RÉSUMÉ
Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.
Sujet(s)
Axe cerveau-intestin , Période post-prandiale , Humains , Période post-prandiale/physiologie , Axe cerveau-intestin/physiologie , Syndrome du côlon irritable/thérapie , Syndrome du côlon irritable/physiopathologie , Syndrome du côlon irritable/immunologie , Syndrome du côlon irritable/diétothérapie , Dyspepsie/thérapie , Dyspepsie/étiologie , Dyspepsie/physiopathologie , Dyspepsie/immunologie , Douleur abdominale/étiologie , Douleur abdominale/immunologie , Douleur abdominale/thérapie , Douleur abdominale/physiopathologie , Microbiome gastro-intestinal/physiologie , Microbiome gastro-intestinal/immunologieRÉSUMÉ
BACKGROUND: Distinct faecal microbiota profiles are reported to be associated with various subtypes of IBS. Circulating antibodies to cytolethal distending toxin B (CdtB) and vinculin are proposed as biomarkers to identify post-infectious IBS. The aim of our study was to analyse serum levels of anti-CdtB and anti-vinculin antibodies in patients with different functional gastrointestinal disorders (FGID) and their correlation with the composition of faecal microbiome. METHODS: The study cohort comprised 65 prospectively recruited individuals: 15 with diarrhoea-type-IBS (IBS-D), 13 with constipation-type-IBS (IBS-C), 15 with functional dyspepsia (FD) and 22 healthy controls. FGID subgroups were defined according to Rome III criteria. Serum levels of anti-CdtB and anti-vinculin antibodies were measured by ELISA. Faecal microbiome composition analysis and assessment of dysbiosis were performed by GA-map® Dysbiosis Test. RESULTS: Positivity rate either for anti-CdtB or anti-vinculin antibodies was higher in the IBS-C group (76.9%) compared to IBS-D (40.0%), FD (60%) and healthy (63.6%) groups. Dysbiosis was more frequent in subjects positive for anti-CdtB antibodies and in IBS-C patients, who showed an increased amount of opportunistic/pro-inflammatory bacteria and reduced gut protective bacteria. IBS-C patients showed a high inter-individual variation of bacterial communities compared to other FGID subgroups and healthy individuals, whereas microbial profiles of patients with IBS-D and FD were overlapping with those of healthy controls. No bacteria markers showed significant differences between FGID subgroups and healthy controls. CONCLUSION: Neither anti-CdtB/anti-vinculin antibodies nor faecal microbial profiles allowed to discriminate between specific FGID subgroups. Dysbiosis was more frequent in patients presenting with anti-CdtB antibodies and in IBS-C patients.
Sujet(s)
Anticorps antibactériens/immunologie , Autoanticorps/immunologie , Toxines bactériennes/immunologie , Dysbiose/immunologie , Maladies gastro-intestinales/immunologie , Vinculine/immunologie , Adulte , Sujet âgé , Études cas-témoins , Constipation/immunologie , Constipation/microbiologie , Réactions croisées/immunologie , Diarrhée/immunologie , Diarrhée/microbiologie , Dysbiose/microbiologie , Dyspepsie/immunologie , Dyspepsie/microbiologie , Femelle , Maladies gastro-intestinales/microbiologie , Microbiome gastro-intestinal , Humains , Syndrome du côlon irritable/immunologie , Syndrome du côlon irritable/microbiologie , Mâle , Adulte d'âge moyen , Jeune adulteRÉSUMÉ
BACKGROUND & AIMS: Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been investigated systematically. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has not been assessed. METHODS: Duodenal biopsy specimens from FD and control subjects, and peroxisome proliferator-activated receptor-α (PPARα) null mice were cultured at a pH of 3.0 and 7.4. Mast cell (MC) number, the release of their mediators, and the expression of transient receptor potential vanilloid receptor (TRPV)1 and TRPV4, were evaluated. All measurements also were performed in the presence of a selective blocker of neuronal action potential (tetradotoxin). FD and control biopsy specimens in acidified medium also were incubated in the presence of different PEA concentrations, alone or combined with a selective PPARα or PPAR-γ antagonist. RESULTS: An acid-induced increase in MC density and the release of their mediators were observed in both dyspeptic patients and controls; however, this response was amplified significantly in FD. This effect was mediated by submucosal nerve fibers and up-regulation of TRPV1 and TRPV4 receptors because pretreatment with tetradotoxin significantly reduced MC infiltration. The acid-induced endogenous release of PEA was impaired in FD and its exogenous administration counteracts MC activation and TRPV up-regulation. CONCLUSIONS: Duodenal acid exposure initiates a cascade of neuronal-mediated events culminating in MC activation and TRPV overexpression. These phenomena are consequences of an impaired release of endogenous PEA. PEA might be regarded as an attractive therapeutic strategy for the treatment of FD.
