Дисертації з теми "Troubles fonctionnels intestinaux – Chimiothérapie"
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Beutheu, Youmba Stéphanie. "Étude des protéines de jonctions serrées au cours de l'inflammation intestinale : impact des acides aminés." Rouen, 2011. http://www.theses.fr/2011ROUENR04.
La fonction de barrière peut être régulée en partie par les jonctions serrées (JS). Les JS sont des structures mufti-protéiques qui jouent un rôle important dans la polarité, la prolifération et la différenciation cellulaire. Plusieurs études ont suggéré que l'augmentation de la perméabilité intestinale pourrait être impliquée dans la survenue de phénomènes inflammatoires tels qu'observés au cours du syndrome de l'intestin irritable (Sul), ou de la mucite induite par le méthotrexate (MTX). Cependant, les régulations et les mécanismes mis en jeu ne sont pas clairement définis. Les objectifs de notre travail étaient d'une part d'étudier la régulation des protéines de JS, claudine-1, occludine et zonula occludens-1 (Z0-1) dans deux modèles i. E. Sur des biopsies coliques de patients atteints du SII et dans des modèles expérimentaux de mucite induite par le MTX in vivo chez le rat et in vitro sur des cellules Caco-2, et d'autre part d'évaluer les effets d'acides aminés dans les modèles expérimentaux de mucite. Nous avons observé des différences dans les altérations des protéines de JS en fonction du phénotype et des symptômes chez les patients SII. Les patients SII diarrhéiques présentaient d'importantes altérations d'expression de l'occludine et de la claudine-1. Cette perte d'expression protéique était corrélée à la durée des symptômes et à l'intensité de la douleur, suggérant donc que ces modifications seraient impliquées dans l'initiation du SIL Dans les modèles expérimentaux de mucite, nous avons observé une augmentation de la perméabilité intestinale induite par le MTX qui serait associée à des altérations de l'expression et de la localisation des protéines claudine-1, occludine et ZO-1. De plus, nous avons pu déterminer que les voies NF-kB, MEK1&2 et JNK seraient impliquées au cours de la perte de la fonction de barrière. Dans le cadre de stratégies nutritionnelles pour moduler ces altérations, nous avons montré que la glutamine prévenait l'augmentation de la perméabilité et restaurait l'expression des protéines de JS via les voies erk. Et NF-kB. La combinaison glutamine plus arginine n'aurait pas d'effet protecteur au cours de la rupture de la barrière intestinale dans ce modèle et semblerait être associée à une mortalité importante. Ces données incitent à poursuivre cette étude pour confirmer les effets préventifs et/ou thérapeutiques de la glutamine au cours de la mucite induite par le MTX mais également au cours du SII
STENGEL, CONRAD. "Mmpi et troubles fonctionnels intestinaux." Toulouse 3, 1988. http://www.theses.fr/1988TOU31151.
Bourdu, Sophie. "Mise au point d'un modèle d'hypersensibilité colique induite par le butyrate chez le rat : approches physiologiques et pharmacologiques." Clermont-Ferrand 1, 2005. http://www.theses.fr/2005CLF1MM05.
Duboc, Henri-Gérard. "Dysbiose et métabolisme des acides biliaires : implications au cours du syndrome de l’intestin irritable." Paris 6, 2013. http://www.theses.fr/2013PA066218.
The irritable bowel syndrome associates chronic abdominal pain and altered bowel transit. This is a common digestive disorder, which in its pathophysiology include the concept of dysbiosis, i. E disruption of the intestinal microbiota (overall micro organisms in a gut). Dysbiosis implies alterations of the host-microbiota dialogue leading to disease, a mainly descriptive concept to date. Bile acids are synthesized by the liver and metabolized by bacteria then reabsorbed from the intestine - so potentially involved in this dialogue. Other pathophysiological axes include motor, permeability, and intestinal secretion, and theses are functions also regulated by bile acids, through the membrane receptor TGR5. This work presents and discusses, through two scientific publications, the links between irritable bowel syndrome, dysbiosis, and TGR5 receptor
Langlois, Ludovic. "Caractérisation d'un effet sensitif de la neuromodulation des racines sacrées." Rouen, 2015. http://www.theses.fr/2015ROUENR05.
Fecal incontinence remains a therapeutic problem in patients when conservative measures fail and sphincter repair is unsuccessful or inappropriate. Sacral nerve stimulation (SNS) is an alternative surgical approach proposed initially to treat urinary incontinence, and has been used for the past decade as a successful treatment of fecal incontinence. Despite its overall efficacy, the mechanisms involved in this symptomatic effect remain unclear. The aim of this study was to evaluate the effect of SNS on rat visceral sensitivity. In an anesthetized rat model, mean arterial pressure variation was recorded in response to colorectal distension (CRD) in sham and effective SNS groups. Healthy and cross-organ sensitization models were studied. Characterization of the pathways involved in the effect of SNS was made by injecting pharmacological agents. Central neuronal activation and p-opioid receptor internalization were assessed by immunohistochemistry. In both models, SNS reduced mean arterial pressure variation. This effect was prevented by opioid receptor antagonist. CRD induced a rise in sacral dorsal horn of the spinal cord, parabrachial nucleus and solitary tract nucleus that was prevented by SNS. Finally, SNS induced an increase of p-opioid receptor internalization in a context of CRD. Concomitantly, we developed an implantable stimulating device in order to study chronic SNS on awaken rats. Implantation technique was validated by obtaining tail tremor response and by performing computed tomography imaging. Micturition frequency was assessed in rats undergoing 3 days of bipolar or unipolar SNS. In both groups, SNS reduced micturition frequency
Jie, Bai. "Effets d'un analogue de la somatostatine, l'octréotide sur la pathogénicité à court et long termes de l'infection par Cryptosporidium parvum dans un modèle de raton nouveau-né immunocompétent." Rouen, 2011. http://www.theses.fr/2011ROUENR03.
