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: 10734338
• 负责人: Jihye Yun
• 金额: $ 16万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734338
• 关键词: Impact; sugary; drinks; gut; microbiota

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 在过去的四十年里，美国结直肠癌（CRC）中最令人不安的现象之一是它的 50岁以下成人的发病率和死亡率增加。在同一时期， 含糖饮料（SSB）的消费量急剧增加。值得注意的是，超过60%的 美国的青少年和年轻人至少消费一罐（12盎司）。在给定的一天， SSB与难治性CRC之间的潜在联系。然而，目前尚不清楚是否存在直接的因果联系， 潜在的分子机制是什么。我们的实验室最近发现了一种直接的因果关系 在SSB和CRC之间使用腺瘤性结肠息肉病（Apc）突变小鼠，这是一种早期- 结肠腺瘤分期（癌前息肉）。用高果糖玉米糖浆（HFCS，The SSBs的主要甜味剂）经口管饲6-8周，显示总肿瘤数量，大小， 与肥胖无关。我们的临床前研究表明，食用SSB可以缩短 其中良性息肉在人类中发展成CRC，这解释了为什么非典型性CRC目前呈上升趋势。 然而，尚不清楚HFCS如何做到这一点。 饮食在塑造肠道微生物组方面起着主导作用，不健康的饮食会导致生态失调， 肠道微生物群失衡。生态失调和CRC发展之间存在联系。然而研究 关于饮食、肠道微生物群和CRC之间的因果关系和机制相互关系的研究仍然缺乏。我们 先前观察到液体HFCS显著增加结肠中果糖的浓度（>5 mM）， 这可能会导致结肠生态失调。此外，我们初步的宏基因组学和 来自野生型小鼠的代谢组学数据表明，慢性HFCS治疗增加了 在人类CRC发展中涉及的特定微生物和代谢途径。根据这些数据， 我们假设HFCS可能促进CRC肿瘤发生，并显示出复发性CRC的特征， 例如肿瘤中的粘液和印戒特征。 为了验证我们的假设，我们将使用人源化的APC突变小鼠，其中人类微生物组已经 通过粪便微生物群移植和离体3D肠道和肿瘤类器官建立。 通过完成建议的项目，我们将能够（1）确定机械和因果关系 糖诱导的微生物群与非典型性CRC肿瘤发生之间的关系;以及（2）确定糖特异性 可以潜在地用作疾病发作的生物标志物和/或治疗靶点的微生物或代谢物， CRC患者。总之，这项研究将大大影响我们对年轻人的病因学的理解， 发病CRC的发展和进展，潜在地改善预防和临床管理， 疾病