Model‐based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine

Abstract

Background Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein‐coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation. Methods In this study, we analyzed the inter‐ and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach. Main findings The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses. Conclusions We conclude that there is considerable inter‐ and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions.

Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes

“…Fourth, we cannot exclude the possibility that patients’ intake changed after the DMR. Fifth, human postprandial bile acid responses display significant inter- and intraindividual variability and, therefore, it could be possible that we did not detect all the differences in postprandial bile acid responses ( 40 ). Finally, we did not determine 24 h fecal bile acids in this study.…”

Differential Effects of One Meal per Day in the Evening on Metabolic Health and Physical Performance in Lean Individuals

“…This may be explained by the fact that the duration of the overnight fast before the MMT was identical for both interventions, so we may have missed acute effects of TRF on bile acid-and FGF19 levels. Alternatively, skipping two meals may have not changed intestinal transit time or gallbladder kinetics, both important factors that determinate plasma bile acid concentrations (Sips et al, 2018;Meessen et al, 2020). Increased cholesterol and LDL-C levels are associated with cardiovascular disease (CVD) (Levine et al, 1995).…”

“…Both bile acids and FGF19 concentrations are still increased 4–5 h after food intake ( Van Nierop et al, 2019 ; Meessen et al, 2020 ). So, from an evolutionary point of view, these prolonged postprandial signals suggest that humans are well prepared for periods with limited food availability.…”

“…Several postprandial signals (e.g., plasma bile acids, fibroblast growth factor 19 (FGF19), lipids) are still increased in the systemic circulation 4–5 h after meal ingestion ( Schrezenmeir et al, 1993 ; Van Nierop et al, 2019 ; Meessen et al, 2020 ). From an evolutionary point of view it may be reasoned that the human body is habituated to a lower meal frequency ( Meiselman, 2000 ).…”

Distinct Postprandial Bile Acids Responses to a High-Calorie Diet in Men Volunteers Underscore Metabolically Healthy and Unhealthy Phenotypes

“…It is likely that apparent conflicting results between these latter reports and our present study primarily result from the distinct study population and the fat content of the meal used. However, factors influencing plasma bile acid dynamics may involve numerous mechanisms which were initially documented in the early works of Hofmann et al [ 52 ] and LaRusso et al [ 53 ] This would need to be investigated more specifically in future studies (e.g., BA synthesis capacity, hepatic spillover and uptake, intestinal uptake, colon transit, microbial transformations and others [ 8 ]) in the light of the current models of integration [ 54 , 55 , 56 , 57 ]. Interestingly, some potential determinants were explored in kinetic studies in a pig trans-organ flux model, in which Eggink et al [ 8 ] determined that the timing and magnitude of the postprandial response exhibited large interindividual variabilities for BAs compared to glucose and insulin responses.…”