0000000000133724
AUTHOR
Victor F. Zevallos
Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders
Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies sug…
Wheat Amylase Trypsin Inhibitors as Nutritional Activators of Innate Immunity
While the central role of an adaptive, T cell-mediated immune response to certain gluten peptides in celiac disease is well established, the innate immune response to wheat proteins remains less well defined. We identified wheat amylase trypsin inhibitors (ATIs), but not gluten, as major stimulators of innate immune cells (dendritic cells > macrophages > monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2 toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17 proteins with molec…
Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid‐like nanoparticles resolves liver fibrosis
Fibrosis accompanies the wound-healing response to chronic liver injury and is characterized by excessive hepatic collagen accumulation dominated by collagen type I that often progresses to cirrhosis. Here we present ample in-vivo evidence of an up to 90% suppression of procollagen α1(I) expression, a reduction of septa formation and a 40–60% decrease of collagen deposition in mice with progressive and advanced liver fibrosis, that received cationic lipid nanoparticles loaded with small interfering RNA to the procollagen α1(I) gene (LNP-siCol1a1). After intravenous injection up to ninety percent of LNP-siCol1a1 were retained in the liver of fibrotic mice and accumulated in nonparenchymal > …
The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update
Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
Nonceliac gluten sensitivity.
During the past decade there has been an impressive increase in popularity of the gluten-free diet (GFD)—now the most trendy alimentary habit in the United States and other countries. According to recent surveys, as many as 100 million Americans will consume gluten-free products within a year. Operating under the concept that the GFD benefits only individuals with celiac disease, health care professionals have struggled to separate the wheat from the chaff; there are claims that eliminating gluten from the diet increases health and helps with weight loss, or even that gluten can be harmful to every human being. However, apart from unfounded trends, a disorder related to ingestion of gluten …
Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal Dysfunction Induced by Immunogenic Wheat Proteins.
Background & Aims Wheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial. Methods C57BL/6 (control), Myd88–/–, Ticam1–/–, and Il15–/– mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and int…
Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells.
Background & Aims Wheat amylase-trypsin inhibitors (ATIs) are nutritional activators of innate immunity, via activation of the toll-like receptor 4 (TLR4) on myeloid cells. We aimed to characterize the biologic activity of ATIs in various foods and their effect on intestinal inflammation. Methods We selected 38 different gluten-containing and gluten-free products, either unprocessed (such as wheat, rye, barley, quinoa, amaranth, soya, lentils, and rice) or processed (such as pizza, pasta, bread, and biscuits). ATIs were extracted and their biological activities determined in TLR4-responsive mouse and human cell lines. Effects of oral ATIs on intestinal inflammation were determined in health…
Sourdough Fermentation Degrades Wheat Alpha-Amylase/Trypsin Inhibitor (ATI) and Reduces Pro-Inflammatory Activity
The ingestion of gluten-containing foods can cause wheat-related disorders in up to 15% of wheat consuming populations. Besides the role of gluten, &alpha
Refractory coeliac disease: one step closer to the origin of aberrant lymphocytes.
Aberrant intraepithelial lymphocytes (IELs) are the key feature of refractory coeliac disease type II (RCDII), but the cellular origin of these aberrant IELs remains unclear. In a recent paper Schmitz et al 1 further explored previously characterised aberrant IEL cell lines from four patients with RCDII by using a broad spectrum of cell specific markers, RNA array and immunological techniques, to compare these cell lines to IELs from the fetal intestine, the intestine of children and adults and the thymus. IELs are a heterogeneous population of lymphocytes with innate and adaptive features that inhabit the small and large intestine. IELs are important for the maintenance of tolerance to com…
A266 AMYLASE TRYPSIN INHIBITORS FROM WHEAT EXACERBATE GLUTEN-INDUCED PATHOLOGY AND ALTER GUT MICROBIOTA IN MICE
BACKGROUND: Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten in genetically susceptible individuals expressing HLA DQ2 or DQ8. The adaptive immune response is characterized by a gluten-specific T-cells, anti-gluten and anti-tissue transglutaminase-2 antibodies. Proliferation and activation of intraepithelial lymphocytes (IELs) is central to the innate immune response, although the triggers and receptors remain unclear. Amylase trypsin inhibitors (ATIs) are pest-resistant molecules in modern wheat with TLR4-activating capacities in mononuclear phagocytic cells. AIMS: Our aim was to determine whether ATIs act as innate activators, enhancing gluten immunopathology in mice.…
Non-celiac wheat sensitivity: differential diagnosis, triggers and implications.