Tarrerias, Anne-Laure. "Relation nutrition et sensibilité colique : effet des fibres et des acides gras volatils chez le rat et chez l'homme." Clermont-Ferrand 1, 2003. http://www.theses.fr/2003CLF1MM18.
Thibault, Ronan. "Utilisation des substrats énergétiques par l'intestin en situation d'agression : utilisation du butyrate par le côlon au cours de l'inflammation intestinale : utilisation de la glutamine par l'intestin grêle dans un modèle de stress chez le volontaire sain." Nantes, 2009. http://www.theses.fr/2009NANT2016.
During intestinal inflammation or critical illness, the availability of the two preferred energy substrates of the intestine, butyrate and glutamine, is dramatically altered. The aim of this work was to obtain further insight into the mechanisms leading to alterations in butyrate and glutamine availability for the colon and the small intestine, respectively, during metabolic stress in vivo in humans. First, using various models of intestinal inflammation, we demonstrate that the defect in butyrate oxidation reported in inflammatory bowel diseases is the consequence of a decrease in butyrate transport into the colonocyte, itself related to a reduced expression of the butyrate intestinal transporter MCT1. We also clearly show that pro-inflammatory cytokines inhibit MCT1 transcription, and that this regulation involves the transcriptional factor USF2. The putative binding sequences involved in the cytokine-mediated inhibition of MCT1 transcription are located in the region -111/+213 of the promoter region. Last, our data indicate that the decrease in MCT1 expression alters cell metabolism, since it favours glucose utilization by the colonic mucosa, by increasing the expression of the glucose transporter GLUT1. This metabolic switch may be involved in the colonic carcinogenesis associated with chronic inflammation. Second, we have studied the effects of the metabolic stress on the glutamine utilization by the small intestine. In critically ill patients, glutamine is considered a conditionally essential amino acid, as muscle free glutamine pool is depleted in spite of high rates of de novo glutamine synthesis. To mimick the catabolic effects of severe illness, we studied the effect of oral corticosteroids on the splanchnic utilization of glutamine in healthy subjects. We show that a 6-day oral treatment with prednisone increases glutamine splanchnic extraction, but not its oxidation. These findings strongly suggest that the metabolic stress increases glutamine requirements by the small intestine, and may contribute to the depletion of muscle free glutamine concentration observed in critically ill patients
Khaldi, Samira. "Apport d'un modèle de rat d'hypersensibilité intestinale induite par Cryptosporidium parvum à la physiopathologie du syndrome de l'intestin irritable post-infectieux ; et transfert des oocystes de Cryptosporidium spp. Dans l'aquifère de la craie." Rouen, 2010. http://www.theses.fr/2010ROUES047.
Cryptosporidiosis, caused by Cryptosporidium spp. , is a self-limiting infection in immunocompetent individuals but may be life-threatening in immunocompromised individuals, in the absence of effective treatment. The pathophysiological mechanisms of cryptosporidiosis are not yet fully understood, but it has been shown that cryptosporidiosis can cause long-term sequelae. The first part of this work was aimed to highligt in a suckling rat model that infection with C. Parvum (isolate Nouzilly) leads to a more severe infection compared to rats that were infected with C. Parvum (isolate Iowa). Moreover, after clearance of infection, sub-mucosal infiltration of activated mast cells was observed in the jejunum. This infiltration is concomitant with the occurrence of a jejunal hypersensitivity to distention at day 50 post-infection. The anomalies observed are similar to those found in patients suffering from a post-infectious irritable bowel syndrome. The second part of the thesis was dedicated to the study of the transfer modalities of Cryptosporidium oocysts in a well-defined karst system, from the entry (swallow hole) to the exit of the system (spring and well-bore). It has been shown that the oocysts are transported in karst conduits, undergoing transfer, depostion and resuspention processes, under the influence of hydrodynamic gradient. Moreover, it was observed that the exploitation of the resource for the drinking water supply by sequences of continuous pumping promoted resuspension of sedimented oocysts and contributes to contamination of water resources
Coppet, Pierre de. "Expression du transporteur des monocarboxylates MCT1 dans le côlon sain et pathologique." Nantes, 2009. http://www.theses.fr/2009NANT2062.
Dietary fibers are digestible food ingredients that reach the colon and are then fermented by colonic bacteria, resulting mainly in the formation of short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate. Especially butyrate plays an important part in maintaining the health and integrity of the colonic mucosa. It is the primary energy source for the colonic epithelium and has most important physiological effect, including regulation of cell proliferation, differentiation and apoptosis. Butyrate oxidation was decrease in pathological situations like chronic inflammatory bowel diseases or colorectoral cancer. The monocarboxylate transporter 1 (MCT1 = SLC16A1) transports butyrate across the apical membrane of human colonocytes. Thus, a decrease in MCT1 expression, which reduces the intra-cellular availability of butyrate could affect not only its oxidation, but also its cell regulatory effects. In this study, we investigated that MCT1 can be identified as a good marker of butyrate exposition in colon epithelial cells and we demonstrate that the defect in butyrate oxidation reported in inflammatory bowel diseases is the consequence of a decrease in butyrate transport into the colonocyte, itself related to a reduced expression of the butyrate intestinal transporter MCT1
Delafoy, Laure. "Les Neurotrophines et l'hypersensibilité viscérale : leur implication dans un modèle de syndrome du côlon irritable chez le rat et dans un modèle d'asthme chez la souris." Clermont-Ferrand 1, 2003. http://www.theses.fr/2003CLF1MM17.
