Non-celiac gluten sensitivity: All wheat attack is not celiac

Abstract

Currently, 1% of the United States population holds a diagnosis for celiac disease (CD), however, a more recently recognized and possibly related condition, "non-celiac gluten sensitivity" (NCGS) has been suggested to affect up to 6% of the United States public. While reliable clinical tests for CD exist, diagnosing individuals affected by NCGS is still complicated by the lack of reliable biomarkers and reliance upon a broad set of intestinal and extra intestinal symptoms possibly provoked by gluten. NCGS has been proposed to exhibit an innate immune response activated by gluten and several other wheat proteins. At present, an enormous food industry has developed to supply gluten-free products (GFP) with GFP sales in 2014 approaching $1 billion, with estimations projecting sales to reach $2 billion in the year 2020. The enormous demand for GFP also reflects a popular misconception among consumers that gluten avoidance is part of a healthy lifestyle choice. Features of NCGS and other gluten related disorders (e.g., irritable bowel syndrome) call for a review of current distinctive diagnostic criteria that distinguish each, and identification of biomarkers selective or specific for NCGS. The aim of this paper is to review our current understanding of NCGS, highlighting the remaining challenges and questions which may improve its diagnosis and treatment.

Keywords: Celiac disease; Gluten; Gluten free diet; Gluten related disorder; Non-celiac gluten sensitivity; Wheat.

Figure 1

Toll like receptors act as primary sensors to gliadin and non-gluten proteins like alpha amylase/trypsin inhibitors, and microbiota derived signals in non-celiac gluten sensitivity. Dysregulated microbiota also release lipopolysaccharide (LPS) in circulation which result in production of LPS-binding protein (LBP) from gastrointestinal and hepatic epithelial cells and soluble CD14 (sCD14) from monocytes/macrophages. This leads to activation of transcription factor nuclear factor-kappaB (NF-κB), which controls the expression of an array of inflammatory cytokine genes resulting in recruitment of neutrophils and macrophages. In contrast to CD, there is limited dendritic cell activation, resulting in reduced expression of Treg cells, reduced FOXP3, TGFβ, IL-10. All these factors with increased expression of claudin-4 culminate in reduced intestinal permeability and increased epithelial barrier. Gut dysbiosis can also promote inflammation through expansion of pro-inflammatory pathobionts. TLRs: Toll like receptors.

Figure 2

Proposed diagnostic algorithm for non-celiac gluten sensitivity. GCD: Gluten containing diet; GFD: Gluten free diet; CD: Celiac disease.