The Gut as an Adaptable Interface: from Genetic Architecture to Physiological Consequences of Adaptive Growth of the Drosophila Gut

饮食是动物健康和健身的主要决定因素，影响生理、衰老、代谢疾病和生殖输出。考虑到人类的平均体重指数正在增加，体重是疾病的主要风险因素，了解饮食如何影响生理具有广泛的社会意义。我们对饮食如何改变个体的生理机能以及哪些基因影响这一过程的理解存在差距。消化道（肠道）是消化的场所，因此充当摄入的食物和个体之间的界面。最近的研究表明，饮食可以影响这个界面的结构和功能，并且在肠道对饮食的反应方面存在很大的个体差异。然而，肠道可塑性的后果和机制的饮食反应仍然在很大程度上没有特点。这项研究旨在了解肠道如何对特定的营养素做出反应，并以果蝇为模型系统调节消化和生理。这项研究将提供一个新的框架来理解营养，包括肠道作为一个活跃和可变的界面，从而为未来在农业应用和人类营养干预中优化营养的工作铺平道路。本研究将支持初中、高中和大学生的教育，并将通过公共网站宣传模式生物对基础科学发现的重要性以及此类研究的社会经济效益。本研究的目标是从肠道功能、营养感测和通量以及响应营养比例变化的基因活性方面解释整体动物营养生理学。果蝇成虫的中肠有能力根据饮食调整自己的大小。特别是，摄入的食物中的营养物质的比例以可塑的方式改变器官的大小，这种现象称为适应性生长（AG）。本研究旨在表征AG的分子机制并确定AG如何影响生物体生理学。此外，AG在个体之间具有高度变异性，该研究旨在了解肠道AG个体间变异的遗传基础。该研究将1）确定触发AG的特定营养素和条件，并通过利用营养几何框架结合代谢测定和微生物学来确定肠道微生物是否参与; 2）确定食物如何重塑肠道结构，关注肠道区域化以及AG对营养同化，营养分配模式和整个昆虫的适应性的影响;（3）利用转录组学和功能遗传学方法鉴定控制AG的基因网络，并通过全基因组关联研究（GWAS）鉴定AG个体间变异的基因。总之，这些结果将表征AG对整个生物体生理学的影响，并确定肠道可塑性遗传学的分子和遗传基础，目前我们对营养的理解存在差距。该项目还将影响初中、高中和本科学生，并支持公共教育。

Diet is a principal determinant of animal health and fitness, affecting physiology, aging, metabolic disease and reproductive output. Considering that the average body mass index of human populations is increasing and weight is a main risk factor for disease, understanding how diet affects physiology has broad societal implications. There is a gap in our understanding of how diet can change the physiology of an individual, and what genes influence that process. The digestive tract (gut) is the site of digestion, and therefore acts as an interface between ingested food and an individual. Recent work has shown that diet can affect the structure and function of this interface, and that there is strong variation among individuals in how the gut responds to diet. However, the consequences of gut plasticity and mechanisms underlying the responses to diet remain largely uncharacterized. This study aims to understand how the gut can respond to specific nutrients and regulate digestion and physiology using the fruit fly as a model system. This study will provide a new framework to understand nutrition, including the gut as an active and variable interface, and will thus pave the way for future work to optimize nutrition in agricultural applications and human nutritional interventions. This study will support the education of middle school, high school, and undergraduate students, and will promote the importance of model organisms for fundamental scientific discovery and the socio-economic benefits of such studies via a public website.The goal of this study is to explain whole-animal nutritional physiology in terms of gut function, nutritional sensing and flux, and gene activity in response to variation in nutrient ratios. The Drosophila adult midgut has the capacity to resize itself depending on diet. In particular, the ratio of nutrients in ingested food alters the size of the organ in a plastic manner, a phenomenon called adaptive growth (AG). This study aims to characterize the molecular mechanisms that underlie AG and determine how AG impacts organismal physiology. In addition, AG is highly variable between individuals, and the study aims to understand the genetic basis for inter-individual variation in gut AG. The study will 1) identify the specific nutrient(s) and conditions that trigger AG and determine if gut microbes are involved by utilizing a nutritional geometric framework in conjunction with metabolic assays and microbiology; 2) determine how gut structure is remodeled by food, with attention to gut regionalization and the impact of AG on nutrient assimilation, nutrient allocation patterns and fitness of the whole insect; and 3) identify the gene network that controls AG using transcriptomics and functional genetics, and identify the genes responsible for inter-individual variation in AG by genome-wide association study (GWAS). Altogether these results will characterize the impact of AG on whole organismal physiology and identify the molecular and genetic basis for gut plasticity to genetics, current gaps in our understanding of nutrition. The project will also impact middle school, high school, and undergraduate students, and support public education.