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Quantification and Potential Functions of Endogenous Agonists Of Gastroenterology 2015;149:433–444 Quantification and Potential Functions of Endogenous Agonists of Transient Receptor Potential Channels in Patients With Irritable Bowel Syndrome Nicolas Cenac,1,2,3 Tereza Bautzova,1,2,3 Pauline Le Faouder,1,2,3,4,5 Nicholas A. Veldhuis,6 Daniel P. Poole,6,7 Corinne Rolland,1,2,3 Jessica Bertrand,1,2,3 Wolfgang Liedtke,8 Marc Dubourdeau,9 Justine Bertrand-Michel,4,5 Lisa Zecchi,10 Vincenzo Stanghellini,10 Nigel W. Bunnett,6,11 Giovanni Barbara,10 and Nathalie Vergnolle1,2,3,12 1Inserm, U1043, Toulouse, France; 2CNRS, U5282, Toulouse, France; 3Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France; 4Inserm U1048, Toulouse, France; 5Lipidomic Core Facility, Metatoul Platform, Université de Toulouse, Université Paul Sabatier, Toulouse, France; 6Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia; 7Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia; 8Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; 9Ambiotis SAS, Toulouse, France; 10Departments of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy; 11Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia; and 12University of Calgary, Department of Pharmacology and Physiology, Calgary, Alberta, Canada supernatants from IBS biopsies. Levels of 5,6-EET and 15-HETE See editorial on page 287. were increased in colons of mice with, but not without, visceral hypersensitivity. PUFA metabolites extracted from IBS biopsies or colons of mice with visceral hypersensitivity activated mouse BACKGROUND & AIMS: In mice, activation of the transient sensory neurons in vitro, by activating TRPV4. Mouse sensory receptor potential cation channels (TRP) TRPV1, TRPV4, and neurons exposed to supernatants from IBS biopsies produced TRPA1 causes visceral hypersensitivity. These receptors and 5,6-EET via a mechanism that involved the proteinase-activated their agonists might be involved in development of irritable receptor-2 and cytochrome epoxygenase. In human dorsal root bowel syndrome (IBS). We investigated whether poly- ganglia, TPV4 was expressed by 35% of neurons. CONCLUSIONS: unsaturated fatty acid (PUFA) metabolites, which activate TRPs, Colon tissues from patients with IBS have increased levels of BASIC AND are present in colon tissues from patients with IBS and act as specific PUFA metabolites. These stimulate sensory neurons from TRANSLATIONAL AT endogenous agonists to induce hypersensitivity. METHODS: mice and generate visceral hypersensitivity via activation of We analyzed colon biopsy samples from 40 patients with IBS TRPV4. (IBS biopsies) and 11 healthy individuals undergoing colorectal cancer screening (controls), collected during colonoscopy at the Keywords: Pain; Proteolytic Activity; Protease; PAR2. University of Bologna, Italy. Levels of the PUFA metabolites that activate TRPV1 (12-hydroperoxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, 5-hydroxyeicosatetraenoic acid, urveys of Western populations have revealed irrita- and leukotriene B4), TRPV4 (5,6-epoxyeicosatrienoic acid [EET] S ble bowel syndrome (IBS) in 15%À20% of adoles- and 8,9-EET), and TRPA1 (PGA1, 8-iso-prostaglandin A2,and cents and adults, with a higher prevalence in women; the 1 15-deoxy-D-prostaglandin J2) were measured in biopsies and prevalence is variable in other populations. Considered as their supernatants using liquid chromatography and tandem a functional bowel disorder, IBS is characterized by mass spectrometry; we also measured levels of the PUFA me- abdominal discomfort or pain associated with constipation, tabolites prostaglandin E2 (PGE2) and resolvins. C57Bl6 mice diarrhea, or mixed bowel habit (IBS-C, IBS-D and IBS-M, were given intrathecal injections of small interfering RNAs to respectively).1 Recently, low-grade inflammation has been reduce levels of TRPV4, or control small interfering RNAs, along described to be associated with IBS.1 Among the with colonic injections of biopsy supernatants; visceral hyper- sensitivity was measured based on response to colorectal Abbreviations used in this paper: AA, arachidonic acid; CRD, colorectal distension. Mouse sensory neurons were cultured and incubated distension; COX, cyclooxygenase; CYPe, cytochrome epoxygenase; DRG, with biopsy supernatants and lipids extracted from biopsies or dorsal root ganglia; EET, epoxyeicosatrienoic acid; FB, Fast Blue; HC, colons of mice. Immunohistochemistry was used to detect TRPV4 healthy control; HETE, hydroxyeicosatetraenoic acid; IBS, irritable bowel syndrome; IBS-D, diarrhea-predominant IBS; IBS-C, constipation-pre- in human dorsal root ganglia samples (from the National Disease dominant IBS; IBS-M, mixed bowel