Anti-inflammatory properties of the vagus nerve: therapeutic implications in gastroenterology

Le nerf vague assure la liaison entre le système nerveux central et le tube digestif. C’est un nerf mixte comprenant 80 % de fibres afférentes et 20 % de fibres efférentes. Il a des propriétés anti-inflammatoires à la fois via ses fibres afférentes capables d’activer l’axe corticotrope en réponse à un stress immunitaire et, de découverte plus récente, via ses fibres efférentes. En effet, la libération d’acétylcholine à l’extrémité de ses fibres efférentes est capable d’inhiber la libération de TNF par les macrophages. Cette propriété anti-TNF du nerf vague peut être utilisée dans le traitement des maladies inflammatoires chroniques de l’intestin mais également dans la polyarthrite rhumatoïde. La neurostimulation vagale peut avoir un intérêt dans cette approche thérapeutique non médicamenteuse en alternative aux anti-TNF conventionnels ou en alternative aux thérapies médicamenteuses.The vagus nerve is the link between the central nervous system and the digestive tract. It is a mixed nerve composed of 80% and 20% of afferent and efferent fibers respectively. The vagus nerve has anti-inflammatory properties both through its afferents, through the hypothalamic-pituitary adrenal axis, and more recently described, through its efferents. Indeed, the release of acetylcholine at the distal end of the vagus nerve is able to inhibit the release of TNF by macrophages. This anti-TNF effect could be used in the treatment of inflammatory bowel diseases but also rheumatoid arthritis. Vagus nerve stimulation may be of interest as a non-drug therapy in alternative to conventional anti-TNF or to drug therapies

Psychological adjustment and autonomic disturbances in inflammatory bowel diseases and irritable bowel syndrome.: Psychological and autonomic dysfunctions in IBD and IBS

International audiencePsychological factors and the autonomic nervous system (ANS) are implicated in the pathogenesis of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). This study aimed to assess, firstly the way IBS and IBD patients cope with their pathology according to their affective adjustment and secondly the possible links between these affective adjustments and ANS reactivity. Patients with Crohn's disease (CD; n=26), ulcerative colitis (UC; n=22), or IBS (n=27) were recruited and compared to 21 healthy subjects based on psychological variables (trait- and state anxiety, depressive symptomatology, negative mood, perceived stress, coping, health locus of control) and sympatho-vagal balance through heart-rate variability monitored at rest. A principal component analysis, performed on all affective variables, isolated a leading factor labelled as "affective adjustment". In each disease, patients were distributed into positive and negative affective adjustment. In all the diseases, a positive affect was associated with problem-focused coping, and a negative affect with emotion-focused coping and external health locus of control. Results show that the sympatho-vagal balance varied according to the disease. In CD presenting positive affectivity, an adapted high sympathetic activity was observed. In UC, a parasympathetic blunt was observed in the presence of negative affectivity and an equilibrated sympatho-vagal balance in the presence of positive affectivity. In contrast, in IBS, an important dysautonomia (with high sympathetic and low parasympathetic tone) was constantly observed whatever the affective adjustment. In conclusion, this study suggests that the equilibrium of the ANS is differentially adapted according to the disease. This equilibrium is conjugated with positive affective and cognitive adjustment in IBD (CD and UC) but not in IBS

Coastal Landscape and Public Use. A Landscape Architecture Proposal for the Los Limites Beach, Chubut, Argentina

Along the Argentinian Patagonia Coast private urbanization develops over public beach areas. This study presents the case of an area called Los Limites Beach situated along the Patagonian coast. After an analysis, survey and diagnosis of natural and social features, a landscape project was developed having the objective to protect Patagonian coastal landscape identity, preserving its natural components and encouraging its public use

Validation of a Piles Dynamic Analysis Computer Code Through In Situ Tests

In order to qualify the CLAPIFOU code, which computes the dynamic response of a pile foundation subjected to earthquake or harmonic forces, a test campaign was carried out on piles, to full scale, on pile groups of 2 x 1 piles and 2 x 3 piles on the Plancoet site. The purpose of the study is to compare the results of the experiments and the digital simulations with the computer code. The comparison is good but confirms the need for a good knowledge of the soil\u27s characteristics

The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis

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Relations neurodigestives et stimulation vagale basse-fréquence chez le rat anesthésié (implications du système nerveux central et du système immunitaire)

