The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice.
The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice.
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DOI：
10.1053/j.gastro.2012.09.055
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发表时间：
2013-01
期刊：
影响因子：
29.4
通讯作者：
Corvera CU
中科院分区：
文献类型：
--
作者：
Alemi F;Poole DP;Chiu J;Schoonjans K;Cattaruzza F;Grider JR;Bunnett NW;Corvera CU
由于疾病或治疗导致的胆汁酸（BA）向结肠的异常递送会通过未知机制引起便秘或腹泻。G蛋白偶联的BA受体TGR 5（或GPBAR 1）由肠神经元和内分泌细胞表达，调节运动和分泌。我们分析了野生型、基因敲除和转基因小鼠（分别为trg 5-wt、tgr 5-ko和tgr 5-tg）的胃肠和结肠转运、排便频率和含水量。我们分析了结肠组织的收缩性、舒张性和递质释放。去氧胆酸抑制tgr 5-wt小鼠结肠纵行肌的收缩，但不抑制tgr 5-ko小鼠。将脱氧胆酸、石胆酸或油酸（TGR 5的选择性激动剂）应用于tgr 5-wt小鼠的粘膜引起口腔收缩和尾部松弛，表明肿胀。BA刺激释放的蠕动递质5-羟色胺和降钙素基因相关肽;这些递质的拮抗剂抑制BA诱导的pathesis，与TGR 5定位肠嗜铬细胞和内在初级传入神经元一致。tgr 5-ko小鼠对BA没有反应，也没有发生神经递质释放。机械诱导的神经元凋亡和递质释放不受tgr 5缺失的影响。tgr 5-ko小鼠的全肠转运比tgr 5-wt或tgr 5-tg小鼠慢1.4倍，而tgr 5-tg小鼠的结肠转运快2.2倍。与tgr 5-wt小鼠相比，tgr 5-ko小鼠的排便频率降低了2.6倍，tgr 5-tg小鼠的排便频率增加了1.4倍。tgr 5-ko小鼠的粪便含水量（37%）低于tgr 5-tg小鼠（58%）或tgr 5-wt小鼠（62%）。受体TGR 5介导BA对结肠运动的影响; TGR 5缺乏导致小鼠便秘。这些发现可能介导了BAs长期以来的泻药特性; TGR 5可能是消化系统疾病的治疗靶点。
Abnormal delivery of bile acids (BAs) to the colon, due to disease or therapy, causes constipation or diarrhea by unknown mechanisms. The G protein-coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion. We analyzed gastrointestinal and colon transit, and defecation frequency and water content, in wild-type, knockout and transgenic mice (trg5-wt, tgr5-ko and tgr5-tg, respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release. Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5-hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with TGR5 localization to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5. Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice, compared to tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%). The receptor TGR5 mediates the effects of BAs on colonic motility; TGR5 deficiency causes constipation in mice. These findings might mediate the long-known laxative properties of BAs; TGR5 might be a therapeutic target for digestive diseases.
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影响因子：
3.7
作者：
Cipriani S;Mencarelli A;Chini MG;Distrutti E;Renga B;Bifulco G;Baldelli F;Donini A;Fiorucci S
通讯作者：
Fiorucci S
DOI：
10.1152/ajpgi.00027.2007
发表时间：
2007-07-01
影响因子：
4.5
作者：
Hamilton, James P.;Xie, Guofeng;Hofmann, Alan F.
通讯作者：
Hofmann, Alan F.
影响因子：
24.5
作者：
ARMSTRONG, DN;KRENZ, HK;BALLANTYNE, GH
通讯作者：
BALLANTYNE, GH
DOI：
10.1016/j.bbrc.2005.01.139
发表时间：
2005-04-01
影响因子：
3.1
作者：
Katsuma, S;Hirasawa, A;Tsujimoto, G
通讯作者：
Tsujimoto, G
影响因子：
24.5
作者：
KIRWAN, WO;SMITH, AN;EASTWOOD, MA
通讯作者：
EASTWOOD, MA