Page 158 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
circulating lipopolysaccharide and chylomicrons that induce mononuclear cell expression of inflammatory proteins such as interleukins, TNFα, and NFκB.91−94 This phenomenon is exaggerated in patients with obesity and type 2 diabetes.14,89
In summary, preclinical evidence shows that TGR5 modulates inflammatory signals predominantly via the monocyte lineage. Whether TGR5 modulates postprandial inflammation under physiological conditions is of clinical interest and remains to be elucidated.
Challenges for clinical application
Although the possible benefits of bile acid therapy could be large, the greatest concern for clinical application will be to restrict unwanted effects, because Tgr5 is widely expressed (panel 1). Several drug development studies done by pharmaceutical companies have led to the discontinuation of TGR5-based trial programmes.
In the gallbladder, where Tgr5 is expressed to a higher degree than in any other tissue, TGR5 activation causes smooth muscle relaxation and secretion of chloride- rich fluid, leading to increased gallbladder filling and potentially increasing the risk of gallstone formation.95 Findings from a drug development study using small molecule agonist compounds showed that exaggerated gallbladder filling occurred at the same doses needed to induce GLP-1 secretion in rats.96
In another pharmacochemical study, Fryer and colleagues97 reported large reductions in peripheral vascular tone and blood pressure immediately upon infusion of low doses of a TGR5 agonist in dogs. They were not able to separate this unwanted effect from the intended effects on inflammation, leading them to discontinue development of these agonists. Other pharmacochemical reports have also mentioned (but did not actually show) cardiovascular effects such as treatment-dependent changes in heart rate and blood pressure.17
Other clear side-effects are nausea or obstipation, mediated by TGR5-expressing neurons in the gastrointestinal tract, and pruritus.15 Bile acids have long been suspected to be the effectors of the itching sensation reported by patients with cholestatic liver disease. Using Tgr5–/– and Tgr5-Tg mice, Alemi and colleages15 showed that activation of TGR5 induced the release of itch neuropeptides. If
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