Alcohol, Gut Dysbiosis, Endotoxemia, and Colorectal Cancer

项目总结 饮酒与结直肠癌(CRC)风险增加有关。然而，潜在的 机制还没有完全确定。来自动物研究的新证据表明，酒精 相关的肠道生物失调和随后的肠道屏障功能障碍和内毒素血症可能是一种重要的和 探索不足的路径。然而，长期饮酒不仅对分类学构成产生影响 而且健康个体的肠道微生物群的功能能力还没有建立起来，而且 这些生物失调将如何影响结直肠癌的发生尚不清楚。与酒精相关的一段 假设腔内毒素进入体循环可激活获得性免疫和先天免疫 以释放抗体、细胞因子和其他炎症介质为特征的系统，这可能 增加随后患炎症相关疾病的风险，包括肥胖和糖尿病，这两种疾病都是 公认的结直肠癌危险因素。然而，内毒素血症在结直肠癌发生中的作用尚未见报道 已经研究过了。因此，我们假设长期饮酒会导致肠道生物失调，损害肠道。 屏障功能，继而内毒素血症和炎症增加了结直肠癌的风险。我们将对此进行测试 假设利用丰富的数据收集了大量且特征良好的前瞻性队列(The Health 专业随访研究)，有健康的亚队列，大便收集和后基因组学和 元翻译鉴定(目标1a)和250例嵌套结直肠癌病例和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)。具体地说，我们将调查 长期饮酒是否通过扰乱微生物组成(例如 变形杆菌)和肿瘤允许的免疫信号和癌前通路的功能 健康人(目标1a)。我们还将调查酒精相关的结直肠癌发生是否 通过首次识别肠壁循环标志物介导肠屏障功能障碍和内毒素血症 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 然后调查它们与随后的结直肠癌风险的关系(目标1c)。我们的发现将为我们提供新的 从机制上洞察肠道微生物和内毒素血症介导的酒精相关性CRCs的发病机制。我们 还将提供临床可翻译的数据，包括特定的微生物靶标，以及循环生物标记物和 反映对随后与酒精相关的癌症风险的易感性的网络。

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.