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: 10633303
• 负责人: Mingyang Song
• 金额: $ 66.47万
• 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/10633303
• 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; Development; Diet; Diet Modification; Dietary Intervention; Encapsulated; Enzymes; Epidemiology; Escherichia coli; Etiology; Eubacterium; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Freeze Drying; Fusobacterium nucleatum; Genes; Goals; Hepatology; Inflammation; Intake; Intervention; Knowledge; Link; Liver; Liver Fibrosis; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to the Liver; Microbe; Natural Products; Nutritional Study; Oncology; Outcome; Pathogenesis; Pathway interactions; Patients; Placebos; Plasma; Prospective cohort; Protons; Randomized, Controlled Trials; Recommendation; Recurrent Malignant Neoplasm; Regulation; Research; Research Personnel; Risk; Risk Reduction; Role; Strategic Planning; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tumor Cell Invasion; United States National Institutes of Health; Volatile Fatty Acids; Work; anti-cancer; 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; secondary metabolite; stool sample; survivorship; targeted treatment; 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.

项目概要/摘要 目前有超过 150 万美国人患有结直肠癌 (CRC)。 饮食是影响 CRC 预后的重要因素。 越来越多的数据表明，补充常规癌症治疗是一种非常实用的方法。 饮用咖啡对癌症有益 在美国，64% 的成年人每天喝咖啡，平均饮用量。 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， 被肠道微生物群和内源性酶降解和修饰，产生次级代谢产物。 这些代谢物可以通过减少炎症、调节代谢和预防结直肠癌 特别是，令人信服的数据表明咖啡有助于减少肿瘤的生长和侵袭。 脂肪肝和肝纤维化的风险，这些疾病与结直肠癌生存率较差有关，可能是通过 促进肝转移是结直肠癌死亡的主要原因，最近，我们展示了四个独立的因素。 前瞻性队列显示，每天饮用 4 杯或更多咖啡的 CRC 患者罹患癌症的风险降低 40-50% 然而，与不饮酒者相比，复发率和结直肠癌特异性死亡的因果关系和特异性。 这种关系的机制仍然未知。为了解决这一知识差距，我们建议开展一项研究。 基于生物标志物的随机安慰剂对照试验并评估相互作用的预后影响 III 期 CRC 患者的咖啡摄入量与代谢组学和微生物特征之间的关系。 咖啡中的化合物及其代谢物通过调节肠道来提高结直肠癌的存活率 微生物组与改善肝脏脂肪和纤维化 在目标 1 中，我们将确定咖啡的作用。 消耗对肠道微生物组和代谢组、肝脏脂肪和纤维化以及结直肠癌复发标志物的影响 在一项针对 80 名 III 期患者进行的为期 3 个月的冻干速溶咖啡和安慰剂随机对照试验中 在目标 2 中，我们将前瞻性评估已完成化疗的结肠癌患者的咖啡摄入量， 450 名 III 期患者队列中粪便微生物特征和代谢物与 CRC 复发和生存的关系 提供详细饮食数据和粪便样本的 CRC 患者是我们实现这些目标的能力。 我们在 CRC 的饮食干预和生物样本库研究方面的经验强调了这一点； 努力阐明饮食、肠道微生物组和宿主代谢在结直肠癌以及我们体内的相互作用； 经验丰富的多学科团队由营养学、微生物组、流行病学、肿瘤学和 该项目提供的机制见解不仅有助于完善建议。 全球最常饮用的饮料之一的癌症存活率，但也导致了发现 基于饮食控制的新型辅助疗法和新型干预措施的开发， 代谢组和微生物组以改善 CRC 管理。

项目成果

New onset of type 2 diabetes after colorectal cancer diagnosis: Results from three prospective US cohort studies, systematic review, and meta-analysis.

结直肠癌诊断后新发 2 型糖尿病：美国三项前瞻性队列研究、系统评价和荟萃分析的结果。

• 发表时间: 2022-12
• 影响因子: 11.1
• 作者: Zeng, Hongmei;Yuan, Chen;Morze, Jakub;Fu, Ruiying;Wang, Kai;Wang, Liang;Sun, Feng;Ji, John S;Giovannucci, Edward L;Song, Mingyang
• 通讯作者: Song, Mingyang