Molecular Characterization of Right-Sided Colonic Hypomotility in GI Symptomatic Children with ASD

Poster Presentation
Thursday, May 10, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
S. J. Walker1, C. D. Langefeld2, K. D. Zimmerman2 and A. Krigsman3, (1)Wake Forest University Health Sciences, Winston Salem, NC, (2)Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston Salem, NC, (3)Pediatric Gastroenterology Resources of New York and Texas, Austin, TX
Background: Constipation is a common and clinically heterogeneous finding in GI-symptomatic children with autistic spectrum disorder (ASD). One recurrent pattern we have observed in children with constipation as their primary gastrointestinal (GI) symptom is fecal loading (“soft stool constipation”), most prominent in the cecum and ascending colon. Regarding this pattern, a divergent clinical course suggests two distinct clinical subtypes characterized as: (1) following the initial colonic cleanout, a continued state of symptomatic remission while on maintenance anti-inflammatory therapy [acute] or, (2) recurrent right-sided fecal loading requiring regular colon cleanouts [chronic]. These observations raise the possibility of a localized dysmotility within the cecum and ascending colon which may contribute to the underlying etiology of constipation in children with ASD.

Objectives: The goal of this study was to compare gene expression in the right (ascending) colon from two groups of GI-symptomatic children with ASD and constipation (acute versus chronic fecal loading). We hypothesize that molecular examination of mucosal biopsy tissue from affected regions of the colon can provide mechanistic insights regarding transient versus chronic right-sided colonic hypomotility in the setting of enterocolitis in children with ASD.

Methods: RNASeq was used to measure the transcriptome in mucosal biopsy samples that had been collected from the ascending colon during elective colonoscopy in GI-symptomatic children with ASD. The children were all diagnosed with enterocolitis and had, as one of their presenting symptoms, constipation with right sided fecal loading (confirmed by abdominal x-ray). Gene expression in tissue from patients who, following an initial colon clean out, continued in a state of remission (acute; “controls”) was compared to gene expression in the second group who continued to require regular colon clean outs (chronic; “cases”).

Results: Hierarchical clustering of colonic gene expression profiles from all cases and controls initially revealed three clusters consisting of: 12 cases (cluster 1), 9 cases + 1 control (cluster 2) and, a mixture of the other 13 cases and controls (cluster 3). Analysis of differential gene expression between all cases (20) versus all controls (15) resulted in no transcripts that reached statistical significance. Gene expression profiles comparing only cases in the first cluster (N=12) and controls in the second cluster (N=9), 441 transcripts found to be significantly differentially expressed. The molecular pathways that were over-represented in this gene set are involved in host inflammatory response (e.g. granulocyte adhesion and diapedesis, T and B cell signaling, and communication between innate and adaptive immune cells). The top molecular and cellular functions that were found to differ between those with acute versus chronic dysmotility relate cell-to-cell signaling and interaction, cellular movement, and cellular growth and proliferation.

Conclusions: This initial comparison of gene expression profiles in the ascending colon from a subset of patients with ASD and chronic versus acute constipation (right-sided colonic hypomotility) revealed a down regulation of hundreds of transcripts that are involved in cell-to-cell communication and cellular growth and proliferation. These findings are suggestive of a coordinate down regulation of genes that may be necessary for normal cellular function in the lower gastrointestinal tract.