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The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is
required for normal defecation in mice
#MMPMID23041323
Alemi F
; Poole DP
; Chiu J
; Schoonjans K
; Cattaruzza F
; Grider JR
; Bunnett NW
; Corvera CU
Gastroenterology
2013[Jan]; 144
(1
): 145-54
PMID23041323
show ga
BACKGROUND & AIMS: Abnormal delivery of bile acids (BAs) to the colon as a result
of 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. METHODS: We analyzed
gastrointestinal and colon transit, as well as 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. RESULTS: 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
localization of TGR5 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 with tgr5-wt mice. Water content in
stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%).
CONCLUSIONS: The receptor TGR5 mediates the effects of BAs on colonic motility,
and deficiency of TGR5 causes constipation in mice. These findings might mediate
the long-known laxative properties of BAs, and TGR5 might be a therapeutic target
for digestive diseases.
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