Abstract Non allergy-non-celiac wheat sensitivity (NCWS) has become a common and often overrated diagnosis. Skepticism mainly relates to patients with prominent intestinal symptoms in the absence of general or intestinal signs of inflammation. There is consensus that the major wheat sensitivities, celiac disease and wheat allergy, have to be ruled out which may be difficult for wheat allergy. The non-inflammatory intolerances to carbohydrates, mainly lactose and FODMAPs (fermentable oligi-, di-, monosaccharides and polyols), which cause bloating or diarrhoea, can usually be excluded clinically or by simple tests. Recent studies and experimental data strongly indicate that NCWS exists in a s…
Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria
Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts' recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation i…
Testing safety of germinated rye sourdough in a celiac disease model based on the adoptive transfer of prolamin-primed memory T cells into lymphopenic mice.
The current treatment for celiac disease is strict gluten-free diet. Technical processing may render gluten-containing foods safe for consumption by celiac patients, but so far in vivo safety testing can only be performed on patients. We modified a celiac disease mouse model to test antigenicity and inflammatory effects of germinated rye sourdough, a food product characterized by extensive prolamin hydrolysis. Lymphopenic Rag1−/− or nude mice were injected with splenic CD4+CD62L−CD44high-memory T cells from gliadin- or secalin-immunized wild-type donor mice. We found that: 1) Rag1−/− recipients challenged with wheat or rye gluten lost more body weight and developed more severe histological…
P68 A diet rich in wheat alpha-amylase/trypsin inhibitors (ATIs) enhances disease progression in the MRL-Fas(lpr) mouse model of systemic lupus erythematosus
Background Wheat alpha-amylase/trypsin inhibitors (ATIs) are the second most prevalent proteins in wheat (3–4% vs 80–90% for gluten) and potent activators of the innate immune system via the toll like receptor 4 (TLR4)-MD2-CD14 complex in cells of the mononuclear phagocyte system (Junker Y et al, J Exp Med 2012), triggering several autoimmune/inflammatory diseases. In contrast, pure gluten that is de-enriched of ATIs shows no stimulatory activity. MRL-Fas(lpr) mice develop progressive and spontaneous glomerular, tubulointerstitial and perivascular kidney disease, arthritis, lymphadenopathy, splenomegaly and circulating autoantibodies in a syndrome that resembles systemic lupus erythematosus…
Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4
Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an ill-defined component of innate immunity in celiac disease. We identify the α-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4–MD2–CD14 complex and lead to up-regulation of maturation markers a…
Wheat amylase-trypsin inhibitors exacerbate intestinal and airway allergic immune responses in humanized mice.
Background Amylase-trypsin inhibitors (ATIs) in wheat and related cereals are potent activators of myeloid innate immune cells via engagement of TLR4. Furthermore, ATIs have been shown to serve as adjuvants in experimental intestinal inflammatory diseases. Objective The aim of this study was to analyze whether ATIs are also modifiers of allergic inflammation. Methods Therefore, CD4 + T cells from donors sensitized to grass or birch pollen were stimulated with autologous allergen-pulsed dendritic cells in the presence or absence of ATIs or the control storage protein zein from corn. To analyze allergen-induced gut and lung inflammation, immunodeficient mice were engrafted with PBMCs from the…