Non-Celiac Gluten Sensitivity: An Update

Abstract

Non-celiac gluten sensitivity (NCGS) is a clinical entity characterized by the absence of celiac disease and wheat allergy in patients that trigger reproducible symptomatic responses to gluten-containing foods consumption. Due to the lack of sensitive and reproducible biomarkers for NCGS diagnosis, placebo-controlled gluten challenges must be carried out for its diagnosis. The gluten challenges can be either double- or single-blind, for research or clinical practice purposes, respectively. For improving our understanding about the magnitude and relevance of NCGS in different populations, epidemiological studies based on self-report have been carried out. However, the gluten challenge-based prevalence of NCGS remains to be estimated. Since NCGS was recently recognized as a clinical entity, more studies are needed to delve into NCGS pathogenesis, for instance, the molecular interactions between the suspected cereal grain components that trigger NCGS, such as fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) and amylase and trypsin inhibitors, and the immune system remains to be elucidated. Although still under debate, NCGS patients can be susceptible to only one or more than one of the NCGS triggers. The treatment of NCGS involves the dietary restriction of the suspected triggers of the disease, but there is controversial data about the effectiveness of different dietary interventions such as the gluten-free diet and low-FODMAP diet. Certainly, our understanding of NCGS is improving quickly due to the constant availability of new scientific information on this topic. Thus, the aim of the present narrative review is to present an up-to-date overview on NCGS from epidemiology to current therapy.

Keywords: NCGS; NCWS; gluten; wheat sensitivity.

Figure 1

Potential predisposing factors of NCGS.

Figure 2

Current evidence of the potential pathogenic mechanism of NCGS. (A) Interactions between gliadin peptides and CXCR3 receptors in the intestinal epithelium trigger the release of zonulin increasing the intestinal permeability. (B) A chain of reactions that involves the decrease of intestinal butyrate, increased levels of FABP2 and low levels of intestinal alkaline phosphatase is induced by an intestinal dysbiosis, which can induce an intestinal barrier dysfunction. (C) Microbial and dietary products can reach the lamina propria from the intestinal lumen due to an increased intestinal permeability. (D) Interactions between gliadin peptides and toll-like receptors 2–4 can occur triggering the release pro-inflammatory cytokines, such as CXCL10, GM-CSF, and TNF-α by myeloid cells. (E) Interactions between the TLR4-MD2–CD14 complex and ATIs/LPS could trigger the release of pro-inflammatory cytokines, such as IL-8, MCP-1, and IL-15 by myeloid cells. ATIs can enhance the adaptive immune response in the gut associated lymphoid tissue inducing the antigen presentation to T cells. (F) The release of pro-inflammatory cytokines can promote the recruitment of myeloid cells in the lamina propria, such as mast cells, eosinophils, monocytes, and dendritic cells, triggering local inflammation. (G) Microbial products can reach the blood stream triggering a systemic immune response. (H) FODMAPs can be fermented by the intestinal bacteria, giving rise to intestinal luminal distention. IL: intestinal lumen, IE: intestinal epithelium, LP: lamina propria, BC: blood circulation, TJ: tight junction, ATIs: amylase and trypsin inhibitors, FODMAPs: fermentable oligo-, di-, monosaccharides, and polyols, IEL: intraepithelial lymphocytes, DC: dendritic cell, TNF-α: tumor necrosis factor α, MCP-1: monocyte chemoattractant protein-1, GM-CSF: granulocyte-macrophage colony-stimulating, AGA: anti-gliadin antibodies, FABP2: intestinal fatty acid-binding protein 2, LBS: lipopolysaccharide-binding protein.

Figure 3

Dietary management in NCGS. Acronyms. GFD: gluten-free diet, FODMAP: fermentable oligo-, di-, monosaccharides, and polyols.