Activiteit: Types gesprekken of presentaties › Genodigd spreker › Wetenschappelijk
Bile acids fulfill a variety of metabolic functions including regulation of glucose and lipid metabolism. Since changes of bile acid metabolism accompany obesity, Type 2 Diabetes and bariatric surgery, there is currently great interest in their role in metabolic health. We use a data-driven physiological modelling approach to obtain quantitative insight into the factors affecting bile acid metabolism. We developed a mathematical model that represents the enterohepatic and peripheral circulation of all major human bile acids. The model includes multiple time scales. It describes 24 hour dynamics associated with responses to meals. Slower dynamics mainly originate from processes in the colon and include transformation of bile acids by gut microbiota. The model is applied to analyse variability in bile acid metabolism in healthy individuals, to identify differences in patients with Type 2 Diabetes and predict metabolic effects of bariatric surgery. Identifiability of model parameters from plasma time-series metabolomics has been determined. A library of 'virtual patients' is created by calibrating the model to data from individuals who repeatedly received the same meal. Models for 15 patients with Type 2 Diabetes are compared against an equal number of healthy controls, identifying differences in bile acid homeostasis and metabolic regulation. Next, the model is adopted to simulate both acute effects of bariatric surgery (within weeks after surgery) and slower physiological and metabolic adaptations that emerge in months and years after surgery. With the model we are able to test numerous factors that could contribute to changes in bile acids after Roux-en-Y gastric bypass in order to isolate the main contributors. The model demonstrates a strong influence of intestinal transit parameters on concentrations of plasma bile acids. In addition to immediate effects of the surgical intervention on intestinal transit, the observed slow progression is probably caused by self-regulating FXR feedback and/or adapted FXR feedback secondary to metabolic improvement.