1.
Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity.
Hollon, J, Puppa, EL, Greenwald, B, Goldberg, E, Guerrerio, A, Fasano, A
Nutrients. 2015;7(3):1565-76
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Celiac disease (CD) and non-celiac gluten sensitivity (GS) are conditions caused by a reaction to gluten in the small intestines. When gluten is ingested, patients with CD produce an immune-mediated response in the intestinal mucosa whereas GS react symptomatically but do not produce an immune response. Due to this difference, it is thought that there may be a common defect in the intestinal barrier function in these two conditions. The aim of this study was to evaluate the response to gliadin exposure, both in terms of intestinal barrier function and immune cell secretion. Gliadin is a peptide in gluten that is responsible for the disassembly of intestinal tight junctions and therefore increased intestinal permeability. The study included intestinal explants from 23 patients. The findings of this study showed that gliadin exposure leads to a significant increase in intestinal permeability in all individuals. A deficiency in anti-inflammatory immune cells was also measured in patients with CD or GS, which is suggested to contribute to increased intestinal permeability.
Abstract
BACKGROUND Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). METHODS Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. RESULTS Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. CONCLUSIONS Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.
2.
Reintroduction of gluten following flour transamidation in adult celiac patients: a randomized, controlled clinical study.
Mazzarella, G, Salvati, VM, Iaquinto, G, Stefanile, R, Capobianco, F, Luongo, D, Bergamo, P, Maurano, F, Giardullo, N, Malamisura, B, et al
Clinical & developmental immunology. 2012;2012:329150
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A lifelong gluten-free diet (GFD) is mandatory for celiac disease (CD) but has poor compliance, justifying new strategies. Chemically altering the protein in wheat flour (transamidation of gliadin) reduces the reaction experienced in vitro in intestinal cells of CD patients. This randomized single blinded, controlled 90-day trial in 47 CD patients examines the safety of transamidated wheat flour compared to control. 35 patients received 50g a day of transamidated flour bread and 12 received 3.7g of non-transamidated flour bread. On day 15, 75% and 37% of patients in the control and experimental groups, respectively, showed clinical relapse whereas intestinal permeability was mainly altered in the control group. On day 90, 0 controls and 14 patients in the experimental group completed the challenge with no change to the autoantibody found in CD (Ttg) and other markers of CD. This study demonstrated that a protracted intake of gluten from chemically treated wheat flour was associated with a reduced number of relapses in challenged patients. Nevertheless, the enzyme reaction did not eradicate gluten activity in all CD patients examined. Whether an upgrade of the transamidation reaction might be instrumental in blocking other immune components involved in the mucosal lesion is under investigation.
Abstract
A lifelong gluten-free diet (GFD) is mandatory for celiac disease (CD) but has poor compliance, justifying novel strategies. We found that wheat flour transamidation inhibited IFN-γ secretion by intestinal T cells from CD patients. Herein, the primary endpoint was to evaluate the ability of transamidated gluten to maintain GFD CD patients in clinical remission. Secondary endpoints were efficacy in prevention of the inflammatory response and safety at the kidney level, where reaction products are metabolized. In a randomized single blinded, controlled 90-day trial, 47 GFD CD patients received 3.7 g/day of gluten from nontransamidated (12) or transamidated (35) flour. On day 15, 75% and 37% of patients in the control and experimental groups, respectively, showed clinical relapse (P = 0.04) whereas intestinal permeability was mainly altered in the control group (50% versus 20%, P = 0.06). On day 90, 0 controls and 14 patients in the experimental group completed the challenge with no variation of antitransglutaminase IgA (P = 0.63), Marsh-Oberhuber grading (P = 0.08), or intestinal IFN-γ mRNA (P > 0.05). Creatinine clearance did not vary after 90 days of treatment (P = 0.46). In conclusion, transamidated gluten reduced the number of clinical relapses in challenged patients with no changes of baseline values for serological/mucosal CD markers and an unaltered kidney function.