Associations Between Cytokines, Endocrine Stress Response, and Gastrointestinal Symptoms in Autism Spectrum Disorder

Background: Many children and adolescents with Autism Spectrum Disorder (ASD) have significant gastrointestinal (GI) symptoms, but the etiology is currently unknown. Some individuals with ASD, show altered reactivity to stress, as well as altered immune markers, particularly stress-responsive cytokines including TNF-α and IL-6. 

Objectives:  To assess potential relationships between GI symptoms and stress response, we examined whether GI symptoms are associated with increases in stress-associated endocrine and cytokine biomarkers in ASD.  We hypothesized that positive relationships would exist between GI symptomatology and cortisol, TNF-α, IL-6.  Furthermore, we conducted exploratory analyses to examine the effects of the presence or absence of key co-occurring medical and psychological conditions on these relationships in ASD.

Methods: A sample of 120 individuals aged 6-18 with ASD that are enrolled in the Autism Treatment Network at the University of Missouri Thompson Center for Autism and Neurodevelopmental Disorders and the Vanderbilt Kennedy Center participated in the study.  Participants provided pre- and post-stress salivary cortisol samples to measure the endocrine stress response, and a pre-stress blood sample to measure levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α).  To assess the response to stress, cold pressor and vibrotactile stimulation were applied to the hands in independent trials.  Upper and lower GI tract symptomatology were assessed using the Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III.  Exploratory analyses were conducted between measures of intelligence, key co-occurring conditions in ASD, and IL-6, TNF- α, and pre- and post-stress cortisol to examine potential relationships. 

Results:  Lower GI tract symptoms were significantly associated with post-stress cortisol concentration.  This relationship between cortisol response to stress and GI functioning was greater for children who had a history of regression or loss of skills that were previously acquired. Exploratory analyses also revealed significant correlations between cortisol change score, IQ, and inappropriate speech.  In contrast, lower GI tract symptoms were not associated with levels of TNF-α or IL-6.  Significant correlations were found, however, between TNF-α and IL-6 and irritability, socialization, and IQ.

Conclusions:  These findings suggest that individuals with ASD and lower GI tract symptoms may have an increased response to stress, but this effect is not associated with concomitant changes in stress-associated cytokines.  This relationship with stress may be relevant for future individualization of treatment of lower GI tract symptoms in ASD.  The relationship between endocrine stress reactivity and lower GI tract symptoms in children with loss of skills, as well as the relationships between cortisol, IL-6, and intelligence in ASD, warrant further investigation.