RESUMEN
Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.
Asunto(s)
Histamina/metabolismo , Canales Catiónicos TRPV/metabolismo , Adulto , Animales , Femenino , Humanos , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/fisiología , Canales Catiónicos TRPV/genética , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
BACKGROUND: Nasal hyperreactivity (NHR) is an important clinical feature of allergic rhinitis (AR). The efficacy of MP29-02 (azelastine hydrochloride (AZE) and fluticasone propionate [FP]) nasal spray on local inflammatory mediators and NHR in AR is unknown. We tested if MP29-02 decreases inflammatory mediators and NHR in AR and if this effect is due to restoration of nasal epithelial barrier function. METHODS: A 4-week double-blinded placebo-controlled trial with MP29-02 treatment was conducted in 28 patients with house dust mite (HDM) AR. The presence of NHR was evaluated by measuring reduction in nasal flow upon cold dry air exposure. The effects of AZE ± FP on barrier integrity and airway inflammation were studied in a murine model of HDM-induced NHR and on reduced activation of murine sensory neurons and human mast cells. RESULTS: MP29-02 but not placebo reduced NHR (P < .0001 vs P = .21), levels of substance P (P = .026 vs P = .941), and ß-hexosaminidase (P = .036 vs P = .632) in human nasal secretions. In wild-type C57BL6 mice, the reduction in ß-hexosaminidase levels (P < .0001) by AZE + FP treatment upon HDM challenge was found in parallel with a decreased transmucosal passage (P = .0012) and completely reversed eosinophilic inflammation (P = .0013). In vitro, repeated applications of AZE + FP desensitized sensory neurons expressing the transient receptor potential channels TRPA1 and TRPV1. AZE + FP reduced MC degranulation to the same extent as AZE alone. CONCLUSION: MP29-02 treatment reduces inflammatory mediators and NHR in AR. The effects of AZE + FP on MC degranulation, nasal epithelial barrier integrity, and TRP channels provide novel insights into the pathophysiology of allergic rhinitis.
Asunto(s)
Androstadienos/uso terapéutico , Antialérgicos/uso terapéutico , Mucosa Nasal/efectos de los fármacos , Ftalazinas/uso terapéutico , Rinitis Alérgica Perenne/prevención & control , Adulto , Animales , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Masculino , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mucosa Nasal/inmunología , Pyroglyphidae/inmunología , Rinitis Alérgica Perenne/inmunología , Adulto JovenAsunto(s)
Capsaicina , Síndrome del Colon Irritable , Recto , Canales Catiónicos TRPV , Femenino , Humanos , MasculinoRESUMEN
The majority of the body's serotonin (5-HT) is produced by the gastrointestinal tract. 5-HT has several functions in the gastrointestinal tract. 5-HT is a paracrine signalling molecule released from enterochromaffin cells, a survival and proliferating factor and a neurotransmitter. The actions of 5-HT are transduced by a large family of 5-HT receptors, several of which are expressed on different gastrointestinal cell types including enteric nerves, smooth muscle and interstitial cells of Cajal (ICC). This review will summarize recent advances in understanding the role of 5-HT in regulating function of ICC, and the expression and function of 5-HT receptors on muscle and enteric nerves in human tissue. Rodent ICC express several 5-HT receptors including 5-HT(2B) receptors which regulate ICC survival and proliferation. Human smooth muscle and enteric neurons also express several 5-HT receptor subtypes. Expression and function of these receptors is significantly different from small laboratory animals. 5-HT(7) receptor activation causes relaxation of muscle, whereas 5-HT(2B) receptors increase muscle activity. The 5-HT(4) receptor appears to mediate both inhibition and activation of smooth muscle involving myogenic as well as neural actions. Despite the abundant expression of 5-HT(3) receptors in the human enteric nervous system no functional correlate has been as yet demonstrated.
