Towards a cognitive neurobiology of brain-gut axis disorders

The past two decades have seen substantial gains in our understanding of the complex processes underlying disturbed brain-gut communication in disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Despite a growing understanding of the neurobiology of brain-gut axis dysfunction, there is a relative paucity of investigations into how the various factors involved in dysregulating the brain-gut axis, including stress, immune activation and pain, could impact on fundamental brain processes such as cognitive performance. To this end, we proposed a cognitive neurobiology of brain-gut axis dysfunction and took a novel approach to examine how disturbed brain-gut interactions may manifest as altered cognitive performance in IBS and IBD, both cross-sectionally and prospectively. We have demonstrated that, disorders of the brain-gut axis are characterised by stable deficits in specific cognitive domains. Specifically, patients with IBS exhibit a consistent hippocampal mediated visuospatial memory impairment. In addition we have found evidence to suggest a similar visuospatial impairment in IBD. However, our most consistent finding within this population was that patients with Crohn’s disease exhibit impaired selective attention/ response inhibition on the classic Stroop interference test. These cognitive deficits may serve to perpetuate and sustain brain-gut axis dysfunction. Furthermore, this research has shed light on some of the underlying neurobiological mechanisms that may be mediating cognitive dysfunction in IBS. Our findings may have significant implications for the individual who suffers from a brain-gut axis disorder and may also inform future treatment strategies. Taken together, these findings can be incorporated into existing neurobiological models of brain-gut axis dysfunction, to develop a more comprehensive model accounting for the cognitive-neurobiology of brain-gut axis disorders. This has furthered our understanding of disease pathophysiology and may ultimately aid in both the diagnosis and treatment of these highly prevalent, but poorly understood disorders.

What is the significance of muciphages in colorectal biopsies?

Muciphages (mucin-containing macrophages), first described in 1966 by Azzopardi & Evans, are a common feature of biopsies of large intestinal mucosa, even in the absence of other abnormalities such as active inflammation or evidence of chronic inflammatory bowel disease. Should they be mentioned in diagnostic reports? Do muciphages reliably indicate previous mucosal disease, now quiescent? In the following articles, Salto-Tellez & Price review what is known about muciphages and conclude that they reflect previous occult and clinically unimportant mucosal damage and that, in an otherwise normal colorectal mucosa, they have no diagnostic significance; and Shepherd draws attention to a wide range of clinically much more significant mucosal infiltrates that could be mistakenly regarded as muciphages and thus overlooked.

Crossing the eukaryote-prokaryote divide:A ubiquitin homolog in the human commensal bacterium Bacteroides fragilis

The resident microbiota of the human gastrointestinal (GI) tract is comprised of ~2,000 bacterial species, the majority of which are anaerobes. Colonization of the GI tract is important for normal development of the immune system and provides a reservoir of catabolic enzymes that degrade ingested plant polysaccharides. Bacteroides fragilis is an important member of the microbiota because it contributes to T helper cell development, but is also the most frequently isolated Gram-negative anaerobe from clinical infections. During the annotation of the B. fragilis genome sequence, we identified a gene predicted to encode a homolog of the eukaryotic protein modifier, ubiquitin. Previously, ubiquitin had only been found in eukaryotes, indicating the bacterial acquisition as a potential inter-kingdom horizontal gene transfer event. Here we discuss the possible roles of B. fragilis ubiquitin and the implications for health and disease. © 2012 Landes Bioscience

Post-Translational Inhibition of IP-10 Secretion in IEC by Probiotic Bacteria: Impact on Chronic Inflammation

Background: Clinical and experimental studies suggest that the probiotic mixture VSL#3 has protective activities in the context of inflammatory bowel disease (IBD). The aim of the study was to reveal bacterial strain-specific molecular mechanisms underlying the anti-inflammatory potential of VSL#3 in intestinal epithelial cells (IEC).

