Kister, B. | Search bioRxiv

bioRxiv2025

A physiologically-based model of bile acid metabolism in humans

Altered serum BA profiles have been reported for several chronic liver diseases. However, relevant modifications in bile acid disposition are difficult to investigate mechanistically due to the interference of the various physiological processes involved at various levels of bile acid metabolism. In this regard, validated computational models represent a promising tool to understand the functional effect of disease-related alterations on bile acid composition along the gut-liver-axis through mechanistic analyses of the underlying physiological processes. We applied a physiologically-based models of bile acid metabolism in humans comprising the five predominant bile acids. The model describes various physiological aspects of bile acid metabolism including synthesis, enterohepatic circulation, hepatic and microbial conversions, postprandial gall bladder emptying as well as excretion via feces and urine. Model development was based on 39 previously published studies in patients without any liver diseases. In the future, the established model may serve as reference for analysis of the role of bile acids in health and disease.

systems biology↗

bioRxiv2022

A physiologically based model of bile acid metabolism in mice

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, conjugation, 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 of 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.

systems biology↗