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

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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.