Determinants of postprandial plasma bile acid kinetics in human volunteers

Abstract

Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual variability. Healthy men and women ( = 72, 62 ± 8 yr, mean ± SE) were enrolled into a 12-wk weight loss intervention. All subjects underwent an oral glucose tolerance test and a mixed-meal tolerance test before and after the intervention. BA were quantified in plasma by liquid chromatography-tandem mass spectrometry combined with whole genome exome sequencing and fecal microbiota profiling. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma BA profiles. Fasting and postprandial BA profiles revealed high interindividual variability, and three main patterns in postprandial BA response were identified using multivariate analysis. Although the women enrolled were postmenopausal, effects of sex difference in BA response were evident. Exome data revealed the contribution of preselected genes to the observed interindividual variability. In particular, a variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases. Fecal microbiota analysis did not reveal evidence for a significant influence of bacterial diversity and/or composition on plasma BA profiles. The analysis of plasma BA profiles in response to two different dietary challenges revealed a high interindividual variability, which was mainly determined by genetics and sex difference of host with minimal effects of the microbiota. Considering the average response of all 72 subjects, no effect of the successful weight loss intervention was found on plasma bile acid (BA) profiles. Despite high interindividual variability, three main patterns in postprandial BA response were identified using multivariate analysis. A variant in the gene, encoding the small intestinal BA transporter organic anion-transporting polypeptide-1A2 (OATP1A2), was associated with delayed postprandial BA increases in response to both the oral glucose tolerance test and the mixed-meal tolerance test.

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism

“…Although the diurnal changes in C4 were more discrete on day 1 of the present study, they are comparable to those previously reported . As expected , levels of BAs, C4 and FGF19 showed considerable interindividual variation, but the patterns observed were consistent (Figure A‐C).…”

A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings

“…BA absorption starts already in the duodenojejunum, with at least 25% of CDCA and DCA conjugates being reabsorbed in that segment, 40 presumably by passive diffusion and via OATP3. 41 An analysis by Fiamoncini et al 35 showed that variability in OATP3 expression may contribute to variability in postprandial plasma BA dynamics, whereas our analysis showed a small impact of duodenojejunal variability on daily average plasma BA levels. This may point to a compensatory increase in ileal BA absorption, preventing BA pool reduction, as detected by delayed BA absorption.…”

“…9 This multifactorial nature of systemic plasma BA measurements complicates the identification of key factors that regulate BA pool distribution and composition. In their recent work, Fiamoncini et al 35 addressed this question by using a mixed-design analysis of a variance model exploiting host genome and microbiota data, in addition to systemic plasma BA profiles. However, interindividual variability is determined not only genetically, numerous additional factors, environmental and physiological, may contribute to the variability in BA pool size and composition.…”

Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss‐mediated metabolic improvements

“…The 13 most abundant bile acids in plasma were quantified with an adaptation of the method described by Tagliacozzi et al (28). In brief, 10 ml plasma was mixed with deuterated internal standards and, after methanolic extraction, the samples were injected into the LC-MS/MS system, as described in Fiamoncini et al (29).…”