Sujet(s)
Amides/métabolisme , Duodénum/anatomopathologie , Dyspepsie/immunologie , Éthanolamines/métabolisme , Muqueuse intestinale/anatomopathologie , Mastocytes/immunologie , Acides palmitiques/métabolisme , Adulte , Amides/administration et posologie , Animaux , Biopsie , Études cas-témoins , Modèles animaux de maladie humaine , Duodénum/composition chimique , Duodénum/immunologie , Duodénum/métabolisme , Dyspepsie/génétique , Dyspepsie/métabolisme , Dyspepsie/anatomopathologie , Éthanolamines/administration et posologie , Femelle , Acide gastrique/métabolisme , Volontaires sains , Humains , Concentration en ions d'hydrogène , Muqueuse intestinale/composition chimique , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Mâle , Mastocytes/métabolisme , Souris , Souris knockout , Adulte d'âge moyen , Récepteur PPAR alpha/génétique , Récepteur PPAR alpha/métabolisme , Acides palmitiques/administration et posologie , Canaux cationiques TRPV/métabolisme , Techniques de culture de tissusRÉSUMÉ
BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.
Sujet(s)
Maladies du duodénum/traitement médicamenteux , Duodénum/effets des médicaments et des substances chimiques , Dyspepsie/traitement médicamenteux , Éosinophilie/traitement médicamenteux , Maladies inflammatoires intestinales/traitement médicamenteux , Muqueuse intestinale/effets des médicaments et des substances chimiques , Mastocytes/effets des médicaments et des substances chimiques , Pantoprazole/usage thérapeutique , Inhibiteurs de la pompe à protons/usage thérapeutique , Adulte , Belgique , Acides et sels biliaires/métabolisme , Études cas-témoins , Maladies du duodénum/diagnostic , Maladies du duodénum/immunologie , Maladies du duodénum/métabolisme , Duodénum/immunologie , Duodénum/métabolisme , Dyspepsie/diagnostic , Dyspepsie/immunologie , Dyspepsie/métabolisme , Éosinophilie/diagnostic , Éosinophilie/immunologie , Éosinophilie/métabolisme , Femelle , Humains , Médiateurs de l'inflammation/métabolisme , Maladies inflammatoires intestinales/diagnostic , Maladies inflammatoires intestinales/immunologie , Maladies inflammatoires intestinales/métabolisme , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Mâle , Mastocytes/immunologie , Mastocytes/métabolisme , Pantoprazole/effets indésirables , Perméabilité , Études prospectives , Inhibiteurs de la pompe à protons/effets indésirables , Facteurs temps , Résultat thérapeutiqueRÉSUMÉ
Se determinó la respuesta inmunológica a proteínas recombinantes de Helicobacter pylori en pacientes dis-pépticos (adultos y niños), pacientes con cáncer gástrico y sus familiares asintomáticos adultos viviendo con ellos. Se utilizó la prueba recomLine® Helicobacter IgG e IgA, y con base en el reconocimiento de los factores de virulencia VacA y CagA se determinó si la cepa de H. pylori era de tipo I o II. El análisis de los datos fue descriptivo y analítico y se estimaron los intervalos de confianza de 95%, con un nivel de error de 0.05 y Odds ratio. El 58.7% (121/206) de los pacientes presentó la bacteria en tinción histológica de biopsia, positividad que disminuyó con la edad y daño histológico. La frecuencia de la respuesta a los anticuerpos IgG fue mayor que IgA, en ambos casos ésta fue menor en los niños. Las proteínas del H. pylori más reconocidas tanto por IgA como IgG fueron VacA y CagA, y la respuesta a las otras proteínas investigadas fue mayor al aumentar el daño histológi-co. La cepa tipo I fue la que predominó en la población en estudio con 66% (136/206). Se deben continuar con los estudios de prevalencia de la cepa tipo I del H. pylori y del reconocimiento de sus antígenos en la población guatemalteca a fin de determinar su utilidad en el diagnóstico y pronóstico de la infección.