Branka, Jean-Éric. "Contrôle des fonctions de la barrière intestinale humaine par le monoxyde d'azote (NO) : apport des cultures primaires pour la modélisation en pharmaco-toxicologie." Nantes, 1998. http://www.theses.fr/1998NANT04VS.
Vries, Philine de. "Développement post natal et ciblage nutritionnel du système nerveux entérique : étude chez le raton nouveau-né." Nantes, 2013. http://archive.bu.univ-nantes.fr/pollux/show.action?id=00363864-558d-4cb2-9e04-f7012a6c2bff.
Digestive dysfunctions are often observed in premature child, such as slowing of intestinal transit to ulceronecrotizing enterocolitis. These symptoms could be a source of morbidity. The enteric nervous system (ENS) is known to be a major regulator of digestives functions. At birth, the child is submitted to environmental factors, and the GI tract is submitted to the influence of nutrients and their derivatives, such as butyrate. The commensal intestinal flora also has close ties with the GI tract. We first studied the maturation of rat pups ENS, and its impact upon the colonic motor functions. Few spontaneous contractions of the colon appeared at P5. Starting P14 rhythmic phasic contractions appeared whose frequency increased over time until P36. In addition, EFS induced contractions were significantly reduced by atropine from P14, while the proportion of ChAT-immuno reactive neurons increased significantly over time. Daily intrarectal administration of 2. 5 mM butyrate, to the pups from P7 to P17, increased the proportion of nitrergic and cholinergic cells and increase colonic motility in vivo. Ex vivo the motor response to EFS were disrupted in the presence of atropine and L-Name. Perinatal administration of oral Metronidazole to pups until P21, altered sensitivity to inflammation. Functional maturation of the colon and structural changes of the SNE occured after birth. Food and antibiotics can influence their development. This opens perspectives for the prevention and treatment of intestinal disorders in premature infants
Chassard, Christophe. "Métabolisme des fibres dans le côlon humain : caractérisation de la flore fibrolytique et des mécanismes microbiens impliqués dans la survenue des troubles fonctionnels intestinaux." Clermont-Ferrand 1, 2005. http://www.theses.fr/2005CLF1MM22.
Ferraro, Fabiana. "Enzyme-sensitive coatings for colon targeting : species-independent drug delivery systems." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS035.
The aim of this thesis is to produce and characterize novel drug delivery systems for colon targeting.This project is part of the Interreg des 2 mers “Site-specific Drug Delivery” (https://www.interreg2seas.eu/fr/Site-Drug). The site-specific delivery of drugs to the colon presents major therapeutical advantages, for example in the treatment of inflammatory bowel diseases which required a local action. Conventional oral dosage forms lead to a fast and complete drug release in the stomach and small intestine and, generally, a systemic absorption into the bloodstream. Therefore, systemic concentrations of drugs and associated adverse effects can be considerable. Furthermore, the resulting concentrations of drug at the site of action (the inflamed colon) are low, resulting in low therapeutic efficacy. An ideal dosage form for the local treatment of colonic diseases should effectively prevent the release of the active substance in the stomach and small intestine. On the other hand, once the colon is reached, the release must begin and be controlled over time (including -if desired- a rapid and complete release). In the case of treatment of inflammatory diseases of the colon (e.g. Crohn's disease and haemorrhagic ulcerative colitis), the active ingredient is thus released at its site of action, offering optimal therapeutic effects and minimized side effects. Different types of drug delivery systems have been described in the literature aiming at site-specific release to the colon. Often, the drug is trapped in a polymeric matrix, or a drug reservoir (e.g. minigranules, capsules or tablets loaded with active ingredient) is coated with a polymeric film. The ideal polymers used for this purpose have low permeability for the drug in the upper part of the gastrointestinal tract, but become permeable as soon as the colon is reached. In order to allow such control delivery, various systems have been proposed, based in particular on: (i) changes in pH along the gastrointestinal tract, (ii) degradation of the polymer by enzymes preferentially located in the colon, or (iii) structural changes in the polymeric networks after a certain delay, such as the formation of cracks in low permeability films. Nevertheless, special attention should be paid because the pathophysiological conditions in the colon of patients with inflammatory bowel diseases may be significantly different from those in healthy subjects.(i) the pH of the contents of the gastrointestinal tract,(ii) the quality and quantity of microflora (secreting enzymes),(iii) transit times in different sections of the gastrointestinal tract. Thus, a galenic formulation which successfully releases an active ingredient in the colon of a healthy subject may fail in a patient. Similarly, the inter- and intra-individual variability of therapeutic effects can be considerable, if the dosage form is not appropriately adapted to the pathological state. The objective of this thesis project is to develop new galenic forms targeting the release of the active ingredient in the colon and which are adapted to the pathological state. The release of the drug will be triggered by enzymes located in the colon, regardless of the pathological state.1. Methods. The systems were prepared by functional coating of microgranules loaded with 5-ASA as drug. These systems have been characterized physico-chemically in different media simulating the gastrointestinal tract, this includes in particular exposure to media containing stools from patients with inflammatory bowel diseases as well as stools from animal models of these diseases (TNBS rats) and dog stools (healthy) under anaerobic conditions, in collaboration with INSERM U995 (Dr. Christel Neut). The main characterization technique used concerns the study of the release kinetics of systems exposed to these different release media [...]
Marger, Fabrice. "Implication des canaux calciques de type T dans la douleur viscérale et recherche de ligands." Montpellier 1, 2009. http://www.theses.fr/2009MON1T006.