Methodology/Principal Findings: VSL#3 inhibited TNF-induced secretion of the T-cell chemokine interferon-inducible protein (IP-10) in Mode-K cells. Lactobacillus casei (L. casei) cell surface proteins were identified as active anti-inflammatory components of VSL#3. Interestingly, L. casei failed to block TNF-induced IP-10 promoter activity or IP-10 gene transcription at the mRNA expression level but completely inhibited IP-10 protein secretion as well as IP-10-mediated T-cell transmigration. Kinetic studies, pulse-chase experiments and the use of a pharmacological inhibitor for the export machinery (brefeldin A) showed that L. casei did not impair initial IP-10 production but decreased intracellular IP-10 protein stability as a result of blocked IP-10 secretion. Although L. casei induced IP-10 ubiquitination, the inhibition of proteasomal or lysosomal degradation did not prevent the loss of intracellular IP-10. Most important for the mechanistic understanding, the inhibition of vesicular trafficking by 3-methyladenine (3-MA) inhibited IP-10 but not IL-6 expression, mimicking the inhibitory effects of L. casei. These findings suggest that L. casei impairs vesicular pathways important for the secretion of IP-10, followed by subsequent degradation of the proinflammatory chemokine. Feeding studies in TNF Delta ARE and IL-10(-/-) mice revealed a compartimentalized protection of VSL#3 on the development of cecal but not on ileal or colonic inflammation. Consistent with reduced tissue pathology in IL-10(-/-) mice, IP-10 protein expression was reduced in primary epithelial cells.

Conclusions/Significance: We demonstrate segment specific effects of probiotic intervention that correlate with reduced IP-10 protein expression in the native epithelium. Furthermore, we revealed post-translational degradation of IP-10 protein in IEC to be the molecular mechanism underlying the anti-inflammatory effect.

Microbiota of De-Novo Pediatric IBD: Increased Faecalibacterium Prausnitzii and Reduced Bacterial Diversity in Crohn's But Not in Ulcerative Colitis

OBJECTIVES: The gastrointestinal microbiota is considered important in inflammatory bowel disease (IBD) pathogenesis. Discoveries from established disease cohorts report reduced bacterial diversity, changes in bacterial composition, and a protective role for Faecalibacterium prausnitzii in Crohn's disease (CD). The majority of studies to date are however potentially confounded by the effect of treatment and a reliance on established rather than de-novo disease.

METHODS: Microbial changes at diagnosis were examined by biopsying the colonic mucosa of 37 children: 25 with newly presenting, untreated IBD with active colitis (13 CD and 12 ulcerative colitis (UC)), and 12 pediatric controls with a macroscopically and microscopically normal colon. We utilized a dual-methodology approach with pyrosequencing (threshold >10,000 reads) and confirmatory real-time PCR (RT-PCR).

RESULTS: Threshold pyrosequencing output was obtained on 34 subjects (11 CD, 11 UC, 12 controls). No significant changes were noted at phylum level among the Bacteroidetes, Firmicutes, or Proteobacteria. A significant reduction in bacterial alpha-diversity was noted in CD vs. controls by three methods (Shannon, Simpson, and phylogenetic diversity) but not in UC vs. controls. An increase in Faecalibacterium was observed in CD compared with controls by pyrosequencing (mean 16.7% vs. 9.1% of reads, P = 0.02) and replicated by specific F. prausnitzii RT-PCR (36.0% vs. 19.0% of total bacteria, P = 0.02). No disease-specific clustering was evident on principal components analysis.

CONCLUSIONS: Our results offer a comprehensive examination of the IBD mucosal microbiota at diagnosis, unaffected by therapeutic confounders or changes over time. Our results challenge the current model of a protective role for F. prausnitzii in CD, suggesting a more dynamic role for this organism than previously described.

