Mediating Role of Gut Microbiota in the Regulation of Colorectal Cancer Risk in the Context of Time-restricted Eating and Calorie Restriction

限时饮食和热量限制背景下肠道微生物群在结直肠癌风险调节中的中介作用

• 批准号: 10818119
• 负责人: Lisa Tussing-Humphreys
• 金额: $ 22.29万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818119
• 关键词: Adherence; Anti-Inflammatory Agents; Butyrates; Caloric Restriction; Calories; Cancer Prevention Intervention; Colon; Colorectal Cancer; Communication; Diet; Eating; Environment; Exposure to; Faculty; Gene Expression Profile; Genetic; Goals; Hispanic; Hour; Inflammatory; Infrastructure; Intermittent fasting; Life Style; Malignant Neoplasms; Mediating; Mediation; Metabolic; Metabolism; Metagenomics; Methodology; Methods; Mucous body substance; Multiomic Data; Nutrient; Obesity; Pathway Analysis; Play; Prevention; Production; Regulation; Research; Research Personnel; Resolution; Risk Factors; Role; Sample Size; System; Time; Time-restricted feeding; Training; United States; Weight maintenance regimen; Woman; cancer prevention; career; colon carcinogenesis; colorectal cancer prevention; colorectal cancer risk; gastrointestinal; gut microbiota; host-microbe interactions; improved; innovation; insight; metabolomics; microbial; microorganism; parent grant; permissiveness; response; tenure track

PROJECT ABSTRACT The goal of this Diversity Supplement is to extend the significance and innovation of the Parent grant by examining the effect of time-restricted eating (TRE) and daily calorie restriction (CR) on the gut microbiota (GM) and host-microbial interactions relevant to the prevention of colorectal cancer (CRC), the third most incident cancer in the United States. The Diversity Supplement will also provide essential training in cancer prevention to a promising Hispanic woman and Early-Stage Career Investigator, Dr. Beatriz Peñalver Bernabé. Obesity is a major modifiable lifestyle risk factor for CRC. TRE is emerging as an alternative approach to managing weight that involves simply watching the clock and eating for 4-10 hours daily, thus restricting the body’s exposure to nutrients for extended periods of time. TRE demonstrates excellent adherence as it is simple and omits burdensome calorie counting, a hallmark of traditional daily CR. The GM can produce beneficial metabolites, such anti-inflammatory butyrate, or improve gut integrity by promoting mucus production, but a dysregulated GM can lead to increase colonic levels of pro-inflammatory and cancer-promoting metabolites. Existing studies on the effects of TRE on the GM are limited in scope and methodology due to small samples sizes, short duration, use of low-resolution methods that fail to examine changes in microbial metabolic function, and lack of a robust assessment of host-microbial interactions in response to TRE. Further, the differential effects of TRE versus CR on the GM and the relevance to colonic carcinogenesis remains unknown. We hypothesize that both TRE and CR will promote a GM environment less permissive of colonic carcinogenesis and that TRE will be superior due to differences in nutrient exposures, a downstream effect of the shortened eating window. Further, we surmise that systems-level approaches, such as network analysis, can identify the key communications between the host and microbial metabolic and colon genetic networks that play mechanistic roles in CRC risk and prevention. Levering the infrastructure of the Parent grant, the proposed Diversity Supplement will use high-resolution methods, such as metagenomics and metabolomics, to characterize GM composition and metabolic function and host systemic metabolism. Statistical and network approaches will be employed to integrate these multi- omics data and colonic transcriptional profiles to determine the effect of TRE and CR on GM and host-microbial interactions. We aim to examine the microbial-regulated metabolite signatures and host-microbial interactions in response to TRE and daily CR while promoting and enhancing diversity among cancer prevention researchers. The Diversity Supplement will provide needed insight into the modulation of the GM and host-microbial interactions in response to TRE and CR and its relevance to the prevention of colorectal carcinogenesis.

项目摘要 这种多样性补充的目标是通过以下方式扩大父母补助金的意义和创新 研究限时进食（TRE）和每日卡路里限制（CR）对肠道微生物群（GM）的影响 和与预防结直肠癌（CRC）相关的宿主-微生物相互作用， 癌症在美国多样性补充方案还将提供预防癌症方面的基本培训 一位有前途的西班牙裔女性，早期职业调查员，比阿特丽斯·佩纳尔弗·伯纳贝博士。肥胖是 一个主要的可改变的生活方式的风险因素为CRC。TRE正在成为管理体重的替代方法 这包括简单地看时钟和每天吃4-10小时，从而限制身体暴露于 长期的营养素。TRE展示了出色的粘附性，因为它简单且省略了 繁琐的卡路里计算，这是传统每日CR的标志。转基因可以产生有益的代谢物， 这类抗炎丁酸盐，或通过促进粘液产生来改善肠道完整性，但GM失调 会导致结肠中促炎和促癌代谢物的水平增加。现有研究 由于样本量小，持续时间短， 使用低分辨率的方法，无法检查微生物代谢功能的变化， 对TRE响应的宿主-微生物相互作用的评估。此外，TRE与CR的差异效应 对转基因和结肠癌的相关性仍然未知。我们假设TRE和 CR将促进一个不太允许结肠癌发生的GM环境，TRE将是上级的， 营养暴露的差异，缩短进食窗口的下游效应。此外，我们还发现 系统级方法（如网络分析）可以识别主机之间的关键通信 以及微生物代谢和结肠遗传网络，在CRC风险和预防中发挥机械作用。 勒韦林母公司赠款的基础设施，拟议的多样性补充将使用高分辨率 表征GM组成和代谢功能的方法，例如宏基因组学和代谢组学 和宿主的全身代谢。将采用统计和网络方法来整合这些多方面的信息， 组学数据和结肠转录谱，以确定TRE和CR对GM和宿主微生物的影响 交互.我们的目的是研究微生物调节的代谢物特征和宿主-微生物相互作用 响应TRE和每日CR，同时促进和增强癌症预防研究人员的多样性。 多样性补充将提供所需的深入了解调制的转基因和宿主微生物 TRE和CR的相互作用及其与预防结直肠癌发生的相关性。