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Noncontaminated dietary oats may hamper normalization of the intestinal immune status in childhood celiac disease
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. (Marie-Louise Hammarström)
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2014 (Engelska)Ingår i: Clinical and Translational Gastroenterology, ISSN 2155-384X, E-ISSN 2155-384X, Vol. 5, artikel-id e58Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVES: Life-long, strict gluten-free diet (GFD) is the only treatment for celiac disease (CD). Because there is still uncertainty regarding the safety of oats for CD patients, the aim was to investigate whether dietary oats influence the immune status of their intestinal mucosa.

METHODS: Paired small intestinal biopsies, before and after >11 months on a GFD, were collected from children with CD who were enrolled in a randomized, double-blind intervention trial to either of two diets: standard GFD (GFD-std; n=13) and noncontaminated oat-containing GFD (GFD-oats; n=15). Expression levels of mRNAs for 22 different immune effector molecules and tight junction proteins were determined by quantitative reverse transcriptase (RT)-PCR.

RESULTS: The number of mRNAs that remained elevated was higher in the GFD-oats group (P=0.05). In particular, mRNAs for the regulatory T cell (Treg) signature molecules interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1), the cytotoxicity-activating natural killer (NK) receptors KLRC2/NKG2C and KLRC3/NKG2E, and the tight junction protein claudin-4 remained elevated. Between the two groups, most significant differences were seen for claudin-4 (P=0.003) and KLRC3/NKG2E (P=0.04).

CONCLUSIONS: A substantial fraction of pediatric CD patients seem to not tolerate oats. In these patients, dietary oats influence the immune status of the intestinal mucosa with an mRNA profile suggesting presence of activated cytotoxic lymphocytes and Tregs and a stressed epithelium with affected tight junctions. Assessment of changes in levels of mRNA for claudin-4 and KLC3/NKG2E from onset to after a year on oats containing GFD shows promise to identify these CD patients.

Ort, förlag, år, upplaga, sidor
2014. Vol. 5, artikel-id e58
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Pediatrik
Forskningsämne
immunologi
Identifikatorer
URN: urn:nbn:se:umu:diva-93052DOI: 10.1038/ctg.2014.9ISI: 000355530800002PubMedID: 24964993Scopus ID: 2-s2.0-84903278030OAI: oai:DiVA.org:umu-93052DiVA, id: diva2:745919
Tillgänglig från: 2014-09-11 Skapad: 2014-09-11 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. Innate immunity of human intestinal epithelium in childhood celiac disease: influences from celiac disease associated bacteria and dietary oats
Öppna denna publikation i ny flik eller fönster >>Innate immunity of human intestinal epithelium in childhood celiac disease: influences from celiac disease associated bacteria and dietary oats
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background & Aims: Celiac disease (CD) is a chronic inflammatory small-bowel enteropathy caused by permanent intolerance to gliadin in wheat gluten, and related proteins in ray and barley. It is disputed whether CD patients tolerate oats. The only treatment of CD is lifelong gluten-free diet (GFD). Only individuals that carry the HLA-DQ2 and/or DQ8 alleles, and eat gluten can develop CD. Dysbiosis in the gut microbiota is a suggested risk factor for CD. T cells in small intestinal mucosa, including intraepithelial lymphocytes (IELs), are known to be important in the pathogenesis of CD. In contrast, the role of intestinal epithelial cells (IECs) is poorly understood. In this thesis we investigated the role of IECs in the immune pathology of CD from duodenal mucosa of children with CD, clinical controls and treated CD. We also investigated the role of CD associated bacteria and oats supplemented GFD on the mucosal immune system.

Results: A new CD-associated bacterium, Prevotella jejuni, was isolated and characterized. It is a saccharolytic and proteolytic anaerobe. More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were upregulated in IECs in active CD. In two in vitro models for intestinal epithelium, small intestine enteroids and T84 polarized tight monolayers, we showed that 70% of these genes were upregulated by interferon (IFN)-γ via the IRF1 pathway. IRF1 was also upregulated by the CD-associated bacteria P. jejuni and Actinomyces gravenitzii. IECs expressed the NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin (IL)-18, which induces IFN-γ in IELs. P. jejuni bound the intestinal epithelial cell lines T84, Caco2, HT29, and INT407, while Lachnoanaerobaculum umeaense preferentially bound Caco2. P. jejuni caused decreased transepithelial resistance over tight monolayers, while L. umeaense caused an increase. P. jejuni upregulated mRNAs for the detoxification molecules CYP1A1, CYP1A2, CYP1B1, and TIPARP, the chemokines CX3CL1, CXCL1, and CXCL10, the sialyltranserase ST3GAL4, and the inflammation promoting protein S100A3 in tight monolayers. L. umeaense upregulated the chemokines CCL20 and CXCL10, and down-regulated TLR2. In a randomized, double-blinded intervention trial comparing two study-groups, standard GFD and oat-containing GFD, we found that mRNAs for several immune effector molecules and tight junction proteins were only reduced in patients receiving GFD, but not in a substantial fraction of patients on GFD with oats. The down-regulatory cytokines IL-10 and TGF-β1, the cytotoxicity-activating NK-receptors NKG2C and NKG2E, and the tight junction protein claudin-4 remained elevated in the study group on GFD with oats.

Conclusions: IECs are far from inactive in CD. A key factor in the epithelial reaction in CD appears to be over-expression of IRF1 in IECs. Dual activation of IRF1 and IRF1-regulated genes, both directly by P. jejuni and indirectly by IFN-γ via the IL-18-inflammasome, would drastically enhance the inflammatory response and lead to the pathological situation seen in active CD. P. jejuni harms the intestinal epithelium, i.e., it is a likely risk factor for CD, while L. umeaense strengthen barrier function and local immunity, possibly acting as a protective. A fraction of CD patients should avoid oats in the diet.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2017. s. 75
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1924
Nyckelord
Celiac disease, dietary oats, gut microbiota, intestinal epithelium, IEL, IFN-γ, IRF1, IL-18, CXC3L1, inflammasome, permeability, Prevotella jejuni, Lachnoanaerobaculum umeaense
Nationell ämneskategori
Immunologi inom det medicinska området
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:umu:diva-140691 (URN)978-91-7601-768-5 (ISBN)
Disputation
2017-11-23, A5_R0, Analysvägen 3, Umeå, 09:00 (Engelska)
Opponent
Handledare
Projekt
Doctoral thesis
Tillgänglig från: 2017-11-02 Skapad: 2017-10-25 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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