An Excess of Risk-Increasing Low-Frequency Variants Can Be a Signal of Polygenic Inheritance in Complex Diseases

In most complex diseases, much of the heritability remains unaccounted for by common variants. It has been postulated that lower-frequency variants contribute to the remaining heritability. Here, we describe a method to test for polygenic inheritance from lower-frequency variants by using GWAS summary association statistics. We explored scenarios with many causal low-frequency variants and showed that there is more power to detect risk variants than to detect protective variants, resulting in an increase in the ratio of detected risk to protective variants (R/P ratio). Such an excess can also occur if risk variants are present and kept at lower frequencies because of negative selection. The R/P ratio can be falsely elevated because of reasons unrelated to polygenic inheritance, such as uneven sample sizes or asymmetric population stratification, so precautions to correct for these confounders are essential. We tested our method on published GWAS results and observed a strong signal in some diseases (schizophrenia and type 2 diabetes) but not others. We also explored the shared genetic component in overlapping phenotypes related to inflammatory bowel disease (Crohn disease [CD] and ulcerative colitis [UC]) and diabetic nephropathy (macroalbuminuria and end-stage renal disease [ESRD]). Although the signal was still present when both CD and UC were jointly analyzed, the signal was lost when macroalbuminuria and ESRD were jointly analyzed, suggesting that these phenotypes should best be studied separately. Thus, our method may also help guide the design of future genetic studies of various traits and diseases.

FOXP3+ regulatory T-cell counts correlate with histological response in Crohn's colitis treated with infliximab

Crohn's disease is a chronic inflammatory bowel disease of unknown aetiology. Mucosal inflammatory dysregulation is likely important, with increased production of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFα). The chimeric monoclonal antibody, infliximab, inhibits TNFα and promotes intestinal mucosal healing. Despite this, many patients still require surgical intervention. Patients who have undergone colonic resection post-infliximab therapy, show markedly variable morphological response to treatment. FOXP3+ CD4+ regulatory T-cells have been shown to have a protective role in autoimmune/inflammatory diseases and their sequestration to the bowel is found in those treated with infliximab. We examined the immunohistochemical profile of lymphoid aggregates in tissue sections from post-infliximab Crohn's colitis resection specimens, classified as morphological responders or non-responders, defined in relation to the absence/presence of mucosal ulceration and active inflammation, and a control group. Results indicated no significant diffences in CD68-positive cell counts but increased FOXP3-positive (P = 0.02) and CD4-positive (P = 0.05) cell counts in responders versus non-responders. Untreated control scores were similar to non-responders. Although based on small study numbers, our results suggest an association between upregulation of FOXP3+/CD4+ regulatory T-cells and morphological response to infliximab therapy. This represents a possible quantitative methodology for monitoring therapeutic response to infliximab therapy, based on immunohistochemical evaluation of endoscopic biopsy specimens.

Development of a Parent Version of the Manchester-Minneapolis Quality of Life Survey for use by Parents and Crers of UK Children: MMQL-UK (PF).