Asunto(s)
Sistema Nervioso Entérico/metabolismo , Músculo Liso/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Serotonina/metabolismo , Animales , Sistema Nervioso Entérico/citología , Motilidad Gastrointestinal/fisiología , Humanos , Músculo Liso/citologíaRESUMEN
The factors underlying the survival and maintenance of interstitial cells of Cajal (ICC) are not well understood. Loss of ICC is often associated with loss of neuronal nitric oxide synthase (nNOS) in humans, suggesting a possible link. The aim of this study was to determine the effect of neuronal NO on ICC in the mouse gastric body. The volumes of ICC were determined in nNOS(-/-) and control mice in the gastric body and in organotypic cultures using immunohistochemistry, laser scanning confocal microscopy and three-dimensional reconstruction. ICC numbers were determined in primary cell cultures after treatment with an NO donor or an NOS inhibitor. The volumes of myenteric c-Kit-immunoreactive networks of ICC from nNOS(-/-) mice were significantly reduced compared with control mice. No significant differences in the volumes of c-Kit-positive ICC were observed in the longitudinal muscle layers. ICC volumes were either decreased or unaltered in the circular muscle layer after normalization for the volume of circular smooth muscle. The number of ICC was increased after incubation with S-nitroso-N-acetylpenicillamine and decreased by N(G)-nitro-l-arginine. Neuronally derived NO modulates ICC numbers and network volume in the mouse gastric body. NO appears to be a survival factor for ICC.
Asunto(s)
Sistema Nervioso Entérico/citología , Sistema Nervioso Entérico/enzimología , Intestino Delgado/inervación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Estómago/inervación , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Femenino , Inmunohistoquímica , Ratones , Ratones Endogámicos , Ratones Mutantes , Músculo Liso/citología , Músculo Liso/inervación , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/genética , Nitroarginina/farmacología , Técnicas de Cultivo de Órganos , Proteínas Proto-Oncogénicas c-kit/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologíaRESUMEN
BACKGROUND: Abnormal abdominal pain perception is the most bothersome and difficult to treat symptom of functional gastrointestinal disorders (FGIDs). Visceral pain stimuli are perceived and transmitted by afferent neurons residing in the dorsal root ganglia that have sensory nerve endings in the gut wall and mesentery. Accumulating evidence indicates that peripheral activation and sensitization of these sensory nerve endings by bioactive mediators released by activated immune cells, in particular mast cells, can lead to aberrant neuroimmune interactions and the development and maintenance of visceral hypersensitivity. Besides direct neuronal activation, low concentrations of proteases, histamine, and serotonin can chronically sensitize nociceptors, such as TRP channels, leading to persistent aberrant pain perception. PURPOSE: This review discusses the potential mechanisms underlying aberrant neuroimmune interactions in peripheral sensitization of sensory nerves. A better understanding of the cells, mediators, and molecular mechanisms triggering persistent aberrant neuroimmune interactions brings new insights into their contribution to the physiology and pathophysiology of visceral pain perception and provides novel opportunities for more efficient therapeutic treatments for these disorders.
Asunto(s)
Enfermedades Gastrointestinales/inmunología , Síndrome del Colon Irritable/inmunología , Neuroinmunomodulación , Dolor Abdominal/inmunología , Animales , Humanos , Mastocitos/inmunología , Neuronas/inmunología , Percepción del Dolor/fisiologíaRESUMEN
Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling.
Asunto(s)
Síndrome del Colon Irritable/diagnóstico , Adulto , Animales , Capsaicina/farmacología , Estudios de Casos y Controles , Colon/patología , Citocinas/metabolismo , Femenino , Ganglios Espinales/patología , Gastroenteritis/complicaciones , Gastroenteritis/patología , Humanos , Mucosa Intestinal/metabolismo , Síndrome del Colon Irritable/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Receptores Histamínicos H1/metabolismo , Transducción de Señal , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismoRESUMEN
Psychological disorders, most notably anxiety and depressive disorders, somatization and catastrophizing, often precede or exacerbate functional gastrointestinal disorder (FGID) symptoms and correlate with symptom severity and health outcomes. Mounting evidence shows that psychological distress alters gut immunity, in particular mast cell activation, leading to a potentiation of sensory nerves and aberrant visceral pain perception. On the other hand, psychological stressors modulate the processing of incoming sensory signals by the brain, thereby contributing to FGID symptom development. A better understanding of the molecular mechanisms underlying stress-induced changes in the immune system or brain processing is crucial for the development of novel beneficial therapeutic strategies.