Sadrin, Stéphane. "Evaluation du bénéfice chez l'homme des probiotiques dans la prise en charge du syndrome de l'intestin irritable : méthodologie de l'essai contrôlé randomisé et allégations nutritionnelles et de santé." Thesis, Toulon, 2017. http://www.theses.fr/2017TOUL0007/document.
A health claim across the EU requires clinical evidence about the efficacy and safety of a nutritionalsupplementation. Probiotics, especially lactic acid bacteria, fall within this regulatory framework inwhich EFSA indicates that the evidence from patients with functional gastrointestinal disorder aretransferable in a population of healthy subjects. The LAPIBSS protocol is a high-quality clinicaltrial assessing the efficacy of 2 strains of Lactobacillus acidophilus to reduce the irritable bowelsyndrome symptoms severity. Results confirm the safety of strains used but do not show asignificant decrease of symptoms compared with placebo after 8 weeks. The overall treatment effectis statistically significant on the flatus score. A placebo effect and the considerable heterogeneity ofsymptoms severity at baseline would explain our results. A better understanding of physiologicaleffects of probiotics in human would be needed to upgrade the rationale for their use in clinicalresearch
Kamphuis, Jasper. "Increased intake of fermentable carbohydrates induces IBS-like symptoms : a complementary understanding of mechanisms involved." Thesis, Toulouse, INPT, 2019. http://www.theses.fr/2019INPT0074.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by abdominal pain, bloating, and erratic bowel habits. It is an affliction with a high prevalence of around 11% worldwide. It carries a significant economic cost in lost productivity and work absence, and more importantly, it has a strong negative impact on quality of life. Because it is a functional disorder of which the causes are not well understood, treatment is difficult. In recent years, a low-FODMAP diet (low in Fermentable Oligo-, Di-, Mono-saccharides And Polyols) has been successfully used to reduce symptoms of IBS. The efficacity of this approach is not completely understood, but a reduction in enteric distension by reduced gas production and small intestinal water bulk by osmotic effects are most often cited. The bacterial metabolic toxin hypothesis, proposed by Campbell et al. poses that anaerobic fermentation of unabsorbed carbohydrates by the colonic gut microbiota, producing such metabolites as alcohols, ketones, and aldehydes, are responsible for food intolerances such as lactose intolerance. We hypothesized that this same mechanism could be extended to FODMAPs to explain the efficacity of the low- FODMAP diet. In this thesis, we looked for complementary mechanisms on how FODMAPs could influence IBS symptoms, besides distension related complaints. Our studies in a healthy mouse model show a complex role for FODMAPs in IBS physiopathology; FODMAP treatments cause a visceral and abdominal hypersensitivity, and a mucus barrier dysregulation, characterized using an innovative approach. We hypothesized that this is due to generation of glycating agents by the intestinal microbiota, and the prevention of these effects by co-treatment with pyridoxamine indicates that this hypothesis is correct. Mucosal mast cell counts were increased in FODMAP treated animals, but not in animals co-treated with pyridoxamine. Mast cells are implicated in visceral hypersensitivity, as well as in mucus barrier dysregulation, and increased mucosal mast cell numbers or activity are often linked to IBS. This work thus offers a link between the efficacity of the low-FODMAP diet and the involvement of intestinal mast cells in IBS
Amsallem, Florent. "Interventions non-pharmacologiques et syndrome de l’intestin irritable : revue de la littérature et méthodologie des essais thérapeutiques pour l’évaluation de l’efficacité de l’ostéopathie." Electronic Thesis or Diss., Lyon, 2022. http://www.theses.fr/2022LYSE1126.
Hypnotherapy, acupuncture, and osteopathy are non-pharmacological interventions (NPIs) that have already shown low to moderate efficacy on the severity of irritable bowel syndrome (IBS) symptoms. However, the results of these studies must be interpreted with caution because of the presence of strong risks of bias related to the methodology used; the design of the existing trials would also explain contradictory results on the effectiveness of NPIs. We have chosen to examine and criticize these sometimes contradictory claims from a growing body of literature. The analysis of all the published and unpublished evidence allows us to take an objective and transparent look at NPIs, including osteopathy for IBS. We hypothesized that osteopathy would decrease the severity of symptoms in adults with IBS at 1-month follow-up. In the systematic review, the objective was to measure the effectiveness of NPIs, namely body therapies and mind-body therapies, and to discuss their role in the treatment of IBS. Several electronic databases were searched to identify randomized controlled trials published in the English language between 1990 and 2020. Efficacy outcomes were examined on the basis of change in overall IBS symptoms or abdominal pain through 12 months of follow-up. We identified 11 parallel-group trials that included a total of 1590 participants. Body therapies (acupuncture and osteopathy) showed a beneficial effect over standard medical treatment for IBS symptoms after 6 months of follow-up, but there was no statistically significant difference between body therapies and sham therapies for these symptoms. It was not possible to conclude that hypnotherapy was superior in terms of efficacy to standard medical treatment for IBS symptoms because of the discordant results. In particular, we discuss the design of the trials included in the systematic review and in particular the choice of the control group. Based on the results of the systematic review, a randomized controlled trial protocol was written to confirm or refute our hypothesis. The experimental group received three active osteopathic treatments performed by an experienced osteopath, each lasting 30 minutes over a period of 15 days. The control group received a fictitious osteopathic treatment of the same duration and period as the experimental group. At inclusion, subjects with IBS diagnosed according to the Rome IV criteria had similar symptom severity and the control group had similar expectations of treatment as the experimental group. The trial was designed to be highly powered and to have a low level of risk of bias. The number of subjects required was calculated to detect a 15% difference in treatment response between the two groups and to achieve 90% power (alpha risk at 0.05). Randomization was stratified by center in a 1:1 ratio, so 202 adults were included in each of the two groups. If efficacy is demonstrated, this two-arm parallel, randomized, double-blind, placebo-controlled trial, in which the control group is considered a comparable experience to the intervention, with similar expectations, would be a design of choice to assert causality. We conclude that it is important to conduct future trials without apparent bias to confirm that nonpharmacologic care has an acceptable benefit-risk balance for an already low-complexity and low-cost use
Rolland-Fourcade, Claire. "Les protéases et leurs inhibiteurs sécrétés par la cellule épithéliale : acteurs de l'inflammation et de la douleur." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30353/document.
