Bile acid metabolites in serum: intraindividual variation and associations with coronary heart disease, metabolic syndrome and diabetes mellitus

Abstract

Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4 are significantly increased in patients with MetS and T2DM but confounded with BMI and TG.

Figure 1. Intraindividual variations of individual unconjugated and conjugated bile acids during one day.

Shown are diurnal profiles of individual unconjugated BAs (A), glycine-conjugated BAs (B), and taurine-conjugated BAs (C) concentrations in subject D. Meals are indicated with arrows. See text for abbreviations.

Figure 2. Intraindividual and interindividual variations of summarized unconjugated and conjugated bile acids during one day.

Diurnal profiles of summarized unconjugated BAs (A), conjugated BAs (B), total BAs (C) and C4 (D) concentrations in all four subjects. Meals are indicated with arrows. See text for abbreviations.

Figure 3. OPLS-DA of combined MetS and T2DM patients (N = 100) versus MetS and T2DM free controls (N = 49).

A) Score plots showing individual measurements (black triangles: controls; white triangles: MetS and T2DM patients). B) Model evaluation: R²X, R²Y and Q²Y represent the amount of explained X-variation, Y-variation and predicted Y-variation respectively. Cross validation (CV) is evaluated using the CV-ANOVA p-value, which represents the significance of the predicted Y-variation for the given F value. Correct classification shows the percentage of values classified correctly for the entire group according to the model and Fisher's probability represents the likelihood of obtaining the same classification result by chance. C) Loading column plots with the weights representing the contribution of each variable to the model component scores. D) Variable importance of the projection (VIP) coefficient plot indicating which variables are important in explaining both the X- and the Y-data. Error bars show 95% confidence intervals for the calculated weights and importance.