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Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.

ABSTRACT: Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability, a postulated early element in the pathogenesis of celiac disease. We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.Alpha-gliadin affinity column was loaded with intestinal mucosal membrane lysates to identify the putative gliadin-binding moiety. In vitro experiments with chemokine receptor CXCR3 transfectants were performed to confirm binding of gliadin and/or 26 overlapping 20mer alpha-gliadin synthetic peptides to the receptor. CXCR3 protein and gene expression were studied in intestinal epithelial cell lines and human biopsy specimens. Gliadin-CXCR3 interaction was further analyzed by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. Ex vivo experiments were performed using C57BL/6 wild-type and CXCR3(-/-) mouse small intestines to measure intestinal permeability and zonulin release.Affinity column and colocalization experiments showed that gliadin binds to CXCR3 and that at least 2 alpha-gliadin 20mer synthetic peptides are involved in this binding. CXCR3 is expressed in mouse and human intestinal epithelia and lamina propria. Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet. Gliadin induced physical association between CXCR3 and MyD88 in enterocytes. Gliadin increased zonulin release and intestinal permeability in wild-type but not CXCR3(-/-) mouse small intestine.Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability.

SUBMITTER: Lammers KM

PROVIDER: S-EPMC2653457 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.

Lammers Karen M KM Lu Ruliang R Brownley Julie J Lu Bao B Gerard Craig C Thomas Karen K Rallabhandi Prasad P Shea-Donohue Terez T Tamiz Amir A Alkan Sefik S Netzel-Arnett Sarah S Antalis Toni T Vogel Stefanie N SN Fasano Alessio A

Gastroenterology 20080321 1

<h4>Background & aims</h4>Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability, a postulated early element in the pathogenesis of celiac disease. We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment.<h4>Methods</h4>Alpha-gliadin affinity column was loaded with intes ...[more]

PMID: 18485912

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Project description:Worldwide, up to 20% of children and adolescents experience mental disorders, which are the leading cause of disability in young people. Research shows that serum zonulin levels are associated with increased intestinal permeability (IP), affecting neural, hormonal, and immunological pathways. This systematic review and meta-analysis aimed to summarize evidence from observational studies on IP in children diagnosed with mental disorders. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the Cochrane Library, PsycINFO, PubMed, and the Web of Science identified 833 records. Only non-intervention (i.e., observational) studies in children (<18 years) diagnosed with mental disorders, including a relevant marker of intestinal permeability, were included. Five studies were selected, with the risk of bias assessed according to the Newcastle-Ottawa scale (NOS). Four articles were identified as strong and one as moderate, representing altogether 402 participants providing evidence on IP in children diagnosed with attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). In ADHD, elevated serum zonulin levels were associated with impaired social functioning compared to controls. Children with ASD may be predisposed to impair intestinal barrier function, which may contribute to their symptoms and clinical outcome compared to controls. Children with ASD, who experience gastro-intestinal (GI) symptoms, seem to have an imbalance in their immune response. However, in children with OCD, serum zonulin levels were not significantly different compared to controls, but serum claudin-5, a transmembrane tight-junction protein, was significantly higher. A meta-analysis of mean zonulin plasma levels of patients and control groups revealed a significant difference between groups (p = 0.001), including the four studies evaluating the full spectrum of the zonulin peptide family. Therefore, further studies are required to better understand the complex role of barrier function, i.e., intestinal and blood-brain barrier, and of inflammation, to the pathophysiology in mental and neurodevelopmental disorders. This review was PROSPERO preregistered, (162208).

Project description:BackgroundAccumulating evidence suggest that gut microbiota may impact urologic health including prostate cancer (PC), potentially via affecting intestinal permeability (IP). Studies have indicated that disrupted IP may be improved by healthy diets and weight loss. In the Carbohydrate and Prostate Study 2 (CAPS2) clinical trial, which showed that a low-carbohydrate diet (LCD) reduced weight significantly in men with PC and suggestively slowed PC disease progression, we explored the impact of LCD on an IP marker, zonulin and an inflammation marker, high sensitivity C-reactive protein (hsCRP).MethodsCAPS2 was a 6-month randomized controlled trial testing a LCD intervention vs. control on PC progression using prostate-specific antigen doubling time (PSADT) as the marker. All 45 participants had prior primary PC treatment, PSADT >3 and <36 months, and body mass index (BMI) ≥24 kg/m2.ResultsAt 6-month, zonulin decreased in the LCD arm (median -8.3%, IQR -16.6, 0.3%) while the control increased slightly (median 1.4%, IQR -3.0, 13.3%; p = .014). No changes were observed in hsCRP. Linear regression models showed that weight change was significantly associated with log(PSADT) such that the greater the weight loss, the longer the PSADT(p = .003). There was a similar inverse trend between change in zonulin and log(PSADT) (p = .050). Nevertheless, the mediation analysis showed that zonulin was not a significant intermediary mechanism of the effect of weight change on PSADT (p = .3).ConclusionFuture studies are merited to examine further the potential association of IP with inflammation and to clarify if improvement in IP is associated with decreased PC progression. Trial registration: NCT01763944. KEY MESSAGESGut microbiota may impact urologic health including prostate cancer, potentially via affecting intestinal permeability.Weight loss significantly improved intestinal permeability in prostate cancer patients.Improvement in intestinal permeability was associated with slowed prostate cancer progression as indicated by the PSA doubling time.

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Dataset Information

Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.

Publications

Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.

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