Proteases are involved in some biologic processes and their origins are variable (immune cells, epithelial cells...). Their activity is regulated by antiproteases. This study investigates the balance between proteases and their inhibitors in pathologies which modify epithelium integrity. Consequences of an unbalance in proteolytic activity was studied in two chronic pathologies with different components: Inflammatory Bowel Disease (IBD) (cycles of inflammatory boost) and Irritable Bowel Syndrome (IBS) (cycles of pain symptoms). Colonic mucosa from IBS patients releases trypsin activity. The origin and the functions of this activity are not well defined. This study investigated the source of this trypsin activity in the côlon of IBS patients, its nature and its role in neuronal activation. Trypsin activity from IBS patients is increased mostly in epithelial cells. Stimulation of epithelial cell monolayers with LPS or epinephrine induces an increase of trypsin-3 quantity and its secretion specifically in the basal side of epithelial cells. This is in correlation with the increase of trypsin activity. Trypsin-3 hyperactivity at the basal side provokes a loss of epithelium barrier function, which is also found in colons of IBS patients. Then, we have highlighted that trypsin-3 is able to activate human myenteric neurons and murine sensitive neurons. In vivo, its intra-rectal administration to mice induces a visceral hypersensitivity dependent of PAR2 (Protease Activated Receptors 2). Thus, intestinal epithelial cells from IBS patients produce and release trypsin-3 specifically on their basal side. This trypsin activity activates sensitive neurons which participate to visceral hypersensitivity, a major symptom of IBS patients. Inflammatory pathologies could be a source of proteolytic malfunction. IBD patients have a dysregulation of elastolytic balance in the colon. Our team has shown that ELAFIN (an elastase inhibitor) delivered by the bacteria genetically modified L.lactis near the inflamed mucosa, protects mice from intestinal inflammation. However, the protective mechanisms induced by ELAFIN need to be investigate. ELAFIN is an elastase inhibitor but have also antimicrobial properties. With the aim to highlight what function of ELAFIN owns anti-inflammatory properties, mutants of ELAFIN have been generated and were insered into L.lactis: a first mutant lacked its antiprotease function, a second lacked antimicrobial properties and a last mutant lacked both properties. In intestinal epithelial monolayers, ELAFIN delivered by L.lactis protects against inflammation: a restauration of epithelial barrier function and a decrease of pro-inflammatory cytokines (CXCL8 and IP10) are observed. Mutation of antimicrobial domain doesn't affected these properties. Nevertheless, the absence of inhibitory loop annihilates anti-inflammatory functions of ELAFIN. This work highlights the importance of proteolytic balance inside the epithelial cell in intestinal pathologies. The balance between proteases and antiproteases plays an important role in epithelial homeostasis
Maillard, Flore. "Identification et caractérisation de souches à potentiel probiotique dans des pathologies intestinales et infections respiratoires." Electronic Thesis or Diss., université Paris-Saclay, 2022. http://www.theses.fr/2022UPASB068.
The goal of this thesis was to identify strains with beneficial properties in IBD, IBS and winter infections, using in vitro and in vivo approaches.The first step was to determine the strains to include in the collection. The strains had to be pre-characterized, free of rights and have a Qualified Presumption of Safety status to facilitate their development. We identified 25 strains from the INRAE and PiLeJe collections meeting these criteria. We also included 17 control strains, marketed by PiLeJe or its competitors.The second step was to achieve the same level of characterization for the entire collection. We tested the immunomodulatory properties of the strains: the reduction of IL-8 production on HT-29 cells and the production of IL-10, IL-12 and IFN-γ on Peripheral Blood Mononuclear Cells (PBMC). We also tested the reinforcement of the barrier by measuring the Trans Epithelial Electrical Resistance (TEER) on Caco-2 cells, as well as the production of Short Chain Fatty Acids (SCFA) and agonists of the Aryl hydrocarbon Receptor (AhR) in the culture supernatants.The third step was to test the best strains in mouse models of the targeted pathologies. For intestinal disorders, we combined the in vitro results in a Principal Components Analysis (PCA), which identified 3 candidate strains PI41, LBH1068 and PI50, with an anti-inflammatory profile close to the strains already marketed by PiLeJe on the intestinal axis. We tested these 3 candidate strains as well as a positive control strain already marketed by PiLeJe and a negative control strain, with a neutral profile in PCA in a model of DNBS-induced colitis. The LBH1068 strain significantly reduced macroscopic and microscopic inflammation in the colons as well as intestinal permeability assessed by serum CD14s. Neither strain altered colonic cytokine production, lymphocyte populations, or AhR agonist and SCFA production.The 3 candidate strains were also tested in a post-infectious IBS model. The 3 strains significantly reduced visceral hypersensitivity measured by colorectal distension. We also investigated the effects of the strains on anxiety, frequently associated with IBS. Strains PI50 and LBH1068 significantly reduced anxious behavior in mice, measured in an elevated plus-maze. Strains PI41 and LBH1068 significantly increased AhR agonist production in feces but did not alter indoles, serotonin, and kynurenine metabolic pathways in feces and serum. In conclusion, our method allowed us to successfully identify two strains LBH1068 and PI41 demonstrating beneficial and superior effects to a strain already marketed by PiLeJe in preclinical models of IBD and IBS. Mechanistic studies should be pursued to identify the mechanisms of action.Concerning the winter infections axis, the test on PBMC allowed us to identify 3 strains LBH1075, PI41 and PI43, with a pro-inflammatory and anti-infective profile. These 3 candidate strains, as well as a mixture of PiLeJe probiotic strains and an acetate solution were tested in an influenza model. PI43 and LBH1075 strains and the probiotic PiLeJe significantly reduced the morbidity score. PI41 and PI43 strains also improved respiratory capacities measured by plethysmography. However, the best scores were obtained in the group treated with acetate. The positive results obtained by the strains do not seem to be linked to the acetate since no increase in SCFA was observed in the feces. These results come from a single trial and should be repeated but are encouraging for further experimentation
Ponce, de Leon Rodriguez Maria del Carmen. "Développement d’un modèle in vitro d’inflammation intestinale par l’utilisation de lignées cellulaires humaines en co-culture pour l’étude des interactionsavec les micro-constituants alimentaires." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTG009/document.