Asunto(s)
Enfermedades Gastrointestinales/etiología , Trastornos Mentales/complicaciones , Estrés Psicológico/complicaciones , Enfermedades Gastrointestinales/genética , Interacción Gen-Ambiente , Humanos , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estrés Psicológico/inmunologíaRESUMEN
BACKGROUND: Infectious gastroenteritis is a major risk factor to develop postinfectious irritable bowel syndrome (PI-IBS). It remains unknown why only a subgroup of infected individuals develops PI-IBS. We hypothesize that immunogenetic predisposition is an important risk factor. Hence, we studied the effect of Citrobacter rodentium infection on visceral sensitivity in Th1-predominant C57BL/6 and Th2-predominant Balb/c mice. METHODS: Eight-week-old mice were gavaged with C. rodentium, followed by 1 h of water avoidance stress (WAS) at 5 weeks PI. At 10, 14 days, and 5 weeks PI, samples were assessed for histology and inflammatory gene expression by RT-qPCR. Visceral sensitivity was evaluated by visceromotor response recordings (VMR) to colorectal distension. KEY RESULTS: Citrobacter rodentium evoked a comparable colonic inflammatory response at 14 days PI characterized by increased crypt length and upregulation of Th1/Th17 cytokine mRNA levels (puncorrected < 0.05) in both C57BL/6 and Balb/c mice. At 5 weeks PI, inflammatory gene mRNA levels returned to baseline in both strains. The VMR was maximal at 14 days PI in C57BL/6 (150 ± 47%; p = 0.02) and Balb/c mice (243 ± 52%; p = 0.03). At 3 weeks PI, the VMR remained increased in Balb/c (176 ± 23%; p = 0.02), but returned to baseline in C57BL/6 mice. At 5 weeks PI, WAS could not re-introduce visceral hypersensitivity (VHS). CONCLUSIONS & INFERENCES: Citrobacter rodentium infection induces transient VHS in C57BL/6 and Balb/c mice, which persisted 1 week longer in Balb/c mice. Although other strain-related differences may contribute, a Th2 background may represent a risk factor for prolonged PI-VHS. As PI-VHS is transient, other factors are crucial for persistent VHS development as observed in PI-IBS.
Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae/genética , Antecedentes Genéticos , Mediadores de Inflamación , Estrés Fisiológico/fisiología , Dolor Visceral/genética , Animales , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Fenómenos Inmunogenéticos/fisiología , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especificidad de la Especie , Células Th2/fisiología , Dolor Visceral/inmunología , Dolor Visceral/metabolismoRESUMEN
BACKGROUND: To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. METHODS: We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. KEY RESULTS: The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. CONCLUSIONS & INFERENCES: Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.
Asunto(s)
Citocinas/genética , Síndrome del Colon Irritable/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-10/genética , Interleucina-4/genética , Interleucina-6/genética , Interleucina-8/genética , Masculino , Persona de Mediana Edad , Receptores de Interleucina/genética , Receptores Tipo I de Interleucina-1/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Factor de Necrosis Tumoral alfa/genética , Adulto JovenRESUMEN
BACKGROUND: Although animal models of the irritable bowel syndrome (IBS) have provided important insights, there are no models that fully express the features of this complex condition. One alternative approach is the use of human intestinal biopsies obtained during endoscopic procedures to examine peripheral mechanisms in this disorder. These studies have served to confirm the existence of peripheral pathways in humans with IBS and have provided many new mechanistic insights. Two general approaches have been employed; one approach has been to examine the biological activity of mediators within the mucosal tissue of IBS patients and the other has been to examine changes in the structural properties of key signaling pathways contained within the biopsies. Using these approaches, important changes have been discovered involving the enteric nervous system and the extrinsic sensory pathway (dorsal root ganglia neurons), the immune system, and epithelial signaling in IBS patients compared to healthy subjects. PURPOSE: This review will systematically explore these mechanistic pathways, highlight the implications of these novel findings and discuss some of the important limitations of this approach.