IntroductionLa neurostimulation vagale (NSV) à haute fréquence (30 Hz) est utilisée commethérapeutique de certaines formes d épilepsie et de dépression réfractaires aux traitements chezl Homme. De plus, la NSV à basse fréquence (5 Hz) a été expérimentée avec succès chez l animalpour traiter différentes inflammations périphériques, notamment digestives. Des travaux récents ontmis en évidence que cet effet anti-inflammatoire est induit par l activation des fibres efférentesvagales, libérant en périphérie de l acétylcholine, inhibant la sécrétion des cytokines proinflammatoires.Cette voie est connue sous le nom de voie anti-inflammatoire cholinergique.Toutefois, le mécanisme d action de la NSV 5 Hz reste mal connu et d autres voies pourraient êtremises en jeu impliquant le système nerveux central (SNC) et le système immunitaire périphérique.ButLes travaux réalisés ont eu pour objectif d étudier l implication du SNC et du systèmeimmunitaire dans la modulation de l inflammation induite par la NSV basse fréquence chez unmodèle de rat anesthésié. Tout d abord, afin d étudier l implication du SNC lors de la NSV 5 Hz, uneétude d imagerie par résonance magnétique fonctionnelle (IRMf) a été réalisée sur le rat sain anesthésié. Ensuite, une étude a été effectuée sur l effet de la NSV sur les cellules immunitairesspléniques ainsi que sur le tube digestif chez un modèle de rat sain puis chez un modèle de ratatteint d une colite expérimentale induite par une injection intra-colique d acide trinitrobenzènesulfonique (TNBS).RésultatsLes données obtenues lors de l étude d IRMf ont mis en évidence un rôle important desfibres afférentes vagales; elles modulent certaines structures du SNC qui pourraient participer à larégulation de l inflammation digestive induite par la NSV 5 Hz. Les études réalisées sur les souspopulationslymphocytaires spléniques ont révélé que d autres cellules immunitaires que lesmacrophages étaient impliquées lors de la NSV. Chez le modèle de rat sain , les résultats decytométrie en flux ont montré que la NSV 3h 5 Hz induisait une diminution de l activation deslymphocytes T CD4 ainsi que du pourcentage de NKT par rapport aux lymphocytes T. Ces résultatssont en faveur d un rôle de la NSV 3h inhibant l activation lymphocytaire et jouant un rôle sur les NKTpossédant des propriétés immunorégulatrices. La NSV 3h n a pas le même effet chez le modèle de ratprésentant une colite. En effet, le dosage de cytokines sécrétées par les splénocytes en culturemontre que la NSV augmente le potentiel de sécrétion d IL-10 (cytokine anti-inflammatoire) dessplénocytes et plus particulièrement des lymphocytes T CD4 spléniques. Parallèlement, l effet antiinflammatoirede la NSV a été mis en évidence au niveau du côlon transverse (au-dessus de la zonelésée) par une diminution des ARNm de SOCS3 et du TNF-a et de la myéloperoxidase. Ces donnéesont démontré un rôle de la NSV sur la fonctionnalité des lymphocytes T CD4 spléniques. La NSV 3h 5Hz orienterait la réponse immunitaire vers une réponse anti-inflammatoire en phase d initiationd inflammation digestive. De plus, l effet anti-inflammatoire de la NSV est retrouvé au niveau du tubedigestif au-dessus de la zone lésée (côlon transverse).ConclusionCes données expérimentales montrent que d autres voies impliquant différents typescellulaires sont susceptibles d être mises en oeuvre par la NSV basse fréquence. Elle induitl implication du SNC par l activation des afférences vagales et des cellules immunitaires spléniquestelles que les lymphocytes T CD4 et les NKT. Un effet anti-inflammatoire de la NSV est retrouvé auniveau du côlon transverse, mais pas au niveau des lésions dans le côlon distal. Ces résultatsprésentent des implications thérapeutiques : la NSV basse fréquence est actuellement en essaiclinique pour être utilisée comme traitement dans la maladie de Crohn.Introduction High frequency(30 Hz)vagus nerve stimulation(VNS)has been approved as a treatment for some types of epilepsy and depression in humans. Low-frequency (5 Hz)VNS has also been successful for the treatment of different animal inflammation models, notably digestive inflammation. Recent studies have shown that the anti-inflammatory effect is induced by the activation of the efferent vagal fibers, which secrete acetylcholine in periphery. It links itself to a-7-nicotinic receptors on the macrophages surface, inhibiting the release of pro-inflammatory cytokines. This pathway is known by the name of the cholinergic anti-inflammatory pathway. However, the mechanism of action of low-frequency VNS remains unclear and other pathways could be involved implicating the central nervous system (CNS) and the immune system. Aim The aim of this study was to evaluate the implication of the CNS and the immune system in the modulation of inflammation induced by low-frequency VNS in an anaesthetized rat model. Firstly, to study the implication of the CNS and the contribution of the afferent vagal fibers during 5Hz VNS, a study using functional magnetic resonance imaging (fMRI) on a healthy anaesthetized rat model was carried out. Secondly, an experiment on the effect of VNS on splenic immune cells as well as on the digestive tract was fulfilled on a healthy rat model followed by a study on a rat model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). Results fMRI data brought to light an important role of the afferent vagal fibers. They modulate some structures of the CNS which could contribute to the modulation of digestive inflammation by 5Hz VNS. The studies carried out by FACS on the sub-populations of splenic lymphocytes revealed that other immune cells than macrophages could be implicated by VNS. In the healthy rat model, with no digestive inflammation, FACS data show that 3h VNS decreases T CD4 lymphocytes activation and the percentage of NKT in relation to T lymphocytes. These data are in favor of an inhibiting role of VNS on lymphocytes activation and also has an impact on NKT cells which have immunoregulatory properties. 3h VNS does not have the same effect on the rat model of colitis. In fact, the quantification of secreted cytokines by cultured splenocytes show that VNS increases the potential of IL-10(anti-iflammatory)cytokine by splenocytes and particularly splenic T CD4 lymphocytes. In the same way, the anti-inflammatory effect of VNS is seen in the transverse colon (above the lesions): decrease of TNF-a and SOCS3 mRNA and of myeloperoxidase. These results show a role of VNS on the functionality of splenic T CD4 lymphocytes inducing an important secretion of IL-10. 3h low-frequency VNS turns the immune response towards an anti-inflammatory response during the early phase of digestive inflammation. Moreover, VNS anti-inflammatory effect is seen in the transverse colon, above the lesions. Conclusion These results reveal that other pathways implicating different cell types are potentially involved besides the classic cholinergic anti-inflammatory pathway by low-frequency VNS. It implicates CNS by the activation of vagal afferents and splenic immune cells such as T CD4 lymphocytes and NKT cells. An anti-inflammatory effect of VNS is found in the transverse colon (above the lesions) even during the initiation phase of digestive inflammation, but not in the distal colon (in the lesions). These date have therapeutic implications: low-frequency VNS is being clinically tested at the moment as a treatment for Crohn's disease.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Safety and efficacy of granulocyte/monocyte apheresis in steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics (ART trial): 12-week interim results

