1.
Plasma IL-2 and Symptoms Response after Acute Gluten Exposure in Subjects With Celiac Disease or Nonceliac Gluten Sensitivity.
Cartee, AK, Choung, RS, King, KS, Wang, S, Dzuris, JL, Anderson, RP, Van Dyke, CT, Hinson, CA, Marietta, E, Katzka, DA, et al
The American journal of gastroenterology. 2022;(2):319-326
Abstract
INTRODUCTION Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure. METHODS Sixty subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up. Twelve serial questionnaires (100 mm visual analog scale; pain, bloating, nausea, and fatigue) and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactulose-13C mannitol ratios and endoscopic mucosal impedance. RESULTS Thirty-five of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS) and sham (9 CeD, 9 NCGS) compared with 9 of 20 (45%) controls after gluten (n = 6) and sham (n = 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge despite no significant intestinal permeability change from baseline. DISCUSSION Symptoms do not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates a rapid-onset gluten-induced T-cell activation in CeD despite long-standing treatment. The effector site is unknown, given no increased intestinal permeability after gluten.
2.
Effect of Gluten Ingestion and FODMAP Restriction on Intestinal Epithelial Integrity in Patients with Irritable Bowel Syndrome and Self-Reported Non-Coeliac Gluten Sensitivity.
Ajamian, M, Rosella, G, Newnham, ED, Biesiekierski, JR, Muir, JG, Gibson, PR
Molecular nutrition & food research. 2021;(5):e1901275
Abstract
SCOPE Since epithelial barrier dysfunction has been associated with gluten and fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAPs), the effect of alterations in FODMAP a gluten intake on epithelial barrier function in patients with irritable bowel syndrome (IBS) who self-reported gluten sensitivity. METHODS AND RESULTS Circulating concentrations of markers of epithelial injury (syndecan-1 and intestinal fatty acid-binding protein) and bacterial translocation (lipopolysaccharide-binding protein and soluble CD14) are measured while consuming habitual gluten-free diet and during blinded challenges with gluten or placebo on a background of low FODMAP intake. In 33 patients, only syndecan-1 concentrations during their habitual diet are elevated (median 43 ng mL-1 ) compared with 23 ng mL-1 in 49 healthy subjects (p < 0.001). On a low FODMAP diet, symptoms are reduced and levels of syndecan-1 (but not other markers) fell by a median 3335% (p < 0.001) irrespective of whether gluten is present or not. CONCLUSION Gluten ingestion has no specific effect on epithelial integrity or symptoms in this cohort, but reducing FODMAP intake concomitantly reduces symptoms and reverses apparent colonic epithelial injury. These findings highlight the heterogeneity of populations self-reporting gluten sensitivity and implicate FODMAPs in colonic injury in IBS.
3.
A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.
Hardy, MY, Goel, G, Russell, AK, Chen Yi Mei, SLG, Brown, GJE, Wang, S, Szymczak, E, Zhang, R, Goldstein, KE, Neff, KM, et al
Frontiers in immunology. 2021;:661622
Abstract
Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
4.
Benefits From and Barriers to Portable Detection of Gluten, Based on a Randomized Pilot Trial of Patients With Celiac Disease.
Wolf, RL, Green, PHR, Lee, AR, Reilly, NR, Zybert, P, Lebwohl, B
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(12):2605-2607
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Abstract
Research links diminished quality of life (QOL) to the challenges of a strict gluten-free diet (GFD), the only treatment for celiac disease (CD).1-4 This pilot study assessed the acceptability and feasibility of a portable gluten sensor device (Nima) to promote GFD adherence and QOL.