A Peripheral Blood-Based Biomarker for Gastrointestinal Inflammation in ASD GI-Symptomatic Children

Background: Gastrointestinal symptoms are a common co-occurring medical issue in ASD children. GI mucosal inflammatory infiltrates of both the small and large intestine have been noted in the setting of GI-symptomatic ASD and may represent a potential etiology for many of the observed GI symptoms. Anecdotal and published reports of behavioral and cognitive improvement upon treatment of ASD-associated GI inflammatory disease supports the plausibility of a GI association for at least some of ASD behavioral and cognitive symptoms. We have previously described unique GI mucosal biomarkers specific for ASD-associated ileocolitis. It is not yet known whether these unique biomarkers are also present in the blood of these children. Identification of a blood based biomarker for ASD-associated enterocolitis could potentially allow for earlier identification of co-morbid GI disease, earlier GI intervention for affected patients, GI prognostic biologic markers, methods of non-invasive monitoring of response to GI treatment, and correlations between GI disease activity and ASD core symptomatology.   

Objectives: The goal of these studies is to develop a non-invasive (blood-based) biomarker for GI inflammation in ASD children. In this talk I will outline our strategy and early results towards this objective.

Methods: The initial study cohort was comprised of tissue (GI biopsy and whole blood) from 24 ASD children undergoing clinically-indicated ileocolonoscopy for chronic GI symptoms, and 24 non-ASD (typically developing, TD) children also undergoing ileocolonoscopy. Differential gene expression between inflamed GI tissue from ASD children and non-inflamed tissue from TD children was examined and compared to differential gene expression in peripheral blood from the same individuals to identify co-differentially expressed transcripts that can serve as a biomarker for GI inflammation.  

Results: We reported in an earlier study (Walker et al., PlosOne, 2013) that inflamed ileocolonic biopsy tissue from GI-symptomatic ASD children has a gene expression profile that overlaps with known inflammatory bowel disease (i.e. Crohn’s disease and ulcerative colitis) yet has distinctive  features that may suggest a novel IBD variant in this population. These earlier findings were apparent in this second cohort as well. In addition, we found that there is significant differential gene expression in peripheral blood derived from children with ASD and ileocolonic inflammation compared to TD children without evidence of GI inflammation. Some of the key biological pathways that are coordinately down-regulated in the blood of the ASD (with inflammation) group are oxidative phosphorylation glutathione metabolism, and NOD-like receptor signaling. The overlap between co-differential gene expression in GI tissue and peripheral blood consisted of 40 potential candidate biomarkers.    

Conclusions: The search for biomarkers of disease ‘pre-disposition’ and disease ‘in-progress’ through the molecular analysis of peripheral blood is gaining favor due to several obvious advantages: (1) tissue accessibility, (2) the ability to sample longitudinally, over time, and (3) the ability to sample pre- and post-treatment. We have identified a number of potential biomarkers that may be diagnostic for ileocolonic inflammation in ASD children. If these biomarkers can be validated and shown to be both specific and sensitive, they would have immediate and significant clinical utility.