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Synthetic GPBA agonists and bile acids act via basolateral receptors in ileal and colonic mucosa

Research output: Contribution to journalArticle

Helen Mary Cox, Iain R. Tough, Thue W. Schwartz

Original languageEnglish
JournalNeurogastroenterology and Motility
Publication statusSubmitted - 2020

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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 (e.g. 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 faecal 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 faecal pellet progression in wild type and PYY-/- colons but not in GPBA-/- colon, while TDCA increased motility in wild type colon. The anti-motile 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 (that release 5-HT) and enteric neurons, and that luminal conjugated BAs require transport across the epithelium via ASBT in order to activate basolateral GPBA.

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