Synthetic G protein‐coupled bile acid receptor agonists and bile acids act via basolateral receptors in ileal and colonic mucosa. Issue 12 (12th July 2020)

• Record Type: Journal Article
• Authors: Tough, Iain R.; Schwartz, Thue W.; Cox, Helen M.
• Is Part Of: Neurogastroenterology & motility. Volume 32:Issue 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-12
• Subjects: colonic ion transport -- fecal pellet transit -- G protein‐coupled bile acid receptor -- peptide YY; Gastrointestinal system -- Motility -- Periodicals; Gastrointestinal system -- Innervation -- Periodicals; 616.33
• DOI: 10.1111/nmo.13943
• Languages: English
• ISSNs: 1350-1925

Abstract

Abstract: Background: The G protein‐coupled bile acid (BA) receptor, GPBA (previously named TGR5), mediates BA gastrointestinal (GI) activities. Our aim was to elucidate the mucosal and motility responses to selective GPBA agonists compared with conjugated BA (eg, taurodeoxycholate, TDCA) in mouse and human colon. Methods: Ion transport responses to GPBA agonists or BAs were measured in mucosal preparations with intact submucous innervation, from C57Bl/6, PYY−/−, or GPBA−/− mice and compared with GPBA signaling in human colon. We also investigated the mechanisms underlying GPBA agonism in mucosae and on natural fecal pellet propulsion. Key Results: GPBA agonist Merck V stimulated basolateral responses involving peptide YY (PYY), cholinergic, and 5‐HT mechanisms in colonic mucosa. The PYY‐mediated GPBA signal was glucose‐sensitive. Luminal TDCA crossed the epithelial lining via the apical sodium‐dependent BA transporter (ASBT) and its inhibitor, GSK2330672 significantly reduced luminal, but not basolateral TDCA activity. Merck V also slowed natural fecal pellet progression in wild‐type and PYY−/− colons but not in GPBA−/− colon, while TDCA increased motility in wild‐type colon. The antimotile GPBA effect was reversed by blockade of glucagon‐like peptide 1 (GLP‐1) receptors or nitric oxide synthase, indicating involvement of GLP‐1 and nitric oxide. Conclusions & Inferences: We conclude that several different targets within the lamina propria express GPBA, including L cells (that release PYY and GLP‐1), enterochromaffin cells and neurons (that release 5‐HT), and other enteric neurons. Furthermore, luminal‐conjugated BAs require transport across the epithelium via ASBT in order to activate basolateral GPBA.