Impact of sugary drinks on gut microbiota and development of young-onset colorectal cancer

含糖饮料对肠道微生物群和年轻发病结直肠癌发展的影响

• 批准号: 10178176
• 负责人: Jihye Yun
• 金额: $ 25.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178176
• 关键词: 3-Dimensional; APC gene; Adolescent and Young Adult; Adult; Affect; Benign; Biological Markers; Calories; Characteristics; Chronic; Clinical Management; Colon; Colonic Adenoma; Colonic Neoplasms; Colorectal Cancer; Consumption; Data; Development; Diet; Disease Management; Epithelial Cells; Etiology; Feces; Fructose; Glucose; Human; Human Microbiome; Incidence; Intestinal Neoplasms; Laboratories; Lead; Link; Liquid substance; Metabolic Pathway; Metagenomics; Microbe; Modeling; Molecular; Mucinous; Mus; Mutant Strains Mice; Obesity; Obesity Epidemic; Oral; Organoids; Outcome; Overweight; Pathway interactions; Play; Polyps; Precancerous Polyp; Prevention; Risk; Risk Factors; Role; Shapes; Sum; Sweetening Agents; Techniques; Testing; Time; Tumor Burden; Unhealthy Diet; Water; Wild Type Mouse; base; colon cancer patients; dysbiosis; early onset colorectal cancer; experimental study; fecal transplantation; gene environment interaction; gut microbiome; gut microbiota; humanized mouse; improved; intestinal epithelium; metabolomics; microbiota; middle age; mortality; mouse model; multiple omics; mutant; novel marker; preclinical study; sugar; sweetened beverage; therapeutic target; transcriptomics; tumor; tumorigenesis; tumorigenic; young adult

Project Summary One of the most disturbing phenomena in colorectal cancer (CRC) in the US in the past four decades is its increasing incidence and mortality in adults younger than 50 years old. Over the same time period, the consumption of sugar-sweetened beverages (SSBs) has dramatically increased. Notably, more than 60% of adolescents and young adults in the US consume at least one can (12 fl. oz.) of SSBs on a given day, suggesting a potential link between SSBs and young-onset CRC. However, it is unclear if there are direct, causal links and what the underlying molecular mechanisms would be. Our laboratory recently showed a direct, causal link between SSBs and CRC using adenomatous polyposis coli (Apc)-mutant mice, which are a model for early- stage colon adenoma (precancerous polyps). Apc-mutant mice treated with high-fructose corn syrup (HFCS, the main sweetener of SSBs) via oral gavage for 6–8 weeks showed an increase in the total tumor number, size, and grade, independent of obesity. Our preclinical studies suggest that consuming SSBs may shorten the time in which benign polyps develop into CRC in humans, explaining why young-onset CRC is currently on the rise. However, it remains unclear how HFCS does this. Diet plays a dominant role in shaping the gut microbiome, and an unhealthy diet can lead to dysbiosis, an imbalance in gut microbiota. A link has been shown between dysbiosis and CRC development. However, studies on the causal and mechanistic interrelationships among diet, gut microbiota, and CRC are still lacking. We previously observed that liquid HFCS dramatically increases the concentration of fructose (>5 mM) in the colonic lumen in mice, which may cause dysbiosis in the colon. Furthermore, our preliminary metagenomics and metabolomics data from wild-type mice have shown that chronic HFCS treatment increases the abundance of specific microbes and metabolic pathways that are implicated in human CRC development. Based on these data, we hypothesize that HFCS may facilitate CRC tumorigenesis and show the characteristics of young-onset CRC such as mucinous and signet ring features in tumors by altering the composition and function of gut microbiota. To test our hypothesis, we will use humanized Apc-mutant mice—in which a human microbiome has been established through fecal microbiota transplantation—and ex vivo 3D intestinal and tumor organoids. By completing the proposed project, we will be able to (1) determine the mechanistic and causal relationships between sugar-induced microbiota and young-onset CRC tumorigenesis; and (2) identify sugar-specific microbes or metabolites that can potentially be used as biomarkers and/or therapeutic targets in young-onset CRC patients. In sum, the proposed study will significantly impact our understanding of the etiology of young- onset CRC development and progression, potentially improving the prevention and clinical management of the disease.

项目摘要 过去四十年中，美国结直肠癌（CRC）最令人不安的现象之一是 年龄在50岁以下的成年人的发病率和死亡率增加。在同一时期， 食用加糖卧室（SSB）的消费大大增加了。值得注意的是，超过60％ 在美国，美国的青少年和年轻人在给定的一天中消费至少一个可以（12佛盎司） SSB和年轻发病的CRC之间的潜在联系。但是，目前尚不清楚是否有直接的因果链接和 基本的分子机制是什么。我们的实验室最近显示了一个直接的因果关系 在SSB和CRC之间使用腺瘤性息肉病（APC） - 突变小鼠，这是早期的模型 阶段结肠腺瘤（癌性息肉）。用高果糖玉米糖浆处理的APC突变小鼠（HFCS， SSB的主要甜味剂）通过口服烤6-8周，显示总肿瘤数量增加，大小， 和等级，独立于肥胖。我们的临床前研究表明，消费SSB可能会缩短时间 其中的良性息肉在人类中发展成CRC，这解释了为什么年轻发病的CRC目前正在上升。 但是，目前尚不清楚HFC如何做到这一点。 饮食在塑造肠道微生物组中起主要作用，不健康的饮食会导致营养不良，这是一种 肠道菌群中的不平衡。营养不良与CRC发育之间已经显示了联系。但是，研究 在饮食，肠道菌群和CRC之间的因果关系和机械相互关系上仍然缺乏。我们 以前观察到液体HFCS急剧增加了结肠中果糖（> 5 mm）的浓度 小鼠中的腔，可能导致结肠营养不良。此外，我们的初步宏基因组学和 来自野生型小鼠的代谢组学数据表明，慢性HFC治疗增加了丰富的丰度 人类CRC开发中实施的特定微生物和代谢途径。基于这些数据， 我们假设HFC可以促进CRC肿瘤发生，并显示年轻发病的CRC的特征 通过改变肠道菌群的组成和功能，例如肿瘤中的粘液和标志环特征。 为了检验我们的假设，我们将使用人源化的APC突变小鼠 - 在人类微生物组中 通过粪便微生物群移植和离体3D肠和肿瘤类器官建立。 通过完成提议的项目，我们将能够（1）确定机械和因果关系 在糖引起的微生物群和年轻的CRC肿瘤发生之间； （2）识别特异性糖 可能用作年轻发病的生物标志物和/或治疗靶标的微生物或代谢产物 CRC患者。总而言之，拟议的研究将显着影响我们对年轻的病因的理解 发作CRC的开发和进展，有可能改善的预防和临床管理 疾病。