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.

项目总结