Diet has been associated with an increasing number of complex diseases, including obesity, diabetes, cardiovascular diseases, and brain health. Many dietary components are not accessible to us; we rely on our microbiome to break them down and to produce essential amino acids and vitamins for us. The gut microbiome encodes 100 times more genes than our own genome, indicating the importance of the correct function of this ?organ? for our well-being. While the link between nutrition and many metabolic diseases is established, the molecular mechanisms by which diet influences our well-being are not well established. I aim to establish a multiscale modeling group for system biology at the LCSB. My group will develop state-of-the-art computational systems biology methods to develop a comprehensive, predictive multiorgan model of human metabolism that will enable the systematic investigation of these interactions. The research focus of my group will build on my extensive experience in reconstructing and interrogating multiscale biochemical reaction networks for biotechnological and biomedical applications. My group at the LCSB will study the mechanistic basis of the links between nutrition, gut microbiota, host metabolism, and complex diseases by continuously strengthening core skills in multiscale reconstruction technologies and developing powerful, scalable, and tractable analysis methods. The project’s specific aims are: 1. Development of multiscale metabolic reconstructions accounting for key organs, employing published models. We will also develop a well-defined gut microbiota, accounting for key representatives. We will specify and validate metabolic interactions between the organs based on literature. 2. Development of multiscale modeling methods and tools. This includes i) a user-friendly modeling interface, ii) fast and tractable methods for solving biomedical problems on a multiscale, and iii) methods to integrate omics and clinical data with multiscale models. 3. Application of the multiorgan metabolic model to four key biomedical issues. i) Defining the role of gut microbiota on host metabolism and energy balance. ii) Defining the characteristics of a vegetarian and omnivore diet, and analyze the consequences of the differences in diet composition to the host?s energy harvest. iii) Predicting candidate dietary therapies for inborn errors of metabolism. iv) Identifying potential dietary contribution to the development of Parkinson?s disease. The proposed project will augment the current state-of-the-art in at least three aspects, i.e., by creating the most comprehensive available multiorgan metabolic reconstruction, by developing novel, efficient computational modeling techniques, and by developing a conceptual framework to investigate systematically in silico the links between nutrition and human health.The proposed multiscale model, describing the metabolic interactions between human organs, including a simplified gut microbiota, will be the first of its kind and broadly applicable within computational systems biology and other biomedical fields. In fact, the multiscale model and modeling tools will be applicable to investigate the contribution of the microbiota and the host genotype on development of any complex human disease that has dietary components. Multiscale modeling will be instrumental for understanding the mechanistic basis of complex diseases and will be an enabling tool for personalized medicine (P4 medicine). A multitude of omics data is planned to be generated by researchers in Luxembourg and at the LCSB in the coming years. By establishing this group, my expertise in reconstruction and modeling of biochemical networks will be established in Luxembourg and available to the Luxembourgian research community through training and collaborations.