Background Although it is now widely endorsed that children should as far as possible rate their own health related quality of life (HRQL), there are situations where proxy information on child HRQL may be useful, especially where a child is too ill or young to provide their own HRQL assessment. There is limited availability of generic HRQL scales that have a parallel child and parent version and that are reliable, valid, brief, comprehensible and suitable for use in UK populations. The aims of this study were therefore to develop and validate a parent version of the anglicised Manchester-Minneapolis Quality of Life child form (MMQL-UK (CF)) and to determine the level of association between the child and parent versions of this form. Methods This study was undertaken concurrently with the anglicisation and validation of the MMQL, a measure of HRQL developed for use with children in North America. At that time, no parent version existed, so the MMQL form for children (MMQL-UK (CF)) was used as the basis for the development of the MMQL-UK parent form (PF). The sample included a control group of healthy children and their parents and five exemplar groups; children diagnosed with asthma, diabetes or inflammatory bowel disease and their parents, children in remission from cancer and their parents and children in public care and their carers. Consistency of the MMQL-UK (PF) components were assessed by calculating Cronbach's alpha. Validation of the parent questionnaire was undertaken by comparing MMQL-UK (PF) component scores with comparable components on the proxy PedsQL™ quality of life scales, comparing MMQL-UK (PF) component scores between parents of healthy and chronic disease children and by comparison of component scores from children and their parents or carers. Reproducibility and responsiveness were assessed by retesting parents by follow-up questionnaires. Results A total of 874 children (completing MMQL-UK (CF)) and 572 parents or carers (completing MMQL-UK (PF)) took part in the study. The internal consistency of all the MMQL-UK (PF) components exceeding the accepted criterion of 0.70 and the construct validity was good with moderate correlations being evident between comparable components of the MMQL-UK (PF) and the proxy PedsQL™. Discriminant validity was demonstrated with significant differences being identified between parents of healthy children and those with chronic conditions. Intra-class correlations exceeded 0.65 for all MMQL-UK (PF) components demonstrating good reproducibility. Weak to moderate levels of responsiveness were demonstrated for all but social functioning. The MMQL-UK (PF) showed moderate parent-child correlation with the MMQL-UK (CF) for all components. The best correlations were seen for those components measuring the same construct (Pearson's r ranged from 0.31 to 0.61, p < 0.01 for equivalent components). Conclusion The MMQL-UK (PF) showed moderate to good correlations with the MMQL-UK (CF) component scores. The MMQL-UK (PF) will be of use when comparing child and parent/carer perception of the impact of a child's condition on their HRQL or where the child is too ill or young to provide their own report.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Recurrent Acute Pancreatitis and Therapy for Ulcerative Colitis.

Drugs are a rare cause of pancreatitis. Whereas some drugs are well known to induce an attack of pancreatitis, some people may be more prone to develop pancreatitis because of personal susceptibility. We describe a recurrent case of acute pancreatitis after administration of several drugs in a patient with intestinal inflammatory bowel disease that needed to be treated with subsequent antiinflammatory agents. Genetic mutation in the CFTR gene was found in the patient that led us to postulate that CFTR was a trigger for drug-induced acute pancreatitis. In conclusion, genetic analysis should be advised in case of recurrent pancreatitis in patient with intestinal inflammatory bowel disease.

A novel gene expression signature in peripheral blood mononuclear cells for early detection of colorectal cancer.

BACKGROUND: Early detection and treatment of colorectal adenomatous polyps (AP) and colorectal cancer (CRC) is associated with decreased mortality for CRC. However, accurate, non-invasive and compliant tests to screen for AP and early stages of CRC are not yet available. A blood-based screening test is highly attractive due to limited invasiveness and high acceptance rate among patients. AIM: To demonstrate whether gene expression signatures in the peripheral blood mononuclear cells (PBMC) were able to detect the presence of AP and early stages CRC. METHODS: A total of 85 PBMC samples derived from colonoscopy-verified subjects without lesion (controls) (n = 41), with AP (n = 21) or with CRC (n = 23) were used as training sets. A 42-gene panel for CRC and AP discrimination, including genes identified by Digital Gene Expression-tag profiling of PBMC, and genes previously characterised and reported in the literature, was validated on the training set by qPCR. Logistic regression analysis followed by bootstrap validation determined CRC- and AP-specific classifiers, which discriminate patients with CRC and AP from controls. RESULTS: The CRC and AP classifiers were able to detect CRC with a sensitivity of 78% and AP with a sensitivity of 46% respectively. Both classifiers had a specificity of 92% with very low false-positive detection when applied on subjects with inflammatory bowel disease (n = 23) or tumours other than CRC (n = 14). CONCLUSION: This pilot study demonstrates the potential of developing a minimally invasive, accurate test to screen patients at average risk for colorectal cancer, based on gene expression analysis of peripheral blood mononuclear cells obtained from a simple blood sample.

Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels.

