A physiologically based model of bile acid metabolism in mice

Bile acid (BA) metabolism is a complex system that encompasses a diverse mixture 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 BAs metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of bile acids along gut the gut-liver axis. In this study, we developed a physiology-based model of murine BA metabolism describing synthesis, conjugation, microbial transformations, systemic distribution, excretion and EHC of BAs as well as an explicit representation of the host physiology at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) was characterized in vivo by measuring BA levels and composition in various organs, expression of transporters along the gut and cecal microbiota composition. Interestingly, 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 earlier experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching of microbial activity in the intestine. The here presented model hence allows functional analysis of BA metabolism in mice. In the future, the model may support the translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.