The immune response to recombinant Helicobacter pylori proteins was determined in dyspeptic patients (adults and children), patients with gastric cancer and their asymptomatic adults' relatives living with them. The recomLine® Helicobacter IgG and IgA test was used and based on the recognition of the virulence factors VacA and CagA, it was determined whether the H. pylori strain was type I or II. The data analysis was descriptive and analytic, and 95% confidence intervals were estimated, with an error level of 0.05, and Odds ratio. The patients that presented the bacterium in histological biopsy were 58.7% (121/206), positivity that decreased with age and histological damage. The frecuency of response to IgG antibodies was higher than IgA, in both cases it was lower in children. VacA and CagA were the H. pylori proteins most recognized by both IgA and IgG and it was observed that the number of recognized proteins was greater with increasing histological damage. The type I strain was the one that predominated in the study population 66% (136/206). Prevalence studies of the type I strain of H. pylori ant the recognition of its antigens in the Guatemalan population should continue in order to determine its usefulness in the diagnosis and prognosis of infection.
Sujet(s)
Humains , Enfant , Adulte , Tumeurs de l'estomac/immunologie , Immunoglobuline A/immunologie , Immunoglobuline G/immunologie , Helicobacter pylori/immunologie , Dyspepsie/immunologie , Tumeurs de l'estomac/microbiologie , Tumeurs de l'estomac/anatomopathologie , Biopsie , Protéines recombinantes/analyse , Protéines recombinantes/immunologie , Immunoglobuline A/analyse , Immunoglobuline G/analyse , Helicobacter pylori/isolement et purification , Helicobacter pylori/pathogénicité , Dyspepsie/microbiologie , Dyspepsie/anatomopathologie , GuatemalaRÉSUMÉ
PURPOSE OF REVIEW: Functional dyspepsia (FD) is a chronic functional gastrointestinal disorder characterised by upper gastrointestinal symptoms. Here, we aimed to examine the evidence for immune responses to food in FD and overlap with food hypersensitivity conditions. RECENT FINDINGS: A feature of FD in a subset of patients is an increase in mucosal eosinophils, mast cells, intraepithelial cytotoxic T cells and systemic gut-homing T cells in the duodenum, suggesting that immune dysfunction is characteristic of this disease. Rates of self-reported non-celiac wheat/gluten sensitivity (NCW/GS) are higher in FD patients. FD patients commonly report worsening symptoms following consumption of wheat, fermentable oligosaccharides, disaccharides, monosaccharides, or polyols (FODMAPs), high-fat foods and spicy foods containing capsaicin. Particularly, wheat proteins and fructan in wheat may drive symptoms. Immune mechanisms that drive responses to food in FD are still poorly characterised but share key effector cells to common food hypersensitivities including non-IgE-mediated food allergy and eosinophilic oesophagitis.