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

Étude génétique et fonctionnelle de variantes de la région chromosomique 3p21 associée aux maladies inflammatoires de l'intestin

Des études de liaison et d’association génétiques ont permis d’identifier certains des facteurs de risque génétiques aux maladies inflammatoires de l’intestin (MII) dans la région chromosomique 3p21. Dans cette région, le polymorphisme nucléotidique simple (SNP) codant non-synonyme du gène MST1, rs3197999, encodant pour la mutation R689C, a été associé et répliqué à la fois à la colite ulcéreuse (CU) et à la maladie de Crohn (MC). Un autre SNP, corrélé à des SNP codants non-synonymes du gène MST1R, a également été associé à la MC. Afin de déterminer si d’autres variantes des gènes MST1 et MST1R sont associés à la CU, nous avons testé pour association des SNP de ces gènes. Seul un proxy de R689C a montré un signal d’association significatif aux MII, ce qui suggère que R689C est la variante causale aux MII dans le gène MST1. En cherchant à déterminer si la région 3p21 contenait plusieurs signaux d’association mutuellement indépendants, trois SNP ont été identifiés comme possible facteurs de risque indépendants, et ont été génotypés dans des cas de CU et de MC et des témoins, puis nos résultats d’association ont été combinés à ceux provenant de trois autres cohortes indépendantes. Les trois SNP, R689C (MST1), rs6802890 et rs7629936 (CDHR4), sont associés aux MII, mais une étude d’association conditionnelle suggère qu’il existe en fait deux signaux d’association mutuellement indépendants dans la région 3p21. Le signal principal provient de R689C, une mutation de la protéine MSP. Cette protéine a un rôle dans l’inflammation chez les macrophages murins, et la migration, la cicatrisation et la survie chez les cellules épithéliales. Dans cette étude, le rôle de la MSP a été investigué dans des modèles de macrophages humains et de cellules épithéliales de côlon, et seule la phosphorylation d’AKT, un acteur dans la voie de signalisation de la survie cellulaire, a été modulée par la MSP dans nos modèles. Ce projet a donc permis d’apporter des connaissances sur les facteurs de risques génétiques aux MII dans la région 3p21, en identifiant 2 signaux d’association indépendants, et en nous informant sur le rôle de MST1, duquel provient le signal d’association principal, chez les cellules humaines.

Développement de modulateurs allostériques peptidiques inhibiteurs de l’activité des récepteurs de l’interleukine 1 et de la vasopressine

L’approche Module X a été créée dans le but de concevoir de petits peptides modulateurs ayant des propriétés allostériques. Module X reproduit de petites parties des portions extracellulaires flexibles des récepteurs. Ces petits peptides vont interagir en s’interposant entre deux sous unités ou entre deux régions de la même sous-unité qui interagissent par des liens hydrogènes, des ponts salins ou des liens disulfure. Ces régions sont spécialement choisies à l’extérieur du domaine de liaison du ligand orthostérique et sont situées dans les régions inter domaines, la portion juxta membranaire ou dans les boucles. Étant donné que les boucles sont exposées durant les changements de conformation, une séquence peptidique reproduisant certaines régions de ces boucles pourrait s’insérer à un endroit approprié dans la structure où se lier à son partenaire de signalisation dans le complexe protéique, ce qui aurait comme effet de déplacer l’équilibre de l’ensemble vers un état particulier et modulerait ainsi la signalisation. De cette façon, certaines voies de signalisation pourraient être partiellement inhibées tandis que d’autres voies ne seraient pas touchées puisque le ligand orthostérique pourrait toujours se lier au récepteur. Dans une première étude, nous avons conçu des peptides inhibiteurs du récepteur de l’interleukine 1 (IL-1R/IL-1RAcP) plus précisément en reproduisant des régions flexibles de la protéine accessoire, sous-unité signalisatrice du récepteur. IL-1 est un médiateur majeur de l’inflammation, mais le seul antagoniste disponible est l’analogue naturel de IL-1, IL-1Ra qui compétitionne avec IL-1 pour le site de liaison sur le récepteur. Nous avons conçu plusieurs peptides à partir des boucles de la protéine accessoire. Un de ces peptides, rytvela (101.10) a démontré des propriétés de non-compétitivité et de sélectivité fonctionnelle caractéristiques des modulateurs allostériques. 101.10 bloque la prolifération des thymocytes et la synthèse de PGE2 avec un IC50 de 1 nM mais une efficacité de 100 % et 45 % respectivement et ne déplace pas IL-1 radioactif dans des essais de radioliaisons. De plus, 101.10 n’a qu’un effet minime sur l’affinité de IL-1 pour son récepteur. 101.10 démontre, de plus, une activité inhibitrice in vivo dans des modèles d’inflammation de l’intestin chez le rat (efficacité supérieure aux corticostéroïdes et à IL-1Ra) et de dermatite chez la souris de même que dans un modèle d’hyperthermie induite par IL-1. La deuxième étude démontre que Module X peut être utilisé pour concevoir des inhibiteurs pour une autre grande famille de récepteurs : les récepteurs couplés aux protéines G. La vasopressine joue un rôle important dans l’équilibre hydro-osmotique et un moindre rôle dans la vasomotricité. Six peptides ont été conçus à partir de régions juxta membranaires du récepteur de la vasopressine V2R. Le peptide le plus actif, VRQ397 (IC50 = 0,69 nM dans un modèle de vasorelaxation du crémastère), a démontré de la sélectivité fonctionnelle en inhibant la synthèse de prostacycline mais sans inhiber l’activation de la protéine Gs et la génération d’ AMP cyclique. Le peptide VRQ397 ne pouvait déplacer le ligand naturel AVP marqué radioactivement; de même VRQ397 radioactif ne se liait que sur V2R et non pas sur d’autres récepteurs de la même famille tel que V1R (récepteur de la vasopressine de type I). Ces études décrivent la caractérisation de petits peptides modulateurs de la signalisation de IL-1R et V2R et présentant des propriétés de modulateurs allostériques.

