Enrichment of Elevated Plasma F2t-Isoprostane Levels in Individuals with Autism Who Are Stratified by Presence of Gastrointestinal Dysfunction

Abstract

Etiology is unknown in the majority of individuals with autism spectrum disorder (ASD). One strategy to investigate pathogenesis is to stratify this heterogeneous disorder based on a prominent phenotypic feature that enriches for homogeneity within population strata. Co-occurring gastrointestinal dysfunction (GID) characterizes a subset of children with ASD. Our current objective was to investigate a potential pathophysiological measure to test the hypothesis that children with both ASD and GID have a more severe metabolic dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable impairment. Plasma levels of F2t-Isoprostanes (F2-IsoPs), a gold standard biomarker of oxidative stress, were measured in 87 children in four groups: ASD-GID, ASD-only, GID-only and Unaffected. F2-IsoP levels were elevated in all 3 clinical groups compared to the Unaffected group, with the ASD-GID group significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and triglyceride levels, F2-IsoP levels remained significantly different between study groups, with a moderate effect size of ηp 2 = 0.187 (p = 0.001). Elevation in peripheral oxidative stress is consistent with, and may contribute to, the more severe functional impairments in the ASD-GID group. With unique medical, metabolic, and behavioral features in children with ASD-GID, the present findings serve as a compelling rationale for both individualized approaches to clinical care and integrated studies of biomarker enrichment in ASD subgroups that may better address the complex etiology of ASD.

The isoprostanes—25 years later

“…Oxidative stress has been implicated in the pathophysiology of multiple human genetic disorders. F 2 -IsoPs levels are increased in patients with autism-spectrum disorders [204,205], Smith-Lemli-Opitz Syndrome (SLOS) [206], sickle cell anemia [207], cystic fibrosis [208–210], and in various inborn errors of metabolism [211]. Interestingly, levels of F 2 -IsoPs are increased in the amniotic fluid of pregnancies carrying fetuses with Down syndrome [212].…”

Autism Spectrum Disorder: Defining Dimensions and Subgroups

“…The presence of gastrointestinal and feeding disorders in ASD has been recognized since Dr. Kanner's early descriptions, which documented feeding difficulties, severe vomiting, and, in one child, the need for tube feeding [1]. The study of gastrointestinal disorders represents a novel area of inquiry, along with investigations of sleep, obesity, and immune function [69, 70, 71•], and has begun to provide insights into the pathophysiology of well-defined ASD medical/genetic subgroups [72, 73]. …”

Depletion of stercobilin in fecal matter from a mouse model of autism spectrum disorders

“…While a GUT for ASD etiology may be unrealistic due to the heterogeneity in causation and severity, the search for potential biomarkers with a focus on metabolites has gained considerable momentum in the past decade (Adamo et al 2014; Altieri et al 2011; Dager et al 2015; Dieme et al 2015; Durieux et al 2016; Faber et al 2009; Gabriele et al 2014; Goldenthal et al 2015; Gorrindo et al 2013; Herbert et al 2006; Jyonouchi et al 2008; Masi et al 2017; Ming et al 2012; Ming et al 2005; Pastural et al 2009; Ramsey et al 2013; Rudolph et al 2013; Woods et al 2015; James et al 2004; Frye et al 2013; Ngounou Wetie et al 2015). Expanding the search to identify potential subgroups within ASD has been of interest.…”