Sujet(s)
Dyspepsie/immunologie , Hypersensibilité alimentaire/immunologie , Aliments/effets indésirables , Muqueuse intestinale/immunologie , Capsaïcine/immunologie , Matières grasses alimentaires/immunologie , Diholoside/immunologie , Duodénum/immunologie , Duodénum/anatomopathologie , Dyspepsie/anatomopathologie , Humains , Immunoglobuline E/immunologie , Muqueuse intestinale/anatomopathologie , Oses/immunologie , Oligosaccharides/immunologie , Polymères , Triticum/immunologieRÉSUMÉ
BACKGROUND: Chronic gastritis is a common histologic finding in children with functional dyspepsia (FD). While Th17 cells have been implicated in other forms of gastritis, they have not been evaluated in chronic gastritis. AIMS: The aim of the current study was to assess Th17 cells in children with FD with and without chronic gastritis. METHODS: Densities were determined for Th17 cells, eosinophils, and mast cells, respectively, in both the gastric antrum and the duodenum. Densities were compared between five groups: FD with chronic gastritis (N = 20), FD without chronic gastritis (N = 20), Helicobacter pylori-associated gastritis (N = 10), Crohn's gastritis (N = 10), and normal controls (N = 10). Th17 densities were also compared between patients with and without early satiety. RESULTS: FD with chronic gastritis was associated with higher Th17 cell density as compared to normal controls and comparable to both H. pylori-associated gastritis and Crohn's gastritis. Eosinophil and mast cell densities were higher in FD patients with chronic gastritis as compared to either FD without gastritis or normal controls. Th17 density was higher in patients reporting early satiety but not in those with epigastric pain. CONCLUSIONS: FD with chronic gastritis is associated with higher Th17 cell, eosinophil, and mast cell density as compared to FD without chronic gastritis or normal controls. Chronic gastritis demonstrated Th17 cell density similar to that seen in other conditions where Th17 cells are believed to play a pathogenic role. Th17 cells may represent another therapeutic target in these patients.
Sujet(s)
Dyspepsie/immunologie , Muqueuse gastrique/cytologie , Muqueuse gastrique/immunologie , Gastrite/immunologie , Cellules Th17 , Adolescent , Numération cellulaire , Enfant , Maladie chronique , Maladie de Crohn/immunologie , Granulocytes éosinophiles/immunologie , Femelle , Infections à Helicobacter/immunologie , Helicobacter pylori , Humains , Mâle , Mastocytes/immunologie , Études rétrospectivesRÉSUMÉ
BACKGROUND: It is unexplained why functional dyspepsia and gastro-oesophageal reflux disease (GERD) overlap more often than expected by chance. Post-prandial distress syndrome has been linked to impaired gastric fundic accommodation which may induce increased transient lower oesophageal sphincter relaxations and consequent GERD. Duodenal eosinophilia has been linked to functional dyspepsia and post-prandial distress syndrome. AIM: To identify if there is an association between duodenal eosinophilia in functional dyspepsia and symptoms of GERD and whether post-prandial distress syndrome or epigastric pain syndrome are associated with new onset GERD. METHODS: Participants (n = 1000) were randomly selected from the national Swedish population register and surveyed by questionnaires and oesophagogastroduodenoscopy in 1999-2001. All eligible subjects (n = 887) were invited to a follow-up study in 2010 (response rate 79%). In a case-control study of 213 subjects (functional dyspepsia vs healthy controls), histology from the duodenum was evaluated at baseline and the possible association of eosinophilia to new onset GERD symptoms was analysed. RESULTS: Functional dyspepsia (OR 7.6; 95% CI 2.93-19.4, P < 0.001) and post-prandial distress syndrome at baseline (OR 9.0, 95% CI 3.36-24.0, P < 0.001) were associated with an increased risk of GERD at follow-up. Eosinophilia in the second part of duodenum only was independently associated with an increased risk of GERD amongst those with functional dyspepsia (OR 4.2; 95% CI 1.2-4.77, P = 0.024) and post-prandial distress syndrome at baseline (OR 6.0; 95% CI 1.50-23.6, P = 0.011), respectively. CONCLUSIONS: Duodenal eosinophilia is associated with increased risk of GERD at 10-year follow-up in those with functional dyspepsia and post-prandial distress syndrome at baseline. Duodenal eosinophilia may explain the link between GERD and functional dyspepsia, suggesting subsets of functional dyspepsia and GERD may be part of the same disease spectrum.