The intestinal epithelium, main place of the absorption of (micro)-nutrients is also the first body's defense system. An imbalance in homeostasis can lead to an inflammatory reaction associated with defects in the intestinal barrier and immune function as well as malabsorption of nutrients, as seen in IBD (Inflammatory Bowel Diseases), in micronutrient fortification strategies and noncommunicable diseases (obesity). It is therefore important to find ways of action, for example through diet, to prevent or at least reduce the nutritional and pathological consequences of intestinal inflammation, and to understand the mechanisms involved. Among intestinal models, in vitro cell culture models are increasingly used and allow to evaluate the molecular mechanisms in a simple and reproducible way and to reduce animal experimentation.In this context and in order to study the interaction of dietary bioactive compounds with the intestine in state of inflammation, the first objective of this work was the development of an in vitro model of inflamed intestine combining in co-culture two human intestinal cell lines: Caco-2 TC7 (enterocytes) and HT29-MTX (goblet cells) and an immune cell line of macrophages (THP1). Several inflammation markers were evaluated and we were able to show that the tri-culture model responded to an inflammatory stimulus (LPS / IFNγ), by increasing the production of pro-inflammatory cytokines (TNF-α, IL6 and IL8) and enzymes (INOS and COX2) as well as the expression of their genes. In addition, an increase of epithelial permeability via tight junctions (TJs) alteration has also been demonstrated, as well as overproduction of mucus, which are recognized inflammation characteristics.The second objective was to study the interaction of β-cryptoxanthin (BCX), a lipophilic and antioxidant carotenoid of citrus, with the inflamed model. To solubilize BCX, we used two types of micelles (artificial and physiological) and studied markers of inflammation. Although it appears from the preliminary results that BCX micelles show a tendency to decrease the production of some cytokines (IL6 and IL8), the role of micelle constituents (Tween 40 or bile salts / phospholipids) in the phenomenon observed and in the epithelial permeability remains to be therefore clarified
Bahlouli, Wafa. "Régulation de la perméabilité intestinale au cours du syndrome de l'intestin irritable : role du système ubiquitine-protéasome et impact de l'obésité." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR047.
Irritable bowel syndrome (IBS) is a multifactorial functional disorder, involving environmental factors (stress and diet for instance), gut-brain-axis dysfunction, micro-inflammation, dysbiosis and an alteration of intestinal permeability. The role of the proteasome in the regulation of the intestinal barrier during IBS has been studied. In addition, these intestinal functional disorders have also been described in patients with obesity. Nevertheless, the mechanisms underlying an association of intestinal functional disorders in the obesity context, remain poorly understood and have therefore been investigated in this thesis. In this study, "IBS-like" mouse models such as water avoidance stress (WAS) and the post-inflammatory (post-TNBS) models, were used to study the impact of proteasome inhibition on the regulation of intestinal permeability. We found that the pharmacological inhibition of the proteasome (with PR-957) or the use of knock-out mice for a subunit of the proteasome (β2i -/-) limit intestinal hyperpermeability occured in IBS-Like models. Moreover, we found that oral supplementation with glutamine also reduces intestinal hyperpermeability, wich, thus, can be considered as a putative nutritional treatment for IBS. A colonic proteomic study of WAS mice and a study of colonic ubiquitoma in IBS patients with diarrheal profiles confirmed the involvement of proteasome in the pathophysiology of IBS. Therefore, the link between obesity and IBS was examined by combining models of obesity (ob/ob genetic and high-fat diet [HFD] models) with WAS model. Only HFD mice displayed enhanced intestinal hyperpermeability and higher plasma corticosterone levels in response to WAS. Further studies suggest that these results, themselve, are independent of leptin, glycaemia and gut microbiota. This study paves new ways of treating patients suffering from IBS, by nutritional intervention via glutamine or by using the proteasome as a therapeutic target. We also suggest a role of diet (high fat) in the development of intestinal functional disorders during obesity
Matricon, Julien. "Étude de l'implication du Nerve Growth Factor et des Acid-Sensing Ion Channels dans l'hypersensibilité colique induite par le butyrate chez le rat." Phd thesis, Université d'Auvergne - Clermont-Ferrand I, 2010. http://tel.archives-ouvertes.fr/tel-00719685.
Laval, Laure. "Caractérisation et analyse des effets probiotiques de souches de Lactobacillus et de Bifidobacterium." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112265.
