Abstract
In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.
Highlights
Gastrointestinal (GI) symptoms are common in children with autism spectrum disorder (ASD)[1] and have been shown to be associated with more severe deficits in ASD core domains related to cognition and behavior[2,3,4,5,6]
Ingenuity Pathway Analysis (IPA) analysis of these differentially expressed transcripts revealed that one of the top physiological system development and function categories most over-represented in this set of genes was digestive system development (p = 4.13 × 10−02–1.91 × 10−03) and the top disease www.nature.com/scientificreports
We present gene expression data that distinguishes ASD fast response constipation from ASD persistent right-sided constipation
Summary
Gastrointestinal (GI) symptoms are common in children with autism spectrum disorder (ASD)[1] and have been shown to be associated with more severe deficits in ASD core domains related to cognition and behavior[2,3,4,5,6]. Of the GI symptoms identified most commonly in children with ASD (abdominal pain, diarrhea and constipation), chronic constipation is the symptom most frequently reported by parents as being especially problematic[7]. Www.nature.com/scientificreports in younger children (age 5–12 years) was far more likely to be the presenting symptom of the ED visit in children with ASD compared to typically developing (TD) children. In our experience treating more than 1500 GI-symptomatic children with ASD, the predominant pattern of ASD-associated constipation is characterized by infrequent stools (two or less per week) that are semi-formed or formed in texture (Bristol Type III-IV), accompanied by fecal incontinence, anal leakage, and stool retention (evidenced in abdominal radiographs). In contrast to pediatric functional constipation seen in TD children where the child is voluntarily attempting to withhold stool, parents of children with ASD often describe their child as making clear efforts to pass stool, but without success. The authors’ unpublished experience is that diarrheal stools are often passed with excessive effort and straining; parents and caretakers often express surprise at the degree of effort needed to pass such loose stools
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