Asunto(s)
Intestinos/patología , Intestinos/fisiopatología , Síndrome del Colon Irritable/patología , Síndrome del Colon Irritable/fisiopatología , Biopsia , Femenino , Humanos , Síndrome del Colon Irritable/etiología , MasculinoRESUMEN
BACKGROUND: In irritable bowel syndrome (IBS), familial clustering and transfer across generations may largely depend on environmental factors but this is difficult to establish in the human setting. Therefore, we aimed to set up a relevant animal model. We investigated whether susceptibility to stress induced visceral hypersensitivity in maternally separated (MS) Long Evans rats can be transferred across generations without further separation protocols and, if so, whether this depends on maternal care. METHODS: At adult age, we evaluated pre- vs post water avoidance (WA) changes in visceromotor response to distension in non-handled second filial generation offspring (NH-F2) of previously separated MS-F1 dams. Furthermore, the role of maternal care was evaluated by cross-fostering F2 offspring of NH-F1 and MS-F1 dams and subsequent sensitivity measurements at adult age. Involvement of mast cells in post stress hypersensitivity of NH-F2 rats was evaluated by mast cell stabilization. KEY RESULTS: In adult NH-F2 offspring of MS-F1 dams, post-WA hypersensitivity to colorectal distension was observed in 80% of rats compared with 19% in offspring of NH-F1 dams. Cross-fostered pups adapted to the phenotype of the foster mother: pups of NH-F1 dams nursed by MS-F1 dams showed post-WA hypersensitivity to distension at adult age and vice versa (100% and 20% respectively). In NH-F2 rats, post-WA hypersensitivity was reversed by mast cell stabilizer doxantrazole. CONCLUSIONS & INFERENCES: Maternal separated-induced susceptibility to stress-triggered visceral hypersensitivity is transferred across generations and this transfer depends on maternal care. Thus, MS is a suitable model to evaluate environmental triggers relevant to IBS clustering in families.
Asunto(s)
Hiperalgesia/etiología , Conducta Materna , Estrés Psicológico/etiología , Animales , Colon/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/fisiopatología , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/genética , Síndrome del Colon Irritable/fisiopatología , Masculino , Mastocitos/fisiología , Linaje , Ratas , Ratas Long-Evans , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Dolor Visceral/fisiopatologíaRESUMEN
BACKGROUND: Acute stress-induced hypersensitivity to colorectal distention was shown to depend on corticotropin releasing factor (CRF)-induced mast cell degranulation. At present it remains unclear whether CRF also induces chronic poststress activation of these cells. Accordingly, the objective of this study was to compare pre- and poststress CRF-receptor antagonist treatment protocols for their ability to, respectively, prevent and reverse mast cell dependent visceral hypersensitivity in a rat model of neonatal maternal separation. METHODS: The visceromotor response to colonic distention was assessed in adult maternally separated and non-handled rats before and at different time points after 1 h of water avoidance (WA). Rats were treated with the mast cell stabilizer doxantrazole and the CRF receptor-antagonist α-helical-CRF (9-41). Western blotting was used to assess mucosal protein levels of the mast cell protease RMCP-2 and the tight junction protein occludin. KEY RESULTS: In maternally separated, but not in non-handled rats, WA induced chronic hypersensitivity (up to 30 days) to colorectal distention. Visceral hypersensitivity was prevented, but could not be reversed by administration of α-helical-CRF (9-41). In contrast, however, the mast cell stabilizer doxantrazole reversed visceral hypersensitivity. Compared with vehicle-treated rats, pre-WA α-helical-CRF (9-41) treated animals displayed higher mucosal RMCP-2 and occludin levels. CONCLUSIONS & INFERENCES: Water avoidance-stress leads to persistent mast cell dependent visceral hypersensitivity in maternally separated rats, which can be prevented, but not reversed by blockade of peripheral CRF-receptors. We conclude that persistent poststress mast cell activation and subsequent visceral hypersensitivity are not targeted by CRF-receptor antagonists.
