Page 160 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
compounds, such as those being developed for other intestinal receptors, might not deliver the desired effect, because basolateral TGR5 stimulation is required for GLP-1 secretion. Hepatic clearance of novel TGR5 agonists should be very high to prevent side-effects. The question then is how TGR5 ligands can be increased and made to be effective in the enterohepatic cycle only. This specificity might be achieved via changes in bile acid pool composition, either by extended administration of bile acids with high TGR5 affinity or manipulation of bile acid biosynthesis and bile acid transporters. Alternatively, synthetic agonists could be developed that are contained within the enterohepatic circulation, either using dual ligand methods or by optimising first pass clearance. Both academic and pharmaceutical researchers have put much effort into developing clinical TGR5 agonists; however, these agonists have not yet reached clinical application.
The metabolic phenotypes of Tgr5 polymorphisms should be studied in human beings to assess the contribution of TGR5 to clinically relevant outcomes. Ultimately, strategies to increase TGR5 signalling will require more insight into the dynamics of physiological bile acid metabolism and transport.
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