Characterisation of Host-Microbiome Interactions and Colorectal Cancer (CRC)

结直肠癌（CRC）是全球癌症死亡的第二大原因，约占全球癌症的10%。然而，发病率在地域上存在很大差异，北美洲、澳大利亚、新西兰和欧洲的发病率最高，非洲和亚洲农村的发病率最低。此外，在阿拉斯加土著人口中观察到极高的发病率，每10万人中发病率超过100例。迁移和实验研究都表明，环境因素在结直肠癌的发展中起着比遗传功能障碍更重要的作用，特别是“西方化”（高脂肪、低纤维）饮食的消费。此外，从理论上讲，饮食相关的风险部分是通过结肠微生物代谢介导的，随后产生促炎和致癌代谢物，并减少促进结肠健康和表现出抗肿瘤作用的代谢物的产生。然而，通过营养-微生物轴调节结直肠癌风险的确切机制尚未明确阐明。使用系统医学方法，我们将尝试进一步定义高风险和低风险种族人群中关键的宿主-微生物组相互作用和代谢途径，即城市非洲人，半城市非洲人和阿拉斯加原住民。匹兹堡大学的合作者（Steve O’keefe教授）此前获得了样本，包括尿液、粪便和血浆，以及营养数据、临床结果数据和微生物组数据。还将从目前在阿拉斯加安克雷奇进行的随机对照临床试验中获得样本。该研究队列由阿拉斯加本地人（最高风险人群）组成，他们正在接受膳食补充抗性淀粉（一种可溶性益生元纤维），通过微生物组和随后的代谢组操作来确定益生元补充对结直肠癌风险的影响。我们假设，来自微生物介导的抗性淀粉代谢的促进结肠健康和抗肿瘤代谢物的产生增加，将抵消肠道致癌物的影响，从而抑制结直肠癌风险的生物标志物。因此，这项工作旨在阐明由饮食调节的关键微生物-宿主相互作用，介导结直肠癌风险，此外，潜在地证明高纤维，低风险饮食在预防结直肠癌发展中的有效性。

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, making up approximately 10% of cancers globally. However, there is a large geographical disparity in incidence, with the highest rates observed in North America, Australia, New Zealand and Europe and the lowest in rural Africa and Asia. Additionally, extremely high incidence is observed within the Native Alaskan population, with rates exceeding 100 cases per 100,000. Both migration and experimental studies suggest that environmental factors play a more significant role in CRC development than genetic dysfunction, particularly the consumption of a 'westernised' (high fat, low fibre) diet. Furthermore, it is theorised that diet associated risk is, in part, mediated via colonic microbial metabolism, and the subsequent production of pro-inflammatory and carcinogenic metabolites combined with reduced production of metabolites that promote colonic health and exhibit antineoplastic effects. However, the precise mechanism by which CRC risk is modulated via the nutrition-microbiome axis is yet to be definitively elucidated. Using a systems medicine approach, we will attempt to further define key host-microbiome interactions and metabolic pathways in high and low risk ethnic populations, namely, Urban Africans, Semi-urban Africans and Native Alaskans. Samples have been previously obtained by collaborators at Pittsburgh University (Prof. Steve O'Keefe) and consist of urine, faeces and plasma along with nutritional data, clinical outcome data and microbiome data. Samples will also be obtained from a randomised, controlled, clinical trial currently being carried out in Anchorage, Alaska. The study cohort, consisting of Alaskan Natives (highest risk population), are receiving dietary supplementation of resistant starch (a soluble prebiotic fibre), to establish the effect of prebiotic supplementation on CRC risk, through microbiome and subsequent metabolome manipulation. We hypothesise that the increased production of colonic health promoting and anti-neoplastic metabolites, derived from microbiota-mediated metabolism of resistant starch, will counteract the effect of luminal carcinogens, thereby supressing biomarkers of CRC risk. As such, this work aims to elucidate the key microbiome-host interactions, modulated by diet, that mediate CRC risk and furthermore, potentially demonstrate the effectiveness of a high fibre, low risk diet in the prevention of CRC development.