Developmental effects of intestinal microbes on metabolic and behavioral circadian rhythms

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PROJECT SUMMARY Metabolic diseases are increasing worldwide in prevalence and severity. Globally, approximately 650 million people are obese or overweight, over half of whom are children. The healthcare burden of obesity is enormous and only growing. Circadian rhythms play a central role in healthy metabolism and in maintaining proper host- microbe interactions. Circadian rhythms in feeding and behavior create a feedback loop, driving rhythms in hepatic transcription, which in turn drive rhythms in host and microbial metabolism that ultimately feedback onto circadian rhythms in host behavior. This network of rhythms is severely disrupted in obese mice consuming a Western diet. Early-life diet interacts with the developing microbiome to program metabolism and disease risk, but how the early-life microbiota contribute to development of the host metabolic circadian network remains unknown. There is an urgent need to identify mechanisms by which gut microbes interact with diet early in life to shape these circadian networks that coordinate daily rhythms in metabolism. Mice devoid of all microbes (‘germ-free’) exhibit disrupted circadian rhythms in numerous aspects of host metabolism compared to mice that have had microbes since birth. Remarkably, repopulating germ-free mice later in adulthood with microbes (‘conventionalization') only partially normalizes their circadian rhythms. This indicates that the age at which gut microbes are acquired must play a critical role in the development of circadian networks that govern metabolism. But when and how healthy and obesogenic microbes first begin to normalize and disrupt, respectively, the circadian network remain unexamined. Our research will bridge this gap in knowledge by testing the hypothesis that the organismal circadian network is shaped by interactions between the type of gut microbes acquired and the developmental age of acquisition. Aim 1 tests the hypothesis that the age when mice acquire a normal, healthy microbiome determines the robustness of their circadian network in adulthood. We will conventionalize germ-free mice with microbes during gestation, at weaning, or in adulthood. Phenotypes across the entire circadian network will be examined later in life, including: hepatic clock and clock-controlled gene expression via RNA-seq, microbial community oscillations via 16S rRNA, and host behavioral circadian rhythms thermoregulation and via wireless telemetry inside sterile isolators. Aim 2 will test the hypothesis that obesogenic diets early in life disrupt normal development of the circadian network through a combination of microbe-dependent and microbe-independent mechanisms. Beginning early in life, germ-free mice will be administered an obesogenic diet alone, obesogenic microbes alone, or both obesogenic diet and microbes. Metabolic circadian networks will be examined as in Aim 1. These studies will specify how diet and microbes interact to affect the developing host-microbial circadian network. New insights into how metabolic programming impacts the circadian system will inform early-life dietary and microbial interventions that may afford prophylaxis against the development of obesity.