Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease - PubMed (original) (raw)

Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease

Jing Cheng et al. BMC Gastroenterol. 2013.

Abstract

Background: Celiac disease (CD) is an autoimmune disorder of the small intestine which is triggered by dietary gluten in genetically predisposed (HLA-DQ2/DQ8 positive) individuals. Only a fraction of HLA-DQ2/DQ8 positive individuals develop CD indicating that other factors have a role in the disorder. Several studies have addressed intestinal microbiota aberrancies in pediatric CD, but the results are inconsistent. Previously, we demonstrated that pediatric CD patients have lower duodenal expression of TLR2 and higher expression of TLR9 as compared to healthy controls (HC) indicating that microbiota may have a role in CD.

Methods: We used bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of CD (n = 10) and HC (n = 9) children. The expression of selected mucosa-associated genes was assessed by qRT-PCR in CD and HC children and in treated CD adults (T-CD, n = 6) on gluten free diet.

Results: The overall composition, diversity and the estimated microbe associated molecular pattern (MAMP) content of microbiota were comparable between CD and HC, but a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between HC and CD. In HC, increased TLR2 expression was positively correlated with the expression of tight junction protein ZO-1. In CD and T-CD, the expression of IL-10, IFN-g and CXCR6 were higher as compared to HC.

Conclusions: The results suggest that microbiota and altered expression of mucosal receptors have a role in CD. In CD subjects, the increased expression of IL-10 and IFN-g may have partly resulted from the increased TLR9 expression and signaling.

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Figures

Figure 1

Figure 1

Composition of the duodenal mucosa-associated microbiota in healthy control (HC and celiac disease (CD) children. Relative proportions of bacterial phylum-like groups of the total microbiota are depicted for each individual (HC1-HC9 and CD1-CD10).

Figure 2

Figure 2

Relative proportion of phylum-like groups in the duodenal microbiota of celiac disease (CD, white columns) and healthy control children (HC, grey columns). Mean and standard error are shown for HC (n = 9) and CD (n = 10) groups.

Figure 3

Figure 3

Duodenal microbiota diversity in healthy control (HC, n = 9) and celiac disease (CD, n = 10) children. The dominant/common species richness and evenness was assessed by Simpson Reciprocal (1/D) and overall species richness and evenness was assessed by Shannon Indices. Boxplot shows 25th to 75th percentile, with a line at median.

Figure 4

Figure 4

Sub-profile of the duodenal microbiota separating celiac disease (CD) and healthy control (HC) children. A) Eight HITChip genus-like level bacterial groups selected with random forest and cross-validation showing higher abundance in either HC (5 groups) or CD (3 groups). The error rate of random forest is 31.6%, whereas 95% confidence intervals for random assignment are [32%, 74%]. B) The profile of eight bacterial groups separates healthy control children (HC) and celiac disease children (CD) in redundancy analysis (RDA). p-value obtained by permutation test (50000 permutations) is 0.050.

Figure 5

Figure 5

The relative expression of zonula occludens 1 (ZO-1) (A) and the scatterplot of ZO-1 and TLR2 expressions (B) in duodenal biopsies. A) Expression of ZO-1 in duodenal biopsies of healthy control children (HC, n = 8), celiac disease children (CD, n = 9) and treated celiac disease adults (T-CD, n = 6). The relative gene expression of ZO-1 is significantly between CD and T-CD (*p < 0.05). Boxplot shows 25th to 75th percentile with a line at median and the whiskers represent interquartile range. Samples, which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. B) The scatterplot of relative expression of ZO-1 and TLR2 in duodenal biopsies of HC. The relationship between ZO-1 and TLR2 expressions is estimated by linear regression, and indicated by dashed line. The effect of slope is significant (p = 0.02), having coefficient of determination (R2) of 0.63.

Figure 6

Figure 6

The relative expression of CXCL6 (A) and CXCR16 (B) in duodenal biopsies of healthy control children (HC, n = 8), celiac disease children (CD, n = 9) and treated celiac adults (T-CD, n = 6). Boxplot shows 25th to 75th percentile with a line at median and the whisker represents interquartile range. Samples, which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. A) The difference in CXCR6 expression between HC and CD or T-CD is statistically significant (*p < 0.05). B) CXCL16 expression shows no significant differences between the groups.

Figure 7

Figure 7

The relative expression of interleukin-10 (IL-10) (A), interferon gamma (IFNγ**) (B) and IL-10 to IFN**γ mRNA ratio (C) in duodenal biopsies of healthy control children (HC, n = 10), celiac disease children (CD, n = 10) and treated celiac adults (T-CD, n = 6). Boxplot shows 25th to 75th percentile with a line at median and the whisker represents interquartile range. Samples which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. A) IL-10 expression is significantly different between HC and CD. B) IFNγ expression is significantly different between HC and CD or T-CD. C) The ratio of IL-10/IFNγ expression is significantly different between HC and CD or T-CD. The significance between study groups: *p < 0.05.

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