Page 100 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 5
with the postprandial state (9). Alternatively, FGF19 is not obligatory for reduced BA biosynthesis (1). Forty hours of fasting induces profound reciprocal changes in energy metabolism that may have influenced FGF19 biology (42). It is also tempting to speculate that ongoing cycling of BAs such as CDCA, which correlated with FGF19 levels, may have led to increased FGF19 production as shown earlier in other models (29, 50).
In the second experiment, we further explored this relationship and administered a single dose of 750 mg gDCA with the meal. The dose is similar to that recommended for ursodeoxycholic acid, prescribed for treatment of primary biliary cholangitis and used in translational studies (11, 15), but lower than the dose of CDCA (15 mg/kg) used in the study by Broeders et al. (4). Unconjugated DCA has been suggested to exert carcinogenic effects in in vitro studies employing supraphysiological concentrations (31). However, in our study, we administered glycine-conjugated DCA, which is abundantly present in the human BA pool and enters the gut lumen in high concentrations after a meal (5).
We found slightly lower plasma glucose levels in our healthy volunteers after gDCA administration between 75 and 180 min after the meal. Although this could be perceived as a chance finding, lower glucose levels were very reproducible between subjects, showed marginal spread, and reached a mean difference of ~0.5 mM at time points 90 and 120 min. We could not attribute this to a relevant increase in insulin levels. Moreover, gDCA supplementation acutely increased GLP-1 levels. This is likely explained by increased secretion and not diminished clearance, because GLP-1 normally is broken down quickly by dipeptidyl peptidase-4 (3). The key question remains then: how does gDCA increase GLP-1 secretion? Stimulation of TGR5 receptors in the gut by gDCA is most likely responsible for this phenomenon, because the GLP-1 effects were rather acute (after 30 min, Fig. 3E) and preceded the increased gDCA plasma levels, which only became evident after ~120 min (Fig. 3C). Our data support previous work that shows bile acids as important regulators of appetite- and metabolism-regulating hormones by activation of basolateral intestinal TGR5 (23). However, the combination of a short GLP-1 surge and healthy lean volunteers may have prevented clear effects on glucose levels. The fact that we found no effects on FGF19 levels after gDCA administration may be explained by lower, but not absent, affinity of gDCA for FXR compared with CDCA (34).
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