Gene Expression Profiles of Inflamed Bowel Biopsy Tissue in ASD Children Are Consistent with Inflammatory Bowel Disease
Saturday, May 19, 2012
Sheraton Hall (Sheraton Centre Toronto)
S. J. Walker1, J. Fortunato2 and A. Krigsman3, (1)Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, (2)Wake Forest University Health Sciences, Winston Salem, NC, (3)Pediatric Gastroenterology Resources of New York, Far Rockaway, NY
Background: Chronic gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD) are common and not well understood. It is unclear if GI symptoms and intestinal mucosal inflammatory changes seen in children with ASD represent a variant of inflammatory bowel disease (IBD) versus non-specific colitis or “normal” mucosal cellular composition. Some studies have demonstrated histochemical and immunohistochemical features of the bowel mucosa, lamina propria and mucosal basement membrane which may be unique to children with ASD. The recent emergence of gene expression profiling as a valid methodology for distinguishing various forms of IBD potentially adds a further tool in defining the characteristics of ASD-associated intestinal inflammation.
Objectives: The goal of this study was to use a molecular approach to evaluate gene expression profiles in both histologically inflamed and non-inflamed ileocolonic biopsy specimens from ASD children with chronic GI symptoms and to compare them to gene expression profiles in ileocolonic tissue of neurotypical children with Crohn’s disease. Significant overlap of gene expression in these two groups would suggest that ASD-GI represents an IBD variant; differences in the ASD-GI gene expression profile would highlight the nature of its distinction from Crohn’s disease.
Methods: Study tissue consisted of ileocolonic biopsies from two groups: (1) children with an ASD undergoing ileocolonoscopy for active gastrointestinal symptoms and, (2) neurotypical children diagnosed with Crohn’s disease. All tissue specimens were collected under appropriate IRB approval. For each individual (seven per group; fourteen in total) two biopsies were used: one from the terminal ileum with active inflammatory changes and one from the colon demonstrating normal mucosa (control). Total RNA was isolated from the individual tissue biopsy specimens and used to query whole genome DNA microarrays. For each of the two groups, ASD-GI and CD, differential gene expression was determined by comparing the inflamed tissue within a group to the control tissues from the same group. Next, differential gene expression was compared between the ASD-GI and CD groups to evaluate similarities and differences.
Results: In each group there were ~2000 transcriptsdifferentially expressed between inflamed and control tissue. Within the 900 differentially expressed genes shared by both ASD-GI and CD, two highly relevant biological functional groups represented by these transcripts were gastrointestinal disease (including CD [p = 0.001] and IBD [p = 0.001]) and inflammatory response [p = 0.000003]. In the 912 differentially expressed transcripts unique to ASD-GI, the most significant biological functional group represented was gastrointestinal disease (including IBD and CD). In contrast, there were 1200 genes uniquely differentially expressed in CD and the primary biological functions represented by these transcripts were immune response [p = 6.6 x 10-14] and autoimmune disease [p = 4 x 10-7].
Conclusions: These results demonstrate that ASD-GI presents a gene expression profile significantly overlapping with Crohn’s disease and consistent with the larger category of inflammatory bowel disease.