Sujet(s)
Douleur abdominale/épidémiologie , Duodénum , Dyspepsie/épidémiologie , Éosinophilie/épidémiologie , Reflux gastro-oesophagien/épidémiologie , Douleur abdominale/immunologie , Douleur abdominale/anatomopathologie , Douleur abdominale/physiopathologie , Études cas-témoins , Duodénum/immunologie , Duodénum/anatomopathologie , Duodénum/physiopathologie , Dyspepsie/immunologie , Dyspepsie/anatomopathologie , Dyspepsie/physiopathologie , Éosinophilie/immunologie , Éosinophilie/anatomopathologie , Éosinophilie/physiopathologie , Femelle , Études de suivi , Reflux gastro-oesophagien/immunologie , Reflux gastro-oesophagien/anatomopathologie , Reflux gastro-oesophagien/physiopathologie , Humains , Mâle , Adulte d'âge moyen , Enquêtes et questionnaires , Suède/épidémiologieRÉSUMÉ
BACKGROUND: Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation. METHODS: Seven literature databases were searched using the keywords: 'functional gastrointestinal disorder', FGID, 'functional dyspepsia', 'non-ulcer dyspepsia', 'idiopathic dyspepsia', 'irritable bowel syndrome', IBS and 'immun*'. RESULTS: Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating α4+ß7+ gut-homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS. CONCLUSIONS: Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs.
Sujet(s)
Lymphocytes B/immunologie , Dyspepsie/immunologie , Éosinophilie/immunologie , Syndrome du côlon irritable/immunologie , Mastocytes/immunologie , Lymphocytes T/immunologie , Côlon/immunologie , Duodénum/immunologie , Maladies gastro-intestinales/immunologie , Humains , Activation des lymphocytes/immunologie , Numération des lymphocytes , Cellules Th17 , Lymphocytes auxiliaires Th2RÉSUMÉ
Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body's stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.
Sujet(s)
Corticolibérine/métabolisme , Dyspepsie/immunologie , Dyspepsie/métabolisme , Muqueuse gastrique/métabolisme , Mastocytes/cytologie , Animaux , Comportement animal , Numération cellulaire , Corticolibérine/déficit , Corticolibérine/génétique , Modèles animaux de maladie humaine , Dyspepsie/anatomopathologie , Dyspepsie/physiopathologie , Muqueuse gastrique/effets des médicaments et des substances chimiques , Transit gastrointestinal/effets des médicaments et des substances chimiques , Hypothalamus/effets des médicaments et des substances chimiques , Hypothalamus/métabolisme , 2-Iodo-acétamide/pharmacologie , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Mâle , Mastocytes/effets des médicaments et des substances chimiques , Interférence par ARN , Rats , Rat Sprague-Dawley , Récepteur CRH/métabolisme , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
INTRODUCTION: Functional dyspepsia (FD) is widespread with 20% prevalence worldwide and a significant economic burden due to health care cost and constraints on daily activities of patients. Despite extensive investigation, the underlying causes of dyspepsia in a majority of patients remain unknown. Common complaints include abdominal discomfort, pain, burning, nausea, early satiety, and bloating. Motor dysfunction of the gut was long considered a major cause, but recent investigations suggest immune-based pathophysiological and molecular events in the duodenum are more probable contributing factors. Areas Covered: Inflammatory mediators and immune cells including duodenal eosinophils, intraepithelial lymphocytes, and T-cells have been implicated in the underlying cause of disease process, as have genetic factors. In this article, we critically reviewed findings, identified gaps in knowledge and suggested future directions for further investigation to identify targets and develop better therapeutic approaches. Expert commentary: Impaired gastric accommodation, slow gastric emptying, and increased visceral sensitivity have long been thought of as main causal factors of FD. However, more recent identification of eosinophilic degranulation and recruitment of T cells that induce mild duodenal inflammation are giving rise to new insights into immune-mediated pathophysiology. These insights offer promising avenues to explore for immune-mediated therapy in the future.
