Obstructive cholestasis alters intestinal transit in mice: role of opioid system

Ghaffari, Kimia; Savadkuhi, Shahab Tour; Honar, Hooman; Riazi, Kiarash; Shafaroodi, Hamed; Moezi, Leila; Ebrahimkhani, Mo R.; Tahmasebi, Mohammad Saeid Radjabzadeh; Dehpour, Ahmad Reza

doi:10.1016/j.lfs.2004.09.002

Cited by 18 publications

(13 citation statements)

References 27 publications

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“…Moreover, abnormal BA delivery to the intestine, which can occur due to disease or therapy, is associated with defects in digestive functions. For example, a reduced colonic delivery of BAs, which can occur during cholestatic disease or after administration of BA sequestrants to treat lipid disorders, is frequently associated with constipation (Knodel and Talbert, 1987;Ghaffari et al, 2004). Conversely, an increased colonic delivery of BAs, due to decreased ileal absorption that is a consequence of inflammatory bowel disease or surgical resection or due to continuous secretion in cholecystectomy patients, is often associated with diarrhoea (Miettinen, 1971;Arlow et al, 1987).…”

Section: Gpba and Intestinal Functionsmentioning

confidence: 99%

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

Lieu¹,

Jayaweera²,

Bunnett³

2014

British J Pharmacology

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Bile acids (BAs) are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Given the episodic nature of BA secretion and intestinal re-absorption, the circulating and tissue levels of BAs, like those of the gut hormones, fluctuate in fasting and fed states, and BA levels and forms are markedly affected by disease. BAs exert widespread hormonal-like effects by activating receptors in the nucleus and at the plasma membrane. The nuclear steroid receptors mediate the genomic actions of BAs on BA, glucose and lipid homeostasis. GPBA (TGR5) is a G-protein coupled plasma membrane receptor for BAs that mediates many of the rapid, non-genomic actions of BAs. GPBA has been implicated in the control of glucose homeostasis, inflammation and liver functions. Recent observations have revealed an unexpected role for GPBA in the nervous system. GPBA is expressed by enteric neurons and enterochromaffin cells that control peristalsis, and GPBA mediates the prokinetic actions of BAs in the colon that have been known for millennia. GPBA is also present on primary spinal afferent and spinal neurons that are necessary for sensory transduction. BA-induced activation of GPBA in the sensory nervous system promotes scratching behaviours and analgesia, which may contribute to the pruritus and painless jaundice that are observed in some patients with chronic cholestatic disease, where circulating BA concentrations are markedly increased. Thus, GPBA has emerged as an intriguing target for diverse metabolic, inflammatory, digestive and sensory disorders, where agonists and antagonists may be of value. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2014.171.issue-5 Abbreviations ADAM, A disintegrin and metalloproteinase domain-containing protein; ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CGRP, calcitonin gene-related peptide; D2, type 2 iodothyronine deodinase; DCA, deoxycholic acid; GLP-1, glucagon-like peptide 1; GPBA, bile acid receptor; KATP, ATP-dependent potassium channels; LCA, lithocholic acid; OA, oleanolic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; UDCA, ursodeoxycholic acid IntroductionBile acids (BAs), a major component of bile, are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Remarkably, BAs are also signalling molecules. The levels of BAs fluctuate in the circulation under physiological conditions and during disease states, rather like the circulating levels of gut hormones, and BAs can regulate cells throughout the body by activating specific BA receptors in the nucleus and at the plasma membrane. These receptors mediate the effects of BAs on diverse physiological processes, ranging from the control of glucose homeostasis to peristaltic contractions of the digestive tract, and have been implicated in disorders as diverse as obes...

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Section: Gpba and Intestinal Functionsmentioning

confidence: 99%

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

Lieu¹,

Jayaweera²,

Bunnett³

2014

British J Pharmacology

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“…Disease- or therapy-related alterations in BA concentrations in the intestine have a marked impact on digestive functions. Decreased colonic delivery of free BAs as a result of cholestatic disease or after treatment of lipid disorders with BA sequestrants results in constipation 9, 10 . Conversely, inflammatory bowel disease or ileal resection lead to impaired ileal BA absorption and increased colonic delivery, which can cause diarrhea 11 .…”

Section: Introductionmentioning

confidence: 99%

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

et al. 2013

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Background & Aims: 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. Methods: 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. 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 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%). Conclusions: 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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“…Many results both from our laboratory and from other institutes on MENK's function of upregulating immune system at suitable dose have been reported previously. [15][16][17][18][19][20][21] Our documented record showed that considerable work of approaches with MENK on its impact on immune cells in vitro and in vivo has been done in our laboratory. [7][8][9][10][11] There are predominantly mu, delta, and kappa-3 types of opioid receptors.…”

Section: Discussionmentioning

confidence: 97%

Methionine enkephalin (MENK) improves lymphocyte subpopulations in human peripheral blood of 50 cancer patients by inhibiting regulatory T cells (Tregs)

Wang

Gao

Yuan

et al. 2014

Human Vaccines & Immunotherapeutics

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Obstructive cholestasis alters intestinal transit in mice: role of opioid system

Cited by 18 publications

References 27 publications

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

Methionine enkephalin (MENK) improves lymphocyte subpopulations in human peripheral blood of 50 cancer patients by inhibiting regulatory T cells (Tregs)

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