Understanding the effects of sleep deprivation on the gut's cellular homeostatic process

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Project Summary Individuals that suffer from chronic sleep disturbances are at high risk of developing intestinal dysfunction, which can promote acute cardiovascular and cardiometabolic diseases. My lab recently discovered that sleep and the gut have a bidirectional relationship. They found that the gut is specifically and critically injured during chronic sleep loss: sleep suppression causes the accumulation of reactive oxygen species (ROS) in this organ, which in turn causes oxidative stress and premature death of animals. The lab also uncovered a gut-to-brain peptidergic signaling pathway that regulates sleep depth. It is critical to determine how low sleep amount and poor sleep quality negatively impact the gut's physiology and function. I will use fruit flies as a model system to study the fundamental molecular, cellular, and functional relationship between sleep and the gut. My study will test the hypothesis that sleep loss results in an altered gut cellular composition that promotes increased sleep depth during recovery from sleep loss. The first aim of the proposal will focus on determining changes to gut cell composition in chronically sleep-deprived flies. I propose that sleep loss promotes intestinal stem cell proliferation and biases daughter cells toward enteroendocrine cell fate (gut sensory and secretory cells). I will combine immunofluorescence and fluorescent reporters to determine changes in intestinal stem cell proliferation and enteroendocrine cell fate determination. The second aim will examine sleep quality and lifespan in flies recovering from chronic sleep loss. I propose that changes in the gut cellular composition resulting from chronic sleep loss promote deeper sleep in flies recovering from sleep loss as a way to compensate for insufficient sleep. I will quantify the depth of sleep in chronically sleep-deprived flies throughout their lifespan and perform functional experiments to assess if peptides secreted by the enteroendocrine cells are responsible for increasing the depth of sleep during recovery. I will also functionally determine the contribution of these enteroendocrine cell-secreted peptides to the longevity of flies recovering from chronic sleep loss. Defining how cellular changes in the gut can impact the function of this organ and its role in regulating sleep will be fundamental for understanding the bidirectional sleep-gut relationship. More generally, this work will contribute to understanding how sleep problems negatively affect health and suggest solutions for how many of the problems can be reversed.