The diurnal dynamics of the gut epithelium are regulated by cross-talk between circadian clocks and nutrient sensing pathways: intermittent fasting to manage chronodisruption.

Perturbations of the circadian system caused by rotating shift work or obesity lead to desynchronization of various circadian clocks and favor the development of metabolic disorders. This study aims to investigate how environmental (chronic jetlag) or genetic (Bmal1-/-) chronodisruption in mice or humans (obesity) affects the rhythmic dynamics in gut epithelial cell function. We hypothesize that alterations in food intake rhythms affect the cross-talk between circadian clocks and nutrient sensing pathways. We aim to study how intermittent fasting in chronodisrupted mice induces robust oscillations of clock genes and restores rhythmicity in gut epithelial functions. A transcriptomic analysis of the intestinal mucosa of these mouse models will reveal alterations in the rhythmic expression of clock genes and key factors that regulate epithelial functions. 3D mouse enteroids will be generated to uncover how rhythmic alterations in nutrient availability influence stem cell behavior and thus change the balance between self-renewal and differentiation. Limited options are available to study the effect of chronodisruption on diurnal rhythms in humans. We will use 3D enteroids from lean and obese patients to determine the food cues that entrain peripheral clocks and that can restore rhythmicity during chronodisruption. This project will provide insights in the molecular pathways that are triggered by intermittent fasting that is currently considered as a popular weight loss strategy.