Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

Abstract

Objective: Wheat gluten and related proteins can trigger an autoimmune enteropathy, known as coeliac disease, in people with genetic susceptibility. However, some individuals experience a range of symptoms in response to wheat ingestion, without the characteristic serological or histological evidence of coeliac disease. The aetiology and mechanism of these symptoms are unknown, and no biomarkers have been identified. We aimed to determine if sensitivity to wheat in the absence of coeliac disease is associated with systemic immune activation that may be linked to an enteropathy.

Design: Study participants included individuals who reported symptoms in response to wheat intake and in whom coeliac disease and wheat allergy were ruled out, patients with coeliac disease and healthy controls. Sera were analysed for markers of intestinal cell damage and systemic immune response to microbial components.

Results: Individuals with wheat sensitivity had significantly increased serum levels of soluble CD14 and lipopolysaccharide (LPS)-binding protein, as well as antibody reactivity to bacterial LPS and flagellin. Circulating levels of fatty acid-binding protein 2 (FABP2), a marker of intestinal epithelial cell damage, were significantly elevated in the affected individuals and correlated with the immune responses to microbial products. There was a significant change towards normalisation of the levels of FABP2 and immune activation markers in a subgroup of individuals with wheat sensitivity who observed a diet excluding wheat and related cereals.

Conclusions: These findings reveal a state of systemic immune activation in conjunction with a compromised intestinal epithelium affecting a subset of individuals who experience sensitivity to wheat in the absence of coeliac disease.

Keywords: CELIAC DISEASE; GUT INFLAMMATION; INTESTINAL BARRIER FUNCTION; INTESTINAL EPITHELIUM.

Figure 1

Markers of coeliac disease and immune reactivity to wheat gluten. Serum levels of (A) IgA antibody to transglutaminase 2 (TG2), (B) IgG antibody to deamidated gliadin, (C) IgA antibody to deamidated gliadin, (D) IgG antibody to native gliadin, (E) IgA antibody to native gliadin and (F) IgM antibody to native gliadin in cohorts of healthy controls, patients with coeliac disease and individuals identified as having non-coeliac wheat sensitivity (NCWS). Horizontal red lines indicate the median for each cohort.

Figure 2

Markers of systemic immune response to microbial components. Serum levels of (A) lipopolysaccharide-binding protein (LBP), (B) soluble CD14 (sCD14), (C) endotoxin-core antibodies (EndoCAb) IgG, (D) EndoCAb IgM, (E) IgG antibody to flagellin and (F) IgM antibody to flagellin in cohorts of healthy controls, patients with coeliac disease and individuals with non-coeliac wheat sensitivity (NCWS). Horizontal red lines indicate the median for each cohort.

Figure 3

Intestinal epithelial cell damage and correlation with systemic immune activation. (A) Serum levels of fatty acid-binding protein 2 (FABP2) in cohorts of healthy controls, patients with coeliac disease and individuals identified as having non-coeliac wheat sensitivity (NCWS). (B and C) Correlation of serum levels of FABP2 with lipopolysaccharide-binding protein (LBP) (B) and soluble CD14 (sCD14) (C) in individuals with NCWS. Horizontal red lines indicate the median for each cohort.

Figure 4

Principal component analysis (PCA) score plot for the complete dataset of serological markers (anti-transglutaminase 2 (anti-TG2) IgA; anti-deamidated gliadin IgG and IgA; anti-gliadin IgG, IgA and IgM; lipopolysaccharide-binding protein (LBP); soluble CD14 (sCD14); endotoxin-core antibodies (EndoCAb) IgG, IgA and IgM; anti-flagellin IgG, IgA and IgM; and fatty acid-binding protein 2 (FABP2)) measured in healthy controls, patients with coeliac disease and individuals with non-coeliac wheat sensitivity (NCWS). Subjects are plotted in two dimensions using the first and second principal components (PC1 and PC2).

Figure 5

Symptoms and anti-gliadin antibody reactivity in response to the restrictive diet. (A and B) Composite scores for intestinal symptoms (bloating, abdominal pain, diarrhoea, epigastric pain and nausea) and extraintestinal symptoms (fatigue, headache, anxiety, memory and/or cognitive disturbances, and numbness in arms and/or legs) before and after 6 months of a diet free of wheat, rye and barley in a cohort of 20 patients with non-coeliac wheat sensitivity (NCWS). (C–E) Levels of IgG, IgA and IgM antibody to gliadin proteins before and 6 months after starting the diet in the NCWS cohort. Each individual is represented by a dot and the two points corresponding to the same individual are connected by a line. Each box indicates the 25th–75th percentiles of distribution, with the horizontal line inside the box representing the median.

Figure 6

Markers of intestinal epithelial cell damage and systemic immune activation in response to the restrictive diet. (A–F) Levels of lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), endotoxin-core antibodies (EndoCAb) IgM, anti-flagellin IgG, anti-flagellin IgM and fatty acid-binding protein 2 (FABP2) before and after 6 months of a diet free of wheat, rye and barley in the cohort of 20 patients with non-coeliac wheat sensitivity (NCWS). Each individual is represented by a dot and the two points corresponding to the same individual are connected by a line. Each box indicates the 25th–75th percentiles of distribution, with the horizontal line inside the box representing the median.