Sujet(s)
Dyspepsie/immunologie , Dyspepsie/anatomopathologie , Dyspepsie/thérapie , HumainsRÉSUMÉ
BACKGROUND AND PURPOSE: Functional dyspepsia (FD) is a gastrointestinal disorder of unknown etiology. Although micro-inflammation appears to be important in the pathogenesis, studies evaluating immune activation in FD have been inconsistent. A systematic review of literature and meta-analysis was performed to compare immunologic cell counts and cytokine levels in the mucosa and peripheral blood of individuals with FD and healthy controls. PubMed, Embase, and the Cochrane library were searched. Data on immunologic cell counts and cytokines levels among individuals with FD and control groups were extracted and compared by calculating standard mean differences (SMD). Thirty-seven studies met the inclusion criteria. Mast cell (SMD = 0.94, 95%CI 0.26-1.62, P = .007) and eosinophil counts (SMD = 0.36, 95%CI 0.06-0.68, P = .03) in the stomach were increased, among individuals with FD compared to controls. Similarly, mast cell (SMD = 0.66, 95%CI 0.20-1.13, P = 0.005) and eosinophil (SMD = 0.95, 95%CI 0.66-1.24; P < .001) counts in the duodenum were also increased in those with FD compared to controls. In a subgroup analysis, elevated eosinophil counts in the duodenum were observed in both post-prandial distress syndrome (SMD = 0.97, 95%CI 0.46-1.47, P = .0002) and epigastric pain syndrome subtypes (SMD = 1.16, 95%CI 0.48-1.83, P = .0008). No differences in mucosal intraepithelial lymphocyte, enterochromaffin cell, and neutrophil counts, as well as, peripheral interlukin-6 (IL-6) and IL-10 levels were observed among individuals with FD and controls. Micro-inflammation in the form of local immune cell infiltration, particularly eosinophils and mast cells, characterizes the pathogenesis of FD.
Sujet(s)
Dyspepsie/immunologie , Inflammation/immunologie , Duodénum/immunologie , Dyspepsie/sang , Dyspepsie/complications , Granulocytes éosinophiles/immunologie , Humains , Inflammation/sang , Inflammation/complications , Médiateurs de l'inflammation/sang , Médiateurs de l'inflammation/immunologie , Mastocytes/immunologieRÉSUMÉ
BACKGROUND: The role of immune activation in Functional Dyspepsia (FD) patients without previous infection is unclear. We compare the gastric and circulating brain-derived neurotropic factor (BDNF), receptor potential vanilloid type (TRPV) families and various cytokines in FD patients. METHODS: Consecutive adult FD patients (Rome III) with no recent history of gastroenteritis and asymptomatic healthy controls were recruited for upper endoscopy. Subjects with GERD and IBS as predominant symptoms, diabetes mellitus, current or previous Helicobacter pylori infection, psychiatric illness and recent use of NSAID or PPI were excluded. Corpus biopsies and serum samples were collected. KEY RESULTS: Forty three [M:F=8:35, mean age: 35.0 (9.3)] FD patients were compared with 23 healthy controls [M:F=8:15, mean age: 36.6 (10.2)]. FD patients had postprandial distress syndrome (PDS) as predominant sub-type (PDS: 36, EPS: 2). There was no significant difference in the median inflammation score (FD:0 (0-1) vs Control:0 (0-1), P=.79). However, FD patients had significantly higher mRNA expression of TRPV1 (FD:0.014±0.007, Control:0.003±0.001, 4.6 fold, P=.02) and TRPV2 (FD:0.012±0.006, Control:0.003±0.001, 4 fold, P=.02) compared to controls. The serum (FD:258.0±12.3 ng ml-1 , Control:319.7±18.1 ng ml-1 , P<.01) and gastric BDNF mRNA (FD:0.06±0.008, Control:0.092±0.01, 0.65 fold, P=.02)levels significantly lower in FD patients. Secretion of cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, G-CSF, TGF-ß2, MCP-1)was also highly correlated with dyspeptic symptoms in patients with FD. CONCLUSIONS & INFERENCES: Despite lacking gastric mucosal inflammation, up-regulation of TRPV1 and TRPV2, down-regulation of BDNF were observed in FD patients. These suggest that immune alteration may contribute to the pathogenesis of FD without any previous infection.