habit IBS; LOX, lipoxygenase; PUFA, Research Interchange). RESULTS: Levels of the TRPV4 agonist polyunsaturated fatty acid; PGA, prostaglandin A; PGE2, prostaglandin E2; PAR2, proteinase-activated receptor 2; PAR2-AP, PAR2-agonist peptide; 5,6-EET, but not levels of TRPV1 or TRPA1 agonists, were Rv, resolving; siRNA, small interfering RNA; TRP, transient receptor po- increased in IBS biopsies compared with controls; increases tential; TRPA1, transient receptor potential ankyrin-1; TRPV, transient correlated with pain and bloating scores. Supernatants from IBS receptor potential vanilloid; VMR, visceral motor response. biopsies, but not from controls, induced visceral hypersensitivity © 2015 by the AGA Institute in mice. Small interfering RNA knockdown of TRPV4 in mouse 0016-5085/$36.00 primary afferent neurons inhibited the hypersensitivity caused by http://dx.doi.org/10.1053/j.gastro.2015.04.011 434 Cenac et al Gastroenterology Vol. 149, No. 2 inflammatory mediators studied in IBS, an increase in pro- from the proximal descending colon. One biopsy was sent to tease concentration or in proteolytic activity appears as a the pathology department for exclusion of microscopic colitis common feature in all IBS subgroups.2,3 Proteolytic activity or other microscopic tissue abnormalities. One biopsy was released from IBS-patient tissues is able to activate sensory snap-frozeninliquidnitrogenforlipidextractionandPUFA neurons and generates visceral hypersensitivity in mice, quantification (Table 1 and Supplementary Methods). Four through a mechanism involving the activation of proteinase- biopsies were used to obtain mucosal mediator release 3 (Table 1).2 Supernatant was used to quantify PUFA metabo- activated receptor-2 (PAR2). Further studies have demon- lites and to test their effect in mouse visceral sensitivity and strated in a mouse model, that PAR2-induced visceral hypersensitivity is dependent on activation of transient re- PUFA metabolites released by mouse sensory neurons ceptor potential vanilloid-4 (TRPV4).4 TRPV4 activation is (Supplementary Methods). not only a downstream effector of PAR2 signaling, but is also responsible for serotonin- or histamine-induced visceral hy- Results persensitivity.5 These results place TRPV4, a cation channel widely expressed in the gastrointestinal tract,6 at the cross- Increased Transient Receptor Potential Vanilloid roads of signaling events associated with visceral hypersen- 4 Agonist in Biopsies From Diarrhea- sitivity. Likewise, other members of the transient receptor Predominant Irritable Bowel Syndrome Patients potential (TRP) family—TRPV1 and transient receptor po- Potential TRP channel agonists and inhibitors were tential ankyrin-1 (TRPA1) —seem to be implicated in visceral quantified in biopsies of IBS patients and healthy controls hypersensitivity in mouse models.7,8 Whether TRP channels (HCs) using liquid chromatography/tandem mass spec- are playing such a role in IBS has not been addressed yet, trometry (Figure 1AÀE). In diarrhea-predominant IBS and the presence and functionality of endogenous agonists (IBS-D) patients, the quantity of 5,6-EET, an eicosanoid of these 3 TRPs in IBS have never been reported. described as a TRPV4 agonist, was significantly increased A common class of molecules: polyunsaturated fatty acid compared with HC (Figure 1A). No significant difference (PUFA) metabolites can signal through TRPV1, TRPV4, and was observed between constipation-predominant IBS TRPA19 (Supplementary Figure 1). In vitro studies have (IBS-C) or mixed bowel habit IBS (IBS-M) and HCs shown that cytochrome epoxygenase (CYPe) products of (Figure 1A). The concentration of 5,6-EET in biopsies of arachidonic acid (AA) metabolism, 50,60-epoxyeicosatrienoic IBS patients and HCs significantly correlated with the acid (5,6-EET) and 8, 9-EET, activate TRPV4.10,11 Metabo- abdominal pain severity and frequency score, and with the TRANSLATIONAL AT lites of AA, such as 12-hydroperoxyeicosatetraenoic acid, bloating severity and frequency score (Figure 2A). Con- BASIC AND 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE, and cerning the quantification of 8,9-EET, an eicosanoid also leukotriene B4 produced by lipoxygenases (LOX) have been described as a TRPV4 agonist, no significant difference characterized in vitro as potential TRPV1 agonists.12 Pros- was observed between groups of IBS patients and HCs taglandin A1 (PGA1), a cyclooxygenase (COX) product of (Figure 1A). No significant difference in the quantity of dihomo-g-linolenic acid is able to activate TRPA1.13 Simi- potential TRPV1 agonists (leukotriene B4, 5-HETE, 12- larly, cyclopentenone prostaglandins, such as 8-iso-PGA2 HETE, and 15-HETE) was detected
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