In Silico Analysis Identifies Intestinal Transit as a Key Determinant of Systemic Bile Acid Metabolism

Fianne L P Sips,Maarten R Soeters,Hannah M Eggink,Albert K Groen,Peter A J Hilbers,Natal A W Van Riel

doi:10.3389/fphys.2018.00631

Abstract

Bile acids fulfill a variety of metabolic functions including regulation of glucose and lipid metabolism. Since changes of bile acid metabolism accompany obesity, Type 2 Diabetes Mellitus and bariatric surgery, there is great interest in their role in metabolic health. Here, we developed a mathematical model of systemic bile acid metabolism, and subsequently performed in silico analyses to gain quantitative insight into the factors determining plasma bile acid measurements. Intestinal transit was found to have a surprisingly central role in plasma bile acid appearance, as was evidenced by both the necessity of detailed intestinal transit functions for a physiological description of bile acid metabolism as well as the importance of the intestinal transit parameters in determining plasma measurements. The central role of intestinal transit is further highlighted by the dependency of the early phase of the dynamic response of plasma bile acids after a meal to intestinal propulsion.

Highlights

Bile acids are amphipathic cholesterol metabolites that fulfill a broad variety of metabolic functions (Lefebvre et al, 2009)
To gain insight into the major determinants of plasma bile acid measurements and postprandial responses in health, we developed a mathematical model of bile acid metabolism
The following sections describe the constructed mathematical model and collection of data used for model calibration, model validation, evaluation of parameter sensitivity and identifiability, and model analysis via decomposition of the postprandial response and sensitivity and control analyses

Summary

Introduction

Bile acids are amphipathic cholesterol metabolites that fulfill a broad variety of metabolic functions (Lefebvre et al, 2009). Bile acids have mainly been studied for their pivotal role in facilitating digestion and absorption of dietary lipids from the intestinal lumen (Lefebvre et al, 2009; Hofmann and Hagey, 2014). Bile acids are potential postprandial signals, as they are released in response to a meal. These functions place bile acids at the crossroads of digestion, metabolic regulation, and cholesterol homeostasis. Obesity itself is associated with elevated bile acid synthesis markers (Steiner et al, 2011; Haeusler et al, 2016). Insulin resistance and Type 2 Diabetes Mellitus, have been linked to an increased fasting plasma concentration in combination with shifts of the conjugation and composition of plasma bile acids (Haeusler et al, 2013; Wewalka et al, 2014; Sonne et al, 2016)

Methods

Results

Conclusion