Sujet(s)
Facteur neurotrophique dérivé du cerveau/métabolisme , Dyspepsie/immunologie , Dyspepsie/métabolisme , Canaux cationiques TRPV/métabolisme , Adulte , Cytokines/métabolisme , Dyspepsie/complications , Femelle , Humains , Inflammation/complications , Inflammation/immunologie , Inflammation/métabolisme , Mâle , ARN messager/métabolisme , Contrôle social formel , Régulation positiveRÉSUMÉ
Functional dyspepsia is a highly prevalent disease, with significant impacts on patients' quality of life and economic robustness of health care systems worldwide. It constitutes a constellation of symptoms located in the gastro duodenal region while its pathogenesis remains poorly understood. Accumulating evidence suggest that small intestinal bacterial overgrowth is associated with the etiology of functional gastrointestinal disorders. We herein present the hypothesis that a causal link between small intestinal bacterial overgrowth and functional dyspepsia might exist. Development of functional dyspepsia symptoms may derive from abnormal fermentation of carbohydrates due to increased proliferation of coliform bacteria, resulting in luminal distension, increased intestinal permeability and immune response perpetuation in predisposed hosts, secondary to an episode of infectious gastroenteritis. Moreover, the treatment of functional dyspepsia remains challenging and we explore the feasibility of innovative therapeutic modalities based on our hypothesis.
Sujet(s)
Dyspepsie/étiologie , Intestin grêle/microbiologie , Infections bactériennes/complications , Métabolisme glucidique , Dyspepsie/immunologie , Dyspepsie/microbiologie , Enterobacteriaceae/croissance et développement , Enterobacteriaceae/immunologie , Enterobacteriaceae/métabolisme , Fermentation , Gastroentérite/complications , Microbiome gastro-intestinal/immunologie , Motilité gastrointestinale , Humains , Modèles biologiques , PerméabilitéRÉSUMÉ
BACKGROUND: Regulatory T Cells (Tregs) and Myeloid-Derived Suppressor Cells (MDSCs) are two main regulatory cells modulating the immune responses in inflammation and cancer. OBJECTIVE: To investigate and compare Tregs and MDSCs in peptic ulcer and gastric cancer. METHODS: Patients with dyspepsia were selected and divided into three groups of non-ulcer dyspepsia (NUD, n=22), peptic ulcer disease (PUD, n=25), and gastric cancer (GC, n=27) according to their endoscopic and histopathological examinations. Helicobacter pylori infection was diagnosed by rapid urease test and histopathology. The number of peripheral blood CD4+CD25+FoxP3+Tregs and CD14+HLA-DR- MDSCs were determined in all patients, by flow cytometry. The number of FoxP3+ regulatory T cells was also determined by immunohistochemistry (IHC). RESULTS: The percentage of peripheral blood Treg cells in both PUD (0.81 ± 0.39, p<0.001) and GC groups (0.98 ± 0.65, p<0.001) were significantly higher than in NUD group (0.46 ± 0.10). These results were also confirmed by IHC. A significantly higher percentage of MDSCs in patients with PUD (0.73 ± 0.19, p<0.001) and GC (0.73 ± 0.16, p<0.001) was also observed when compared to NUD group (0.46 ± 0.16). There was no difference in the percentages of these two cell types between the PUD and GC groups. The percentages of Tregs and MDSCs in patients with PUD and GC were not significantly correlated. CONCLUSIONS: Both Tregs and MDSCs showed higher frequencies in PUD and GC. These results suggest that immune-modulation by the Tregs and MDSCs may play a role in the pathogenesis of PUD and GC.
