Increased Plasma Levels of the High Mobility Group Box 1 Protein (HMGB1) Are Associated With a Higher Score of Gastrointestinal Dysfunction in Individuals With Autism

Abstract

Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8±11.7 ng/ml vs. 7.90±4.0 ng/ml, p<0.02). In subjects with plasma HMGB1levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms.

Increased Serum Concentrations of High Mobility Group Box 1 (HMGB1) Protein in Children with Autism Spectrum Disorder

“…Moreover, research has shown that HMGB1 plasma levels are related to a low concentration of epidermal growth factor (EGF) and higher EGF receptor (EGFR) levels in ASD individuals, suggesting that both EGF and EGFR abnormal levels found in ASD persons may be associated with inflammation and generally increased neuroimmune activity [21,30]. Furthermore, in a study comprising low-functioning ASD individuals aged 2-22 years, plasma HMGB1 levels were found significantly higher in the ASD group than in controls [22]. Additionally, elevated HMGB1 plasma and fecal levels have been associated with higher severity of gastrointestinal (GI) problems in children and young individuals with ASD [22,31].…”

“…Furthermore, in a study comprising low-functioning ASD individuals aged 2-22 years, plasma HMGB1 levels were found significantly higher in the ASD group than in controls [22]. Additionally, elevated HMGB1 plasma and fecal levels have been associated with higher severity of gastrointestinal (GI) problems in children and young individuals with ASD [22,31]. Recent findings of note have shown that HMGB1 may play a role in the stress-induced sensitization of innate immune cells and subsequent neuroinflammation [32].…”

“…In view of the above, HMGB1 is a candidate biomarker that may be involved in altered molecular pathways leading to the immune dysfunction reported in individuals with ASD. Previous studies have reported higher HMGB1 serum or plasma concentrations mainly in low-functioning ASD individuals comprising samples of young adults (18 to 44 years old) [20], male children (mean age 10.6 years) [21], and ASD individuals aged 2-22 years [22], compared with age-and gender-matched healthy controls. The objective of the current cross-sectional study was to assess the concentrations of the HMGB1 in serum samples of school-aged, male children diagnosed with high-functioning ASD (i.e., children of normal intelligence) compared to typically developing (TD) controls.…”

The performance of the alarmin HMGB1 in pediatric diseases: From lab to clinic

“…Additionally, in ASD children, there was a strong correlation between HMGB1 and the reduction in plasma epithelial growth factor levels, which was associated with the severity of some symptoms 123 . In addition to core symptoms, higher HMGB1 levels can lead to more severe chronic gastrointestinal dysfunction in children with ASD than those with lower HMGB1 levels 121 . High serum levels of HMGB1 may be biomarkers of the severity of ASD symptoms.…”

“…Immune dysregulation is thought to be involved in the pathophysiological process of ASD 118,119 . HMGB1 levels are increased in adult and pediatric ASD patients and are independently associated with autism scores that reflect social deficits 120,121 . Monocyte cultures from children with ASD were more sensitive to signaling through selected TLRs, indicating dysfunction in monocyte pathogen recognition and/or TLR signaling pathways 122 .…”