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

项目摘要/摘要 超过150万美国人目前患有结直肠癌(CRC)。提高CRC存活率 是一个高度优先的问题。饮食是影响结直肠癌预后的重要因素。使用饮食改良法 补充传统的癌症治疗是一种非常实用的方法。越来越多的数据表明， 咖啡消费对癌症的好处。在美国，%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，它们是 被肠道微生物区系和内源性酶降解和修饰以产生次生代谢物。 这些代谢产物可能通过减少炎症、调节新陈代谢和 抑制肿瘤生长和侵袭。特别是，令人信服的数据表明，咖啡对减少 脂肪肝和肝纤维化的风险，这些情况与结直肠癌的存活率更差有关，可能是通过 促进肝转移是结直肠癌死亡的主要原因。最近，我们在四个独立的 每天饮用4杯或更多咖啡的结直肠癌患者患结直肠癌的风险降低40%-50% 与不饮酒者相比，复发和特定于结直肠癌的死亡。然而，因果关系和具体情况 这种关系的机制仍不清楚。为了解决这一知识差距，我们建议开展一项 基于生物标志物的随机安慰剂对照试验，并评估相互作用对预后的影响 III期结直肠癌患者的咖啡摄入量与代谢和微生物特征之间的关系。我们 假设咖啡及其代谢物中的化合物通过调节肠道来提高结直肠癌存活率 微生物群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 肠道微生物组和代谢组的消耗、肝脏脂肪和纤维化以及结直肠癌复发的标志 在80个III期中进行了为期3个月的冷冻干燥速溶咖啡和安慰剂的随机对照试验 已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， 粪便微生物特征和代谢产物与结直肠癌复发和在450例III期队列中的生存相关 提供详细饮食数据和粪便标本的结直肠癌患者。我们实现这些目标的能力是 我们在结直肠癌饮食干预和生物库研究方面的经验强调了这一点；我们的多组学特征 努力阐明饮食、肠道微生物群和宿主代谢之间的相互作用在结直肠癌中；以及我们的 经验丰富的多学科团队，由营养、微生物组、流行病学、肿瘤学和 肝病。该项目提供的机械性见解不仅有助于完善以下建议 世界上最常消费的饮料之一的癌症幸存者，但也导致了发现 新的辅助疗法和基于饮食操作的新干预措施的开发， 新陈代谢组和微生物组，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.