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

项目总结/摘要 目前，超过150万美国人患有结直肠癌（CRC）。提高CRC生存率 是最重要的饮食是影响结直肠癌预后的重要因素。使用饮食调整， 补充常规癌症治疗是非常实用的方法。越来越多的数据表明， 喝咖啡对癌症的好处在美国，64%的成年人每天喝咖啡， 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， 通过肠道微生物群和内源性酶降解和修饰以产生次级代谢产物。 这些代谢物可以通过减少炎症、调节代谢和调节细胞增殖来预防CRC。 抑制肿瘤生长和侵袭。特别是，令人信服的数据表明，咖啡的好处是减少 脂肪肝和肝纤维化的风险，这些疾病与CRC的生存率下降有关，可能是由于 促进肝转移，这是CRC死亡的主要原因。最近，我们展示了四个独立的 前瞻性队列研究表明，每天饮用4杯或更多咖啡的CRC患者， 复发率和CRC特异性死亡率。然而，因果关系和具体 这种关系的机制仍然未知。为了弥补这方面的知识差距，我们建议进行一项 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 咖啡摄入量与III期CRC患者的代谢组学和微生物特征之间的关系。我们 假设咖啡中的化合物及其代谢物通过调节肠道来改善CRC生存 微生物组和改善肝脏脂肪和纤维化。在目标1中，我们将确定咖啡的效果 消耗对肠道微生物组和代谢组、肝脏脂肪和纤维化以及CRC复发标志物的影响 在一项随机对照试验中，80名III期患者服用冻干速溶咖啡和安慰剂3个月， 完成化疗的结肠癌患者。在目标2中，我们将前瞻性地评估咖啡摄入量， 450例III期结直肠癌患者的粪便微生物特征和代谢物与复发和生存的关系 CRC患者提供详细的饮食数据和粪便标本。我们实现这些目标的能力是 我们在CRC中进行饮食干预和生物库研究的经验强调了这一点; 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，由营养学、微生物组学、流行病学、肿瘤学和 肝病学该项目提供的机制性见解不仅有助于完善以下建议： 癌症存活率为世界上最常用的饮料之一，但也导致发现 新的辅助治疗和基于饮食控制的新干预措施的发展， 代谢组和微生物组，以改善CRC管理。

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.