King's College London, Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
Novo Nordisk Foundation Centre for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, University of Copenhagen, Copenhagen, Denmark.
Neurogastroenterol Motil. 2020 Dec;32(12):e13943. doi: 10.1111/nmo.13943. Epub 2020 Jul 12.
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.
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.
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.
G 蛋白偶联胆汁酸（BA）受体 GPBA（以前称为 TGR5）介导 BA 的胃肠道（GI）活性。我们的目的是阐明与结合型 BA（例如，牛磺胆酸钠，TDCA）相比，选择性 GPBA 激动剂在小鼠和人结肠中的黏膜和运动反应。
使用具有完整黏膜下神经支配的黏膜制剂测量 GPBA 激动剂或 BA 对离子转运的反应，来自 C57Bl/6、PYY-/-或 GPBA-/-小鼠，并与 GPBA 信号在人结肠中的信号进行比较。我们还研究了 GPBA 激动剂在黏膜中的作用机制以及对天然粪便推进的作用机制。
Merck V 刺激了 GPBA 激动剂，刺激了 colonic 黏膜中的 PYY、胆碱能和 5-HT 机制的基底外侧反应。PYY 介导的 GPBA 信号对葡萄糖敏感。腔内 TDCA 通过顶端钠依赖性 BA 转运体（ASBT）穿过上皮衬里，其抑制剂 GSK2330672 显著降低了腔内但不降低基底外侧 TDCA 活性。Merck V 也减缓了野生型和 PYY-/-结肠中的天然粪便颗粒推进，但在 GPBA-/-结肠中没有，而 TDCA 增加了野生型结肠的运动。GLP-1 受体或一氧化氮合酶的阻断逆转了 GPBA 的抗运动作用，表明 GLP-1 和一氧化氮的参与。
我们得出结论，固有层中的几个不同靶标表达 GPBA，包括 L 细胞（释放 PYY 和 GLP-1）、肠嗜铬细胞和神经元（释放 5-HT）以及其他肠神经元。此外，腔内结合型 BAs 需要通过 ASBT 穿过上皮转运才能激活基底外侧 GPBA。