Health benefits of probiotic bacteria are numerous: beneficial effects on the intestinal microbiota, digestive comfort, modulation of the immune system and prevention of winter infection. These diverse and various effects are strain-specific. Nowadays, numerous studies aim at better characterizing those probiotics effects.This project aimed at identifying and analyzing the probiotic effects of three strains from Danone collection: Lactobacillus paracasei CNCM I-3689, L. rhamnosus CNCM I-3690 and Bifidobacterium animalis subsp. lactis CNCM I-2494. First, their effects were assessed in in vitro models for immunomodulation properties, antipathogens activity and intestinal barrier protection. Secondly, their beneficial effects were confirmed in low-grade inflammation murine model.The analysis of the underlying mechanisms has been initiated both in the bacterial strains by the construction and the functional analysis of genomic libraries and in the host by measuring the modulation of the genes involved in the intestinal barrier maintain
Esquerre, Nicolas. "L’aluminium, facteur de risque environnemental impliqué dans la physiopathologie des maladies intestinales." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S008/document.
Aluminium (Al) is the most abundant metal in our environment. Al naturally occurs in soils, rocks, minerals, air, water and its use in consumer products increase exponentially in industrialized countries. During last decades, human activities led to an increase in the bioavailability of Al and populations are exposed daily to multiple sources and doses of Al, including the oral route. Based on the description of toxic and deleterious effects of Al in various pathologies as well as ingested doses of Al, we showed that Al could participate in the exacerbation of intestinal inflammation, decrease mucosal healing and cell renewal (Pineton de Chambrun et al., 2014).In order to understand the mechanisms involved in the perturbations of the intestinal epithelium, Al toxicity was evaluated on intestinal epithelial cells. This study showed that Al decrease cell viability, promote apoptosis and disturb cell cycle. Al had also pro-tumorigenic and pro-inflammatory effects on intestinal epithelial cells. Thus, we demonstrated that Al could promote toxic effects on intestinal mucosa.Then, we evaluated the effects of Al on visceral sensitivity in rodents. We have demonstrated that currently ingested amounts of Al, in humans, induced in mice and rats a dose dependent increase of colorectal sensitivity. Al-induced hypersensitivity persists over time so that intoxication was arrested, and appears again when Al intoxication resumes, dismissing any tolerance phenomenon. Moreover, female gender was more affected by Al-induced hypersensitivity than male gender. Mechanisms involved an increased permeability and were dependent on mast cell degranulation and protease activated receptor 2. These results are relevant to the mechanisms observed in the pathogenesis of irritable bowel syndrome (IBS). Indeed, patients usually exhibit visceral hypersensitivity, increased permeability, impaired microbiota and low inflammation degree of the gastrointestinal tract. Causes of the disease remain unknown but environmental factors are strongly suspected to be involved in the pathogenesis. Thus, Al could be a new environmental risk factor involved in the development of IBS.In conclusion, these results demonstrate the toxicity of Al on the digestive tract and highlight a new environmental risk factor in the physiopathology of intestinal diseases such as inflammatory bowel diseases and irritable bowel syndrome
Dupont, Claire. "Séquelles anatomiques et fonctionnelles des maladies inflammatoires chroniques de l'intestin (MICI) de l'enfant." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR065.
The course of pediatric-onset inflammatory bowel disease (Crohn’s diseae, ulcerative colitis and IBDD unclassified) can be complicated by structural or functional sequelae. Structural complications include intestinal fibrosis which can cause bowel strictures. IBD can be associated with functional abdominal pain persisting despite remission of inflammation. The purpose of our work was to determine the burden of these complications and search for association with previous severity of inflammation, based on!two clinical studies and two animal models. In the first study, TFI-MICI, we showed that 20% of children and adolescents with IBD in clinical and biochemical Remission had functional gastrointestinal disorders, among which 15% had functional abdominal pain disorders (FAPD). FAPD was! Ssociated with increased fatigue, depressive symptoms and reduced quality of life, but not with anxiety. There was no association between the severity of IBD and presence of FAPD. The second study, STENO-PED, focused on imaging and clinical predictors of response!to treatment in children and adolescents with stricturing small bowel Crohn’s disease. We showed that the predictors for surgery were a dilation proximal to the stricture of >30mm, and a PCDAI score at diagnosis of stricture > 22.5. Receiving an anti-TNFα treatment after diagnosis of stricture was a protective factor from surgery. Experimental models allowing to follow the progression of fibrosis along with inflammation and assess response to Treatment are lacking, in particular for pre-pubertal animals. We adapted to Sprague-Dawley pre-pubertal rats a model of acute (1 dose of! TNBS) and chronic (3 doses of TNBS) hapten-induced colitis. The rats in both models developed significant inflammation, based on histology and magnetic resonance colonography. Rats in the chronic colitis model developed histologic fibrosis. There was a non-significant trend to fibrosis in the acute model. !We treated rats in both models with MODULEN IBD® from induction of colitis to collection of colonic samples. This treatment did not reverse inflammation nor fibrosis. Fibrosis and functional abdominal pain in pediatric-onset IBD are two important problems, although functional pain appeared to be not more frequent than in the general population. Animal models could be of great assistance in order to better decipher the link between inflammation and fibrosis, and see if an effective early suppression of inflammation along with new anti-fibrotic therapies could halt the progression of fibrosis
Picard, Elodie. "Implication physiopathologique et pharmacologique des canaux calciques Cav 3.2 dans la douleur chronique." Thesis, Université Clermont Auvergne (2017-2020), 2017. http://www.theses.fr/2017CLFAS008/document.