Rôles et régulation des enzymes antioxydantes paraoxonases au niveau intestinal et implication dans les maladies inflammatoires de l'intestin

Le stress oxydant joue un rôle majeur dans le développement et l’évolution des maladies inflammatoires de l’intestin. Le corps humain est doté d’une panoplie d’enzymes antioxydantes ayant pour fonction de protéger l’intégrité cellulaire. De nouvelles enzymes au fort potentiel antioxydant, les paraoxonases (PON) 1, 2 et 3, ont récemment été identifiées tout au long du tube digestif, mais leurs rôles y restent inconnus. Les cellules intestinales Caco-2/15, qui ont la capacité de se différencier et d’acquérir les caractéristiques physiologiques de l'intestin grêle, ont été utilisées dans le présent travail pour étudier la régulation des PON. Les cellules ont été traitées avec différents effecteurs physiologiques (cytokines, LPS, stress oxydant) et pharmacologiques (fibrates, thiazolidinédiones) et l’expression des leurs gènes et protéines a été évaluée. Les résultats ont mis en lumière la modulation distincte de l’expression des PON par le stress oxydant et l’inflammation. Ceci suggère que chaque PON peut jouer un rôle différent au niveau intestinal et être impliquée dans le maintien de l’homéostasie. La régulation de l’expression des PON a également été largement explorée dans un article de revue. Pour définir le rôle de PON2, celle-ci étant potentiellement la plus importante pour l’homéostasie intestinale, les cellules Caco-2/15 ont été infectées à l’aide de lentivirus contenant des ARN d’interférence, ce qui a fortement réduit l’expression de PON2. En l’absence de PON2, les cellules Caco-2/15 étaient plus susceptibles face à un stress oxydant, la réponse inflammatoire était exacerbée et la perméabilité cellulaire paraissait altérée. Toutes ces composantes sont majeures dans le développement des maladies inflammatoires de l’intestin chez l’humain. De plus, des cellules Caco-2/15 de la PON2, ce qui a renforcé la force de la défense antioxydante cellulaire. Les résultats suggèrent que les PON jouent un rôle dans le maintien de l’homéostasie intestinale et pourraient être impliquées dans l’étiologie et la pathogenèse des maladies inflammatoires de l’intestin.