Circadian Rhythms and Gut Microbiota: Implications of Diurnal Interactions on Host Metabolism and Immunity

Metabolic diseases, including type 2 diabetes and cardiovascular disease, are a worsening epidemic, affecting millions of people worldwide. These disorders are complex and particularly difficult to treat clinically due to their multifactorial nature, which involves both environmental and genetic factors. Metabolic disease onset and progression are impacted by two seemingly disparate systems: the trillions of microbes that make up the gut microbiome and host circadian networks, which govern the host’s capacity to adapt to 24-hour environmental rhythms, such as feeding and fasting. Gut microbiota community membership and functional dynamics are shaped by dietary intake, while circadian rhythms are critical for maintaining metabolic homeostasis; disruption of either results in significant physiological dysfunction. Studies have revealed gut microbes exhibit diurnal patterns in abundance and functional outputs, which feeds back onto host circadian networks. Conversely, host circadian disruptions induce changes in the gut microbiome that can feedback onto the host, particularly affecting metabolic regulation. Despite the strong evidence linking these two important systems, fundamental knowledge of the basic mechanisms behind their interactions remains limited. This thesis describes two studies that explored the complex diurnal interactions between the gut microbiome and mammalian host factors in the context of metabolic disorders. The first study examines the liver circadian clock as an essential transducer of cues from gut microbes that aid in the regulation of diurnal patterns in homeostatic mechanisms associated with fuel utilization, glucose regulation, and lipid metabolism. The second study explores how bidirectional interactions between the host innate immune factor REG3g and diet-induced gut microbiota are important for maintaining small intestinal, host-microbe interactions and metabolic homeostasis. Together, this thesis fills gaps and provides an essential knowledge base, spanning multiple systems, to interrogate the mechanistic underpinnings of key host-microbe circadian interactions that direct metabolism