Chronic pain is a central concerns to public health. In France, it affects about 20% of the population and has a negative impact on the patients’ quality of life. Current treatments are generally ineffective or associated with strong adverse effects. Therefore, new therapeutic approaches are needed. Among the potential targets, the T-type voltage-dependent calcium channels, in particular the Cav3.2 isoform, constitute candidates of interest. Thus, the objective of this thesis is to characterize their functional implication in two types of chronic pain: visceral and somatic. We have developed a murine model of colonic hypersensitivity associated with low grade inflammation, two symptomatic features close to the symptomatology found in most patients suffering from irritable bowel syndrome (IBS) or with diseases inflammatory bowel disease (IBD) during remission periods. Concerning the somatic pain, we used two murine models of inflammatory pain, one with subacute inflammation and another with persistent inflammation. In these different models, a pharmacological inhibition with the administration of a Cav3.2 channel antagonist, TTA-A2, or a genetic approach using Cav3.2 knockout (KO) mice induced a robust analgesic effect demonstrating a functional implication of Cav3.2 channels in the development and maintenance of these types of pain. Moreover, the use of mice with a Cav3.2 conditional KO, specifically in the C-dorsal root ganglia (DRG) fibers, and the use of ABT-639, a peripherally acting pharmacological blocker of type T channels, allowed us to specify the localization of this implication. Thus, a pre-synaptic spinal action of the Cav3.2 channels has been demonstrated for visceral pain whereas a more complex action of these channels is involved for inflammatory somatic pain. Indeed, for the latter, Cav3.2 channels present a spinal and peripheral implication. In addition, we have shown the role of Cav3.2 channels in the inflammatory process, with an involvement located in the immune cells. Finally, with a translational research approach, we evaluated the effect of ethosuximide (ETX), a T-channel blocker, clinically used in the treatment of epilepsy. We have described an analgesic effect of the latter in both studied models as well as an anti-inflammatory action. These results constitute a pre-clinical proof of concept for a clinical efficacy evaluation of ETX in a context of visceral pain or somatic inflammatory diseases. Altogether these results provide new insight about the involvement of Cav3.2 channels in chronic pain and allow us to propose these channels as targets of interest for the development of new therapeutic strategies to relieve patients
Melchior, Chloé. "Role du fructose dans la physiopathologie du syndrome de l'intestin irritable." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMR029/document.
Fructose intake has increased by up to 50 g per day in the USA and Western Europe. Fructose is increasingly incorporated in beverages, dairy products and canned, baked or processed foods worldwide. Fructose has been shown to trigger or worsen digestive symptoms not only in healthy volunteers, but also in patients with irritable bowel syndrome. The involvement of visceral hypersensitivity has been suspected but has never been assessed. The prevalence of fructose malabsorption in patients with irritable bowel syndrome in Western Europe remains poorly documented, due to the heterogeneity of available tests. Therefore, the first objective of this present work was to assess the prevalence of fructose malabsorption in patients with irritable bowel syndrome. We assessed fructose malabsorption with a fructose breath test, after a 25 g load. We systematically ruled out small intestinal bacterial overgrowth which could promote false positive. In our irritable bowel syndrome patients, 22% had fructose malabsorption. Young, male patients were more likely to have fructose malabsorption. We also assessed the association between fructose malabsorption and other abnormalities. We did not observe any association between low-grade inflammation (with faecal calprotectin dosage) or fructose malabsorption. In contrast, an association between fructose malabsorption and visceral hypersensitivity was evidenced. Low fructose diet is known to improve symptoms in patients with irritable bowel syndrome. The presence of fructose malabsorption could be predictive of the efficacy of a low fructose diet. The second objective of this work was to determine if an abnormal fructose breath test was a predictor of symptomatic response to low fructose diet in irritable bowel syndrome. Our study has confirmed the efficacy of low fructose diet on irritable bowel syndrome. However, the results of the fructose breath test had no impact on its efficacy. One explanation for this result could be the presence of other abnormalities (including visceral hypersensitivity) that were not addressed only with a diet. The last objective of this work was to model fructose malabsorption in mice, in order to identify the underlying mechanisms. We used three models of fructose malabsorption (high fructose diet, invalidation of GLUT5 and GLUT2 coding gene). In these models, fructose malabsorption induced visceral hypersensitivity and increased intestinal permeability, the two abnormalities being reported in irritable bowel syndrome. In our models, there was no low-grade inflammation. Increased elastase activity in mice faeces was associated with visceral hypersensitivity. Protease-activated receptor-2 is known to be associated with visceral hypersensitivity and increases intestinal permeability. Further works are warranted to determine the involvement of protease-activated receptor-2 in fructose malabsorption-associated visceral hypersensitivity. The results of this work underlined the role of fructose malabsorption in irritable bowel syndrome, in the onset of visceral hypersensitivity and increased intestinal permeability. A low fructose diet is not helpful to improve symptoms of irritable bowel syndrome with fructose malabsorption
Atmani, Karim. "Modulation neuro-glial associée à la sensibilisation croisée des organes pelviens : Effet sur la nociception viscérale." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMR039/document.
Irritable bowel syndrome (IBS) and Bladder pain syndrome (BPS) are bothcharacterized by visceral hypersensitivity to distension. Epidemiology showed thatthese two syndromes are closely associated since IBS patients have a prevalence ofbladder pain syndrome that is 7 times higher than the general population. However,the mechanism responsible for sensitization of the gastrointestinal tract and theurinary tract has never been studied. Given the common innervation of these twoorgans, it is likely that this mechanism involves long-term phenomena of neuro-glialplasticity at the common levels of integration of pelvic sensitivity.The overall objective of this work was to establish and characterize an animalmodel of bladder / colon cross-sensitization, acute and chronic, to better understandthe mechanisms involved in cross-visceral hypersensitivity