Examining the synergy of Hp 2-2 and ASD gut microbiota on altered behaviors in mice and intestinal barrier function in humans
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Abstract
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by an impairment in neurobiological development, which causes limited social communications and interactions. However, the exact etiology remained unknown, but both genetic and environmental contribute to the diseases. Previous studies have discovered that gastrointestinal (GI) symptoms correlate positively with the severity of ASD core behavior symptoms and are associated with the production of zonulin, a protein that regulates the permeability of intestinal barrier by changing the structure of tight junction (TJ) in the epithelial intestinal layer. Furthermore, ASD patients are characterized by gut dysbiosis, and this is thought to alter the gut-brain-axis (GBA) signaling, and critical social and emotional brain function. Based on these findings, we used a Zonulin-transgenic mice (Ztm) model in which mice have a haptoglobin (Hp) 2 allele to analyze changes after maternal separation, antibiotic treatment, FMT treatment, and in behavior compared to WT mice. We also generated organoid-derivation monolayer that were derived from intestinal biopsies from ASD children genotyped for Hp 1-1 versus Hp 2-2 ASD to compare the leakiness of the gut. Our results suggested that the Hp 2-2 genotype predisposes one to greater gut permeability and that ASD FMT can exacerbate the leakiness. Overall, ASD patients with GI disorders altered intestinal barrier function in humans, and Hp 2-2 with ASD-treated mice and maternally separated showed hyperactivity, a core symptom of ASD.
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Attribution 4.0 International