Alcohol, Gut Dysbiosis, Endotoxemia, and Colorectal Cancer

项目摘要 饮酒与结直肠癌（CRC）的风险增加有关。然而，底层 机制尚未完全确定。动物研究的新证据表明，酒精 相关的肠道生态失调和随后的肠道屏障功能障碍和内毒素血症可能是一个重要的， 探索不足的途径。然而，长期酒精摄入的影响，不仅对分类化妆， 而且健康个体中肠道微生物组的功能能力尚未建立， 这些生态失调如何影响结直肠癌发生仍然是未知。酒精相关性 假设腔内毒素进入体循环激活适应性和先天性免疫 以释放抗体、细胞因子和其他炎症介质为特征的系统， 增加随后患炎症相关疾病的风险，包括肥胖症和糖尿病，这两种疾病都是 明确的CRC风险因素。然而，内毒素血症在结直肠癌发生中的作用还没有得到证实。 本文研究了因此，我们假设长期酒精摄入会导致肠道生态失调， 屏障功能，然后是内毒素血症和炎症，增加CRC的风险。我们将测试这个 假设利用收集的丰富数据，建立了一个大型且特征良好的前瞻性队列（健康 专业随访研究），其中健康子队列具有粪便收集和宏基因组， 元转录组学分析（Aim 1a）和250例巢式CRC病例和250例对照， 诊断血液和正在进行的血浆蛋白质组学分析（目标1b和1c）。具体来说，我们将调查 长期酒精摄入是否通过微生物组成的扰动诱导肠道生态失调（例如， 变形菌）和肿瘤允许的免疫特征和致癌途径的功能， 健康人（目标1a）。我们还将研究酒精相关的结直肠癌发生是否是 通过首先鉴定肠壁的循环标志物， 完整性丧失、细菌移位、内毒素血症、与酒精摄入相关的炎症（目标1b），以及 然后研究其与随后的CRC风险的关系（目标1c）。我们的发现将提供新的 对肠道微生物和内毒素血症介导的酒精相关CRC发病机制的机制性见解。我们 还将提供临床可翻译的数据，包括特定的微生物靶标和循环生物标志物， 反映酒精相关CRC后续风险的易感性。

PROJECT SUMMARY Alcohol consumption has been linked to increased risk of colorectal cancer (CRC). However, the underlying mechanisms have not yet been fully defined. Emerging evidence from animal studies suggest that alcohol associated gut dysbiosis and subsequent gut barrier dysfunctions and endotoxemia may be an important and underexplored pathway. However, the impact of long-term alcohol intake on not only the taxonomic makeup but also the functional capacity of the gut microbiome among healthy individuals has not been established, and how these dysbiosis will influence colorectal carcinogenesis remain unknown. Alcohol-associated passage of luminal endotoxin into systemic circulation is hypothesized to activate both adaptive and innate immune systems characterized by a release of antibodies, cytokines, and other inflammatory mediators, which may increase subsequent risk of inflammation related diseases, including obesity, and diabetes, both of which are well-established risk factors for CRC. However, the role of endotoxemia in colorectal carcinogenesis has not been studied. We therefore hypothesize that long-term alcohol intake induce gut dysbiosis, impair the gut barrier function, and followed by endotoxemia and inflammation to increase risk of CRC. We will test this hypothesis leveraging rich data collected a large and well-characterized prospective cohort (the Health Professional Follow-up Study) with a healthy sub-cohort with stool collection and metagenomic and metatranscriptomic profiling (Aim 1a) and 250 nested CRC cases and 250 controls with archived pre- diagnostic blood and ongoing plasma proteomic profiling (Aim 1b and 1c). Specifically, we will investigate whether long-term alcohol intake induce gut dysbiosis through perturbations in microbial composition (e.g. Proteobacteria) and function of tumor-permissive immune signatures and procarcinogenic pathways among healthy individuals (Aim 1a). We will also investigate whether alcohol-associated colorectal carcinogenesis is mediated by gut barrier dysfunction and endotoxemia through first identifying circulating markers of gut wall integrity loss, bacteria translocation, endotoxemia, inflammation associated with alcohol intake (Aim 1b), and then investigate their associations with subsequent risk of CRC (Aim 1c). Our findings will provide novel mechanistic insight into gut microbial and endotoxemia mediated pathogenesis of alcohol-related CRCs. We will also provide clinically translatable data including specific microbial targets, and circulating biomarkers and network that reflect susceptibilities to subsequent risk of alcohol-related CRCs.