Project Summary The intestine plays essential roles in health and disease based on its two main functions: nutrient absorption and immune defense. These two processes are highly intertwined with each other and are influenced by a variety of genetic and environmental factors. Abnormal absorption causes nutrient deficiency or excess, which leads to various metabolic diseases. Compromised immune defense increases the exposure to pathogens and other noxious agents, and promotes systemic immune activation, infections and metabolic disorders. Therefore, understanding how the two processes are regulated in the intestine is critical for fighting these digestive system diseases. Intriguingly, many of the metabolic and immune functions are integrated in the same group of cells, the intestinal epithelial cells. However, how these cells coordinate the two distinct processes, especially in the face of environmental challenges, remains a puzzle. We recently identified that the gut microbiota, a community of microorganisms in the gut, controls a 24-hour diurnal rhythm in the intestinal epithelium through an epigenetic mechanism. This leads to a hypothesis that the microbiota may temporally orchestrate metabolic and immune functions in the intestine to maintain just-in-time capacities of nutrient uptake and immune defense in response to the diurnal oscillations of nutrient availability and microbial burden. In this proposal, we will examine how metabolic and immune activities are temporally coordinated in the intestine and how these rhythms are affected by environmental interventions. We will scrutinize the components and activities of the microbiota to understand how gut microbes regulate the circadian system to influence host metabolic health and immune integrity. We will identify and characterize other epigenetic programs that integrate microbial and circadian cues to regulate intestinal physiology. From a preliminary screen, we found that the microbiota drives the rhythm of another chromatin modification that is only present in male mice but not females. This finding provides a new avenue for understanding how microbial, circadian and sexual dimorphic signals converge in the intestine to control metabolic and immune functions. We will exploit multidisciplinary techniques including bacteria and mouse genetics, genomics, gnotobiotics, and more importantly we will develop new computational approaches and screening assays to understand the crosstalk between the gut microbiota and host circadian rhythms. These studies will provide novel mechanistic insights into the microbial regulation of host circadian programs and shed light on unexpected roles of the microbiota and epigenetic modification in regulating sexual dimorphisms of mammalian metabolism and immunity. Ultimately, the findings will help develop new strategies to protect against metabolic and immune diseases by targeting the microbiota or epigenetic pathways.

Project Narrative Digestive system diseases are causally associated with a wide variety of environmental factors including the diet composition, eating and sleeping schedules and the gut microbes, yet the molecular basis remains un- clear. This project will study how the gut microorganisms regulate diurnal rhythms and sexual dimorphisms in the intestine via epigenetic programs, and how this impacts nutrient absorption and immune integrity. The find- ings will provide novel avenues for ameliorating intestine-associated metabolic and immune disorders by tar- geting the microbiota or epigenetic machinery.