Asunto(s)
Hormona Liberadora de Corticotropina/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Mastocitos/efectos de los fármacos , Mastocitos/fisiología , Privación Materna , Fragmentos de Péptidos/efectos de los fármacos , Estrés Psicológico , Dolor Visceral/fisiopatología , Animales , Quimasas/metabolismo , Colon/fisiología , Electromiografía , Femenino , Motilidad Gastrointestinal/fisiología , Hiperalgesia/fisiopatología , Mastocitos/citología , Embarazo , Ratas , Ratas Long-Evans , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Early life trauma can predispose to increased visceral pain perception. Human neuroimaging studies emphasize that altered brain processing may contribute to increased visceral sensitivity. The aim of our study was to evaluate brain responses to painful visceral stimuli in maternal-separated rats before and after acute stress exposure in vivo. METHODS: H(2)(15)O microPET scanning was performed during colorectal distention in maternal-separated rats before and after water avoidance stress. Brain images were anatomically normalized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2). Colorectal induced visceral pain was assessed by recording of the visceromotor response using abdominal muscle electromyography. KEY RESULTS: Colorectal distention (1.0-2.0 mL) evoked a volume-dependent increase in visceromotor response in maternal-separated rats. Stress [water avoidance (WA)] induced an increased visceromotor response to colorectal distention in awake and anesthetized rats. In pre-WA rats, colorectal distention evoked significant increases in regional blood flow in the cerebellum and periaquaductal gray (PAG). Colorectal distention post-WA revealed activation clusters covering the PAG as well as somatosensory cortex and hippocampus. At maximal colorectal distention, the frontal cortex was significantly deactivated. CONCLUSIONS & INFERENCES: WA stress induced increased pain perception as well as activation of the somatosensory cortex, PAG, and hippocampus in maternal-separated rats. These findings are in line with human studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans.
Asunto(s)
Encéfalo/fisiopatología , Hiperalgesia/fisiopatología , Intestinos/fisiopatología , Estrés Psicológico/fisiopatología , Dolor Visceral/fisiopatología , Animales , Encéfalo/diagnóstico por imagen , Dilatación Patológica/fisiopatología , Electromiografía , Femenino , Privación Materna , Tomografía de Emisión de Positrones , Ratas , Ratas Long-EvansRESUMEN
Genome wide association studies and meta-analyses identified risk factors related to epithelial integrity of the intestinal barrier, innate immune responses and autophagy in inflammatory bowel disorder (IBD) and celiac disease. Irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder (FGID), coexists and shares common, although milder, features with IBD and celiac disease. Although our knowledge on genetic variability in IBS symptom generation is very limited, smaller scale studies attempt to provide insight in the mechanisms underlying IBS. Camilleri et al. identified associations for susceptibility loci in inflammatory and epithelial barrier genes with colonic transit in lower FGID. Their report is the first descriptive study to assess potential genetic factors involved in motor function. Further exploration of genetic variation in IBS will be crucial to unravel its' pathogenesis.
Asunto(s)
Enfermedades Gastrointestinales/genética , Animales , Enfermedades Gastrointestinales/etiología , HumanosRESUMEN
The enteric nervous system regulates diverse functions including gastrointestinal motility and nociception. The sensory neurons detect mechanical and chemical stimuli while motor neurons control peristalsis and secretion. In addition to this extensive neuronal network, the gut also houses a highly specialised immune system which plays an important role in the induction and maintenance of tolerance to food and other luminal antigens and in the protection of the epithelial barrier against pathogenic invasion. It is now increasingly recognised that the gastrointestinal immune system and the enteric nervous system closely interact. This review will focus on two common functional gastrointestinal disorders in which neuroimmune interaction is involved in the pathophysiology: i.e. postoperative ileus and irritable bowel syndrome. Postoperative ileus arises after almost every abdominal surgical procedure. Handling of the bowel results in local inflammation and activation of inhibitory neuronal pathways resulting in a generalised impairment of gastrointestinal motor function or ileus. On the other hand, postinfectious irritable bowel syndrome (PI-IBS) occurs in 10 to 30% of patients who suffer from infectious gastroenteritis. PI -IBS patients develop abnormal gastrointestinal sensitivity, motility and secretion which contribute to abdominal pain and discomfort, bloating and abnormal bowel function (diarrhoea and/or constipation). Biopsy studies revealed persistent low-grade inflammation and altered immunological function which may lead to abnormal pain perception and motor activity within the gastrointestinal tract.
