Innate Versus Adaptive Immune Response Pathways in Peripheral Blood from ASD Children with Ileocolonic Inflammation

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 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 validated blood-based biomarker of ASD-associated ileocolitis would allow for earlier identification of co-morbid GI disease and earlier GI intervention in affected patients. Moreover, it would provide insight into the relevant genes and biologic pathways in ASD-ileocolitis.

Objectives: The goal of these studies is to evaluate blood-based gene expression In GI-symptomatic ASD children with demonstrated histologic ileocolitis to identify the genes and biological pathways most affected.

Methods: The study cohort was comprised of whole blood from 22 ASD children undergoing clinically-indicated ileocolonoscopy for chronic GI symptoms, and 24 non-ASD (typically developing, TD) children undergoing ileocolonoscopy for a variety of GI symptoms. All ASD children had histologic inflammation of the ileum, colon, or both. The TD “controls” used for this study were selected based on absence of histologic inflammation anywhere in the GI tract and absence of a neurodevelopmental disorder. Differential gene expression in peripheral blood from ASD children (with ileocolitis) compared to TD children (without ileocolitis) was examined to identify differentially expressed transcripts that may serve as a proxy 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. These earlier findings were apparent in inflamed ileocolonic mucosal tissue in this second cohort as well. In addition, we found that there is significant differential gene expression in peripheral blood of children with ASD and ileocolitis compared to TD children without GI inflammation. Two key immune-related pathways that were up-regulated in the blood of ASD cases are B cell receptor signaling and the Wnt signaling pathway, both important components of the adaptive immune response. In contrast, some of the key biological pathways that are coordinately down-regulated in the blood of the ASD (with inflammation) group are NOD-like receptor signaling, hematopoietic cell lineage, and Toll-like receptor signaling. Each of these pathways is important for pathogen recognition and for generating the host innate immune response.

Conclusions: Gene expression in peripheral blood from ASD children with ileocolitis reveals a down-regulation of the host defense mechanism (innate immune response) together with an up-regulation of pathways that constitute the adaptive immune response, a pattern seen in other inflammatory bowel diseases. Studies are ongoing to validate these findings in additional samples.