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Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity - PubMed

  • ️Sat Jan 01 2011

Comparative Study

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

Anna Sapone et al. BMC Med. 2011.

Abstract

Background: Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders.

Methods: CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity.

Results: Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293).

Conclusions: This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

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Figures

Figure 1
Figure 1

Reduced intestinal permeability in gluten-sensitive (GS) patients. Small intestinal permeability was probed by measuring the urinary cumulative 5-hour amount of lactulose (LA) (percentage of ingested), mannitol (MA) and the LA-to-MA ratio as described in (see Methods). Boxes represent the medians and interquartile ranges, and whiskers represent the range of independent determinations in 13 GS patients, 11 celiac disease (CD) patients, and 14 dyspeptic controls (DC) (see intestinal permeability section of the text, pages 8-9). *P < 0.05 relative to DC and †P < 0.05 relative to CD (Mann-Whitney U test).

Figure 2
Figure 2

The relative expression of tight junction (TJ)-related genes in the mucosa of gluten-sensitive patients (GS) versus celiac disease patients (CD). Expression of the indicated genes encoding for components of the TJ complex was measured by quantitative polymerase chain reaction assay of RNA extracted from small intestinal bioptic specimens (see Methods). Boxes represent the median (interquartile ratio), and whiskers represent the range of relative RNA levels, expressed as a percentage of an 18S housekeeping gene in 24 GS patients, 31 CD patients and 24 dyspeptic controls. *P < 0.05 relative to CD (Mann-Whitney U test).

Figure 3
Figure 3

Reduced numbers of intraepithelial lymphocytes (IELs) in gluten-sensitive patients (GS) versus celiac disease patients (CD). Small intestinal bioptic specimens were stained for the T-cell marker CD3 in immunohistochemistry, and CD3+ cells are enumerated as indicated in Methods. Boxes represent the median (interquartile range), and whiskers represent the range of IEL numbers relative to 100 enterocytes in the same samples in 16 GS, 11 CD and 12 dyspeptic controls (DC). ***P < 0.0005 relative to DC; †††P < 0.0005 relative to CD (Mann-Whitney U test).

Figure 4
Figure 4

Increased levels of transcripts for effector cytokines in the mucosa from celiac disease patients (CD) but not gluten-sensitive patients (GS). Expression of the indicated genes was measured by quantitative polymerase chain reaction assay (see Methods). Boxes represent the median (interquartile range) and whiskers represent the range of RNA levels relative to an 18S housekeeping gene in 13 GS, 19 CD and 11 dyspeptic controls (DC). *P < 0.05 relative to DC (Mann-Whitney U test).

Figure 5
Figure 5

Increased levels of transcripts for pattern recognition receptors in the mucosa from gluten-sensitive patients (GS) but not celiac disease patients (CD). Expression of the indicated genes encoding for Toll-like receptors TLR1, TLR2 and TLR4 was measured by quantitative polymerase chain reaction assay (see Methods). Boxes represent the median (interquartile range) and whiskers represent the range of RNA levels relative to an 18S housekeeping gene in 8 GS, 12 CD and 5 dyspeptic controls (DC). *P < 0.05 relative to DC (Mann-Whitney U test).

Figure 6
Figure 6

Reduced levels of transcripts of immune regulatory genes in the mucosa from gluten-sensitive patients (GS), but not celiac disease patients (CD). Expression of the indicated genes was measured by quantitative polymerase chain reaction assay (see Methods). Boxes represent the median (interquartile range) and whiskers represent the range of RNA levels relative to an 18S housekeeping gene in 19 GS, 12 CD and 8 dyspeptic controls (DC). *P < 0.05 relative to DC (Mann-Whitney U test).

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