Page 61 - Human Bile Acid Metabolism: a Postprandial Perspective

We focused on human BAs and the porcine BA profile mainly consists of
CDCA and HDCA forms. CDCA is a primary BA, whereas HDCA may be both
primary (since it was detected in germ free pigs [31]) and secondary. Notably, the concentration of the unconjugated forms was unaffected by the ingestion of a meal.
So the postprandial response was mainly explained by the glycine-conjugated
forms of CDCA and HDCA. Differences in the postprandial response between
conjugated and unconjugated BAs may be due to microbiota and the affinity of 3 the BA forms for their transporters [1]. We found that conjugated BAs are more
Transhepatic bile acid kinetics
efficiently cleared than their unconjugated forms, showing the high effectiveness and expression of NTCP in the liver.
HDCA cannot diffuse passively and is only a substrate for OATP1, but not for NTCP, which might explain the relative lower HDCA clearance compared to CDCA forms [32]. Despite the large increase in conjugated BA flux through the enterohepatic pathway after food intake, hepatic clearance of the BAs remained stable. The unconjugated BAs flow through the enterohepatic cycle passively regardless of food status and do not appear to have an additional role in postprandial fat digestion [33].
LCA forms have the highest TGR5 affinity, but are often ignored in humans because of their low peripheral plasma concentrations. In the pigs, we showed that unconjugated LCA outnumbered conjugated LCA forms in contrast to HDCA and CDCA forms. The unconjugated LCA can either be derived from deconjugation and transformation of CDCA, or deconjugation of gLCA or tLCA by gut bacteria [34]. LCA was already high in fasted samples and did not show a postprandial change, again indicating ongoing cycling and deconjugation without food intake. However, gLCA showed an increase after the meal, which is likely to rely on early re-uptake of gLCA that has been excreted by the liver. The human LCA conjugation profile was very much comparable to the porcine profile enabling translation. In the enterohepatic circulation the LCA forms and concentrations are likely sufficient to signal TGR5 in intestinal L-cells or liver Kupffer cells.
The porcine BA forms, i.e., HDCA, are not found in humans, whereas pigs do not have DCA which has a relatively high TGR5 affinity [11]. To speculate on the potential of the plasma bile acid pool to activate TGR5 we used a simplified method to calculate the hypothetical TGR5 activating capacity for which we used the plasma BA concentration and the published EC50 of the BAs for TGR5
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