Sujet(s)
Dyspepsie/immunologie , Cellules myéloïdes suppressives/immunologie , Ulcère peptique/immunologie , Tumeurs de l'estomac/immunologie , Lymphocytes T régulateurs/immunologie , Adulte , Sujet âgé , Femelle , Facteurs de transcription Forkhead/métabolisme , Humains , Immunomodulation , Sous-unité alpha du récepteur à l'interleukine-2/métabolisme , Antigènes CD14/métabolisme , Mâle , Adulte d'âge moyenRÉSUMÉ
Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori-infected dyspeptic patients with IgAD. Case samples were drawn from all subjects ≥ 12 years of age (n = 104729) who had undergone serum total IgA measurements during 2004-14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA < 0·07 g/l. The control group was comprised of a random sample of remaining patients with a case-control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD-9-CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24·2%) versus 821 (23·6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori-positive subjects [59 (17·1%) versus 524 (15·1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61·9%) versus 38 (21·6%), P < 0·001), duodenal ulcers [seven (33·3%) versus 19 (10·8%); P = 0·01] and nodular lymphoid hyperplasia (NLH) [two (9·5%) versus none; P = 0·011]. IgAD is not associated with increased prevalence of H. pylori-associated dyspepsia; nevertheless, H. pylori-infected dyspeptic IgAD subjects experience more EGD-proved gastritis, duodenal ulcers and NLH.
Sujet(s)
Hyperplasie lymphoïde angiofolliculaire/diagnostic , Ulcère duodénal/diagnostic , Dyspepsie/diagnostic , Gastrite/diagnostic , Infections à Helicobacter/diagnostic , Déficit en IgA/diagnostic , Adolescent , Adulte , Sujet âgé , Études cas-témoins , Hyperplasie lymphoïde angiofolliculaire/complications , Hyperplasie lymphoïde angiofolliculaire/immunologie , Enfant , Bases de données factuelles , Ulcère duodénal/complications , Ulcère duodénal/immunologie , Dyspepsie/immunologie , Dossiers médicaux électroniques , Gastrite/complications , Gastrite/immunologie , Infections à Helicobacter/complications , Infections à Helicobacter/immunologie , Helicobacter pylori/croissance et développement , Helicobacter pylori/immunologie , Humains , Déficit en IgA/complications , Déficit en IgA/immunologie , Immunoglobuline A/sang , Israël , Adulte d'âge moyenRÉSUMÉ
Dietary antigens are normally rendered nonimmunogenic through a poorly understood "oral tolerance" mechanism that involves immunosuppressive regulatory T (Treg) cells, especially Treg cells induced from conventional T cells in the periphery (pTreg cells). Although orally introducing nominal protein antigens is known to induce such pTreg cells, whether a typical diet induces a population of pTreg cells under normal conditions thus far has been unknown. By using germ-free mice raised and bred on an elemental diet devoid of dietary antigens, we demonstrated that under normal conditions, the vast majority of the small intestinal pTreg cells are induced by dietary antigens from solid foods. Moreover, these pTreg cells have a limited life span, are distinguishable from microbiota-induced pTreg cells, and repress underlying strong immunity to ingested protein antigens.
Sujet(s)
Protéines alimentaires/immunologie , Dyspepsie/immunologie , Microbiome gastro-intestinal/immunologie , Intestin grêle/immunologie , Intestin grêle/microbiologie , Lymphocytes T régulateurs/immunologie , Animaux , Antigènes/immunologie , Régime alimentaire , Axénie , Tolérance immunitaire , Immunité muqueuse , Activation des lymphocytes , Souris , Souris de lignée C57BLRÉSUMÉ
Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia.