Wirtz, T. H. | 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↗

bioRxiv2019

Dietary intake regulates the circulating inflammatory monocyte pool

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPAR) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.\n\nHighlightsO_LIFasting reduces the numbers of peripheral pro-inflammatory monocytes in healthy humans and mice.\nC_LIO_LIA hepatic AMPK-PPAR energy-sensing axis controls homeostatic monocyte numbers via regulation of steady-state CCL2 production.\nC_LIO_LIFasting reduces monocyte metabolic and inflammatory activity.\nC_LIO_LIFasting improves chronic inflammatory diseases but does not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair.\nC_LI

immunology↗