A physiologically based model of bile acid metabolism in mice
Bastian Kister,
Alina Viehof,
Ulrike Rolle-Kampczyk,
Annika Schwentker,
Nicole Simone Treichel,
Susan A.V. Jennings,
Theresa H. Wirtz,
Lars M. Blank,
Mathias W. Hornef,
Martin von Bergen,
Thomas Clavel,
Lars Kuepfer
Affiliations
Bastian Kister
Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany; Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
Alina Viehof
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Ulrike Rolle-Kampczyk
Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany
Annika Schwentker
Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Nicole Simone Treichel
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Susan A.V. Jennings
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Theresa H. Wirtz
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
Lars M. Blank
Institute of Applied Microbiology - iAMB, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Aachen, Germany
Mathias W. Hornef
Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Martin von Bergen
Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
Thomas Clavel
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital RWTH Aachen, Aachen, Germany
Lars Kuepfer
Institute for Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany; Corresponding author
Summary: Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically based model of murine BA metabolism describing synthesis, hepatic and microbial transformations, systemic distribution, excretion, and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut, and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching off microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.
