes of Health; Volatile Fatty Acids; Work; anti-cancer; base; biobank; cancer prevention; cancer recurrence; cancer survival; cancer therapy; chemotherapy; cohort; colon cancer patients; colorectal cancer risk; dietary; experience; fecal metabolome; fecal microbiome; gut microbiome; gut microbiota; improved; indexing; insight; liver function; metabolome; metabolomics; microbial; microbial signature; microbiome; mortality; multidisciplinary; multiple omics; novel; novel therapeutics; nutrition; patient subsets; polyphenol; precision nutrition; prognostic; prospective; randomized placebo controlled trial; screening; stool sample; survivorship; targeted treatment; therapeutic development; tumor DNA; tumor growth; tumor progression; ultrasound

PROJECT SUMMARY / ABSTRACT More than 1.5 million Americans are currently living with colorectal cancer (CRC). Improving CRC survivorship is a high priority. Diet is an important factor influencing CRC prognosis. The use of dietary modification to supplement conventional cancer therapy is an eminently practical approach. Growing data indicate the anti- cancer benefit of coffee consumption. In the US, 64% of adults drink coffee daily, with an average consumption of 2.7 cups per day. Coffee contains hundreds of antioxidants and other bioactive compounds, which are degraded and modified by the gut microbiota and endogenous enzymes to generate secondary metabolites. These metabolites may protect against CRC by reduction of inflammation, modulation of metabolism, and inhibition of tumor growth and invasion. In particular, compelling data indicate the benefit of coffee for reducing risk of fatty liver and liver fibrosis, conditions that have been linked to worse survival of CRC, possibly by promotion of liver metastasis, the major cause of CRC death. Recently, we showed in four independent prospective cohorts that CRC patients consuming 4 cups/d or more of coffee had a 40-50% lower risk of recurrence and CRC-specific death compared with nondrinkers. However, the causality and specific mechanisms for this relationship remain unknown. To address this knowledge gap, we propose to conduct a biomarker-based randomized placebo-controlled trial and assess the prognostic influence of the interplay between coffee intake and the metabolomic and microbial signatures in patients with stage III CRC. We hypothesize that compounds in coffee and their metabolites improve CRC survival by modulating the gut microbiome and ameliorating liver fatness and fibrosis. In Aim 1, we will determine the effect of coffee consumption on the gut microbiome and metabolome, liver fatness and fibrosis, and markers of CRC recurrence in a randomized controlled trial of freeze-dried instant coffee and placebos for 3 months among 80 stage III colon cancer patients who have completed chemotherapy. In Aim 2, we will prospectively assess coffee intake, fecal microbial features and metabolites in relation to CRC recurrence and survival in a cohort of 450 stage III CRC patients who provide detailed dietary data and stool specimens. Our ability to accomplish these aims is underscored by our experience with dietary intervention and biobanking studies in CRC; our multi’omic profiling effort to elucidate the interplay between diet, the gut microbiome, and host metabolism in CRC; as well as our experienced multidisciplinary team comprised of experts in nutrition, microbiome, epidemiology, oncology, and hepatology. The mechanistic insights provided by the project will not only help refine the recommendations for cancer survivorship for one of the most commonly consumed beverages worldwide, but also lead to discovery of novel adjuvant therapeutics and development of novel interventions based on manipulation of the diet, metabolome, and microbiome for improved CRC management.

项目摘要 /摘要 目前有150万美国人患有结直肠癌（CRC）。改善CRC幸存者 是高度优先事项。饮食是影响CRC预后的重要因素。饮食修改的使用 补充常规癌症治疗是一种非常实用的方法。增长的数据表明抗 咖啡消费的癌症益处。在美国，有64％的成年人每天喝咖啡，平均消费量 每天2.7杯。咖啡含有数百种抗氧化剂和其他生物活性化合物， 通过肠道菌群和内源性酶降解并修饰，以产生继发代谢产物。 这些代谢产物可以通过减少炎症，代谢调节和 特别是，引人注目的数据表明咖啡的好处减少 脂肪肝和肝纤维化的风险，与CRC生存差有关的疾病可能 促进肝转移，这是CRC死亡的主要原因。最近，我们在四个独立 预期的同类群体，CRC患者食用4杯/d或更多的咖啡，降低了40-50％的风险 与非裁缝相比，复发和CRC特异性死亡。但是，休闲和具体 这种关系的机制仍然未知。为了解决这一知识差距，我们建议进行 基于生物标志物的随机安慰剂对照试验和评估相互作用的预后影响 在III期CRC患者的咖啡摄入量与代谢组和微生物特征之间。我们 假设咖啡中的化合物及其代谢产物通过调节肠道来改善CRC的生存 微生物组和改善肝脂肪和纤维化。在AIM 1中，我们将确定咖啡的影响 肠道微生物组和代谢组，肝脂肪和纤维化以及CRC复发的标志 在冻干的速溶咖啡和安慰剂的随机对照试验中，在80阶段III中3个月 已经完成化疗的结肠癌患者。在AIM 2中，我们可能会评估咖啡摄入量， 粪便微生物特征和代谢产物与CRC复发和生存有关450期III 提供详细的饮食数据和粪便标本的CRC患者。我们实现这些目标的能力是 我们在CRC中在饮食干预和生物群研究方面的经验强调；我们的多媒体分析 努力阐明CRC中饮食，肠道微生物组和宿主代谢之间的相互作用；以及我们的 经验丰富的多学科团队完成了营养专家，微生物组，流行病学，肿瘤学和 肝病学。项目提供的机械见解不仅将有助于完善建议 癌症生存是全球最常见的床之一，但也导致发现 基于操纵饮食的新型可调节疗法和新干预措施的发展， 代谢组和用于改进CRC管理的微生物组。