Alcohol, Gut Dysbiosis, Endotoxemia, and Colorectal Cancer

酒精、肠道菌群失调、内毒素血症和结直肠癌

• 批准号: 9895402
• 负责人: Yin Cao
• 金额: $ 26.96万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895402
• 关键词: Acetaldehyde; Activities of Daily Living; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Antibodies; Archives; Bacteria; Blood; Blood Circulation; Blood specimen; C-reactive protein; CD14 gene; Carcinogens; Chronic Disease; Cirrhosis; Collection; Colorectal Cancer; Cytoskeleton; Data; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Endotoxemia; Endotoxins; Epithelial Cells; Equipment and supply inventories; Ethanol Metabolism; Family; Feces; Follow-Up Studies; Foundations; Functional disorder; Generations; Gram-Negative Bacteria; Growth; Haptoglobins; Health Professional; Health Resources; Immune; Impairment; Individual; Inflammation; Inflammation Mediators; Innate Immune System; Insulin Resistance; Interleukin-1 beta; Interleukin-17; Interleukin-6; Interleukin-8; Interleukins; Intestinal permeability; Intestines; Investigation; Lead; Light; Link; Lipopolysaccharides; Malignant Neoplasms; Mediating; Mediator of activation protein; Metagenomics; Microtubules; Multiple Trauma; Nitric Oxide; Obesity; Pathogenesis; Pathway interactions; Permeability; Plasma; Positioning Attribute; Predisposition; Prevention; Preventive; Prospective cohort; Prospective cohort study; Proteobacteria; Proteomics; Risk; Risk Factors; Role; Shotguns; Specific qualifier value; TNF gene; Taxonomy; Testing; Therapeutic Intervention; Tubulin; United States; Virulence Factors; Woman; acute infection; alcohol effect; alcohol risk; bactericidal permeability increasing protein; case control; chronic infection; circulating biomarkers; clinically translatable; cohort; colon carcinogenesis; colorectal cancer risk; cytokine; dysbiosis; genotoxicity; gut microbiome; human data; insight; interleukin-22; interleukin-23; intestinal barrier; intestinal epithelium; intestinal fatty acid binding protein; lipopolysaccharide-binding protein; men; metatranscriptomics; microbial; microbiota; multidisciplinary; novel; population based; sex disparity; stool sample; targeted biomarker; therapeutic biomarker; tissue injury; tumor

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.

项目概要 饮酒与结直肠癌 (CRC) 风险增加有关。然而，底层 机制尚未完全确定。来自动物研究的新证据表明，酒精 相关的肠道菌群失调以及随后的肠道屏障功能障碍和内毒素血症可能是一个重要且重要的因素。 尚未探索的途径。然而，长期饮酒不仅对分类构成产生影响 但健康个体肠道微生物群的功能能力尚未确定，并且 这些生态失调将如何影响结直肠癌的发生仍然未知。酒精相关的通道 假设管腔内毒素进入体循环可以激活适应性免疫和先天免疫 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 增加随后发生炎症相关疾病的风险，包括肥胖和糖尿病，这两种疾病都是 CRC 的既定危险因素。然而，内毒素血症在结直肠癌发生中的作用尚未明确。 被研究过。因此，我们推测长期饮酒会导致肠道菌群失调，损害肠道 屏障功能，然后是内毒素血症和炎症，增加结直肠癌的风险。我们将测试这个 利用丰富数据的假设收集了一个大型且特征良好的前瞻性队列（健康 专业随访研究），具有健康的子队列，具有粪便收集和宏基因组学和 宏转录组分析（目标 1a）和 250 个嵌套 CRC 病例和 250 个对照，并存档预转录组 诊断性血液和持续的血浆蛋白质组分析（目标 1b 和 1c）。具体来说，我们将调查 长期饮酒是否会通过微生物组成的扰动（例如， 变形菌）以及肿瘤允许的免疫特征和致癌途径的功能 健康个体（目标 1a）。我们还将研究酒精相关的结直肠癌是否会发生 通过首先识别肠壁循环标志物，由肠屏障功能障碍和内毒素血症介导 完整性丧失、细菌易位、内毒素血症、与酒精摄入相关的炎症（目标 1b）以及 然后调查它们与后续 CRC 风险的关联（目标 1c）。我们的研究结果将提供新颖的 深入了解肠道微生物和内毒素血症介导的酒精相关结直肠癌的发病机制。我们 还将提供临床可转化的数据，包括特定的微生物目标、循环生物标志物和 反映对酒精相关结直肠癌后续风险的易感性的网络。