Asunto(s)
Sistema Nervioso Entérico/inmunología , Ileus/inmunología , Síndrome del Colon Irritable/inmunología , Sistema Nervioso Entérico/fisiología , Gastritis/complicaciones , Gastritis/microbiología , Humanos , Ileus/etiología , Ileus/terapia , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/terapia , Complicaciones PosoperatoriasRESUMEN
BACKGROUND: Functional dyspepsia is one of the most prevalent (15-40%) functional gastrointestinal disorders. Antidepressants such as amitriptyline are often used in these patients, but clinical studies are currently lacking. AIM: To evaluate the effect of 8 weeks of treatment with amitriptyline on drinking capacity, symptoms evoked by a standardised drink test (primary endpoint) and clinical symptoms (secondary endpoint). METHODS: Patients meeting the Rome III criteria for functional dyspepsia (FD) were invited to participate in a double blind, randomised, placebo-controlled trial and were treated with either amitriptyline (12.5-50 mg) or placebo during 8 weeks. All included patients underwent a nutrient drink test before and after treatment. Drinking capacity and evoked symptoms were recorded. In addition, dyspeptic symptoms were weekly assessed using PAGI SYM (patient assessment of upper gastrointestinal symptom severity index) questionnaire. RESULTS: Thirty-eight patients (amitriptyline n=18, placebo n=20; age 41±2year, 61% F) completed the study. The drinking capacity of liquid meal was not affected by either amitriptyline or placebo treatment. Postprandial symptoms were not significantly different between amitriptyline and placebo. During the entire treatment, total symptom score (0.47 points, P=0.02) and nausea (0.86 points, P=0.004) on PAGI SYM were significantly reduced by amitriptyline compared with placebo. CONCLUSIONS: Amitriptyline did not affect drinking capacity and postprandial symptoms evoked by the drink test in FD patients. However, total clinical symptom score and nausea were reduced during 8 weeks of treatment. Our data suggest that amitriptyline particularly improves nausea in functional dyspepsia, but larger clinical trials are needed to further confirm our findings.
Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Amitriptilina/uso terapéutico , Ingestión de Líquidos/efectos de los fármacos , Dispepsia/tratamiento farmacológico , Periodo Posprandial/efectos de los fármacos , Adolescente , Adulto , Anciano , Método Doble Ciego , Dispepsia/fisiopatología , Humanos , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Normal gastrointestinal motility requires intact networks of interstitial cells of Cajal (ICC). Interstitial cells of Cajal numbers are maintained by a balance between cell loss factors and survival/trophic/growth factors. Activation of 5-HT(2B) receptors expressed on ICC increases ICC proliferation in vitro. It is not known whether 5-HT(2B) receptors on ICC are activated in vivo. The aims of this study were to investigate if adult ICC proliferate, whether the proliferation of ICC in vivo is affected by knocking out the 5-HT(2B) receptor, and if alterations in proliferation affect ICC networks. METHODS: Proliferating ICC were identified by immunoreactivity for Ki67 in both the myenteric and deep muscular plexus regions of the jejunum in mice with a targeted insertion of a neomycin resistance cassette into the second coding exon of the htr2b receptor gene. KEY RESULTS: Adult ICC do proliferate. The number of proliferating ICC was lower in the myenteric plexus region of Htr2b(-/-) compared to Htr2b(+/+) mice. The volume of Kit-positive ICC was 30% lower in the myenteric plexus region and 40% lower in the deep muscular plexus region in Htr2b(-/-) mice where the number of ICC was also reduced. CONCLUSIONS & INFERENCES: Interstitial cells of Cajal proliferate in adult mice and activation of 5-HT(2B) receptors results in increased proliferation of ICC in vivo. Furthermore, lack of 5-HT(2B) receptor signaling reduces the density of ICC networks in mature mice. These data suggest that 5-HT(2B) receptor signaling is required for maintenance of ICC networks, adding 5-HT to the growing number of factors shown to regulate ICC networks.