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  • br BA induced activation of TGR TGR

    2021-10-19


    BA-induced activation of TGR5 TGR5 is a membrane-bound G protein-coupled receptor for BAs and its activation is dependent on cAMP formation and further stimulation of protein kinase A [53], [31]. The receptor is expressed in the enterochromaffin cells, smooth muscles, immune cells and more importantly by myenteric, cholinergic and nitrergic neurons in the small and large intestines [81], [82]. In comparison to FXR, TGR5 is likely to be activated by hydrophobic BAs (the presence of taurine further increases their potency), both primary and secondary BAs, that enable permanent signals transmission. The activation of TGR5 in colonic epithelial cells reduces the basal secretory tone and inhibits cholinergic-induced secretory responses [31], [33]. TGR5 can also participate in the regulation of the intestinal epithelial transport. In line, the activation of TGR5, either by a naturally occurring ligand, LCA, or a semisynthetic agonist, INT-777, diminished basal chloride secretion and impaired cholinergic-induced secretory response in rats [83]. Moreover, studies demonstrated that excessive activation of epithelial TGR5 by lipophilic BAs, e.g. DCA and LCA, promoted colonic motility and contributed to the onset of diarrhea through the pathway mediated by 5-HT [84]. On the other hand, insufficient delivery of BAs to the colon caused by defective ileal Phenytoin sodium mg or low bile secretion promotes constipation, perhaps due to desensitization of TGR5. In TGR-5-lacking mice, reduced transit time and increased constipation have been reported [84]. It is therefore conceivable that any variations in colonic TGR5 expression can alter small bowel and colonic transit. Appropriate peristalsis and transit time depend on TGR5, which was confirmed in studies with TGR5 knockout mice, TGR5 transgenic mice and studies incorporating TGR5 agonists. The association between gene encoding TGR5 and intestinal transit has been recently confirmed also in IBS-D patients, which indicate a potential therapeutic use of TGR5-targeted agents in the management of intestinal disease [32], [34].
    Future potential of BA modulators in IBS Ileal bile acid transporter (IBAT) is expressed in the distal ileum and is responsible for the reabsorption of BAs in the ileal mucosa what impacts colonic secretion and motility [85]. It retransports about 95% of BAs from the intestine and ensures the correct flow of BAs in the enterohepatic circulation [86], [87]. Elobixibat (A3309) is an IBAT inhibitor which is a new compound that aims to treat constipation. Elobixibat is highly selective against IBAT and acts locally, resulting in minimal systemic exposure [60], [61]. In the randomized, placebo-controlled trials the administration of A3309 accelerated colonic transit, improved the stool form and the number of spontaneous intestinal movements in constipated patients. By inhibiting the re-uptake of BAs in the colon, the compound also decreased the level of FGF19 in plasma and caused changes in C4 value, cholesterol and low-density lipoprotein levels (i.e. reduction in cholesterol and the low- to high- density lipoprotein ratio) [76], [88]. Currently, A3309 completed Phase IIb clinical trial (ClinicalTrials.gov Identifier: NCT01007123) in the treatment of constipation and CC and showed the potential in accelerating colonic, but not intestinal motility, increasing stool frequency and improving constipation-related symptoms, including straining or distension [76]. In the study of Japanese constipated patients, the administration of A3309 caused a significant change in the frequency of spontaneous and complete spontaneous bowel movements in comparison to healthy controls. The efficacy of A3309 over placebo was also confirmed in terms of most secondary endpoints. Given once daily at the dose of 10 and 15 mg for 14 days, A3309 showed benefit for patients with CC [85]. Recent Phase 2 clinical trials evaluated the efficacy, safety and tolerability of GSK2330672 (ClinicalTrials.gov Identifier: NCT02966834), another inhibitor of IBAT, on the BA pool in participants with primary biliary cholangitis [87]. Treatment with GSK2330672 reduced total BAs in serum and decreased the number of primary conjugated BAs. GSK2330672 did not affect the absorption and recycling of the UDCA; however, a significant increase in UDCA concentration was observed after treatment [87]. The effect of GSK2330672 on the motility of the lower GI tract is unknown.