Dataset Information

µ-opioid receptor, ?-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients.

ABSTRACT: BACKGROUND AND AIMS:The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ-opioid receptor (MOR), its ligand ?-endorphin (?-END), and cannabinoid receptor-2 (CB2 ) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception. METHODS:Mucosal biopsies were obtained from the left colon of 31 IBS patients (45% women) with predominant constipation (IBS-C, 9) or diarrhea (IBS-D, 10) or with mixed bowel habits (IBS-M, 12) and 32 AC (44% women) and processed for qRT-PCR, Western blotting, and immunohistochemistry. KEY RESULTS:µ-opioid receptor and CB2 mRNA and protein expression and ?-END protein levels were increased in patients with IBS compared to AC (all Ps=0.021). A significant sex by IBS interaction was found in relation to CB2 mRNA expression (P = .003) with women showing a markedly higher expression to men (P = .035). In contrast, in AC, men had higher expression than women (P = .033). ?-END, MOR, and CB2 immunoreactivities (IR) were localized to CD4+T cells including EMR-1+ eosinophils and CD31+ T cells but not to mast cells. CONCLUSIONS:The increased expression of MOR, ?-END, and CB2 in the mucosa of IBS patients, where they are localized to immune cells, suggests that opioid and cannabinoid systems play an immune-related compensatory role in visceral pain in IBS patients. Further work is necessary to support this hypothesis.

SUBMITTER: Dothel G

PROVIDER: S-EPMC6791736 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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µ-opioid receptor, β-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients.

Dothel Giovanni G Chang Lin L Shih Wendy W Barbaro Maria Raffaella MR Cremon Cesare C Stanghellini Vincenzo V De Ponti Fabrizio F Mayer Emeran A EA Barbara Giovanni G Sternini Catia C

Neurogastroenterology and motility 20190723 11

<h4>Background and aims</h4>The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ-opioid receptor (MOR), its ligand β-endorphin (β-END), and cannabinoid receptor-2 (CB<sub>2</sub> ) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception.<h4>Methods</h4>Mucosal biopsies were obtained from the lef ...[more]

PMID: 31336406

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Project description:Background & aimsCannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms.MethodsSeventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881.ResultsIn all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), and increased colonic compliance (P = .058). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P = .022; compliance, overall P = .03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P = .075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P = .046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P = .045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P = .013).ConclusionsIn patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility.

Project description:Background & aimsIrritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals.MethodsColon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy.ResultsIn colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P < .0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect.ConclusionsWe found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

Dataset Information

µ-opioid receptor, ?-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients.

Publications

µ-opioid receptor, β-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients.

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