International audienceBACKGROUND AND AIMS: Patients with active, steroid-dependent ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologic therapies have limited treatment options. Adacolumn, a granulocyte/monocyte adsorptive apheresis device, has shown clinical benefit in these patients. This study aimed to provide additional clinical data regarding the safety and efficacy of Adacolumn in this patient subgroup.METHODS: This single arm, open-label, multicentre trial (ART) was conducted at 18 centres across the UK, France and Germany. Eligible patients were 18-75 years old with moderate-to-severe, steroid-dependent active ulcerative colitis with insufficient response or intolerance to immunosuppressants and/or biologics. Patients received ≥5 weekly apheresis sessions with Adacolumn. The primary endpoint was clinical remission rate (clinical activity index ≤4) at Week 12.RESULTS: Eighty-six patients were enrolled. At Week 12, 33/84 (39.3%) of patients in the intention-to-treat population achieved clinical remission, with 47/84 (56.0%) achieving a clinical response (clinical activity index reduction of ≥3). Clinical remission was achieved in 30.0% of patients with prior immunosuppressant and biologic failure; steroid-free clinical remission and response were observed in 22.6% and 35.7% of these patients, respectively. Quality of life (Short Health Scale) significantly improved at Week 12 (p\textless0.0001). The majority of adverse events were of mild/moderate intensity.CONCLUSIONS: At Week 12, Adacolumn provided significant clinical benefit in a large cohort of steroid-dependent ulcerative colitis patients with previous failure to immunosuppressant and/or biologic treatment, with a favourable safety profile. These results are consistent with previous studies and support Adacolumn use in this difficult-to-treat patient subgrou

Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs

peer-reviewedBackground: Carotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia-insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity. Methods: Adult male guinea-pigs were exposed to CIH (6.5% O2 at nadir, 6 cycles.hour−1) for 8 h.day−1 for 12 consecutive days. Findings: CIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but β-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls. Interpretation: Increased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota-gut-brainstem axis. The findings have relevance to human sleep-disordered breathing

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders

Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCG

The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update

Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion