Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis

Abstract

<jats:p>Worldwide, up to 20% of children and adolescents experience mental disorders, which are the leading cause of disability in young people. Research shows that serum zonulin levels are associated with increased intestinal permeability (IP), affecting neural, hormonal, and immunological pathways. This systematic review and meta-analysis aimed to summarize evidence from observational studies on IP in children diagnosed with mental disorders. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the Cochrane Library, PsycINFO, PubMed, and the Web of Science identified 833 records. Only non-intervention (i.e., observational) studies in children (&lt;18 years) diagnosed with mental disorders, including a relevant marker of intestinal permeability, were included. Five studies were selected, with the risk of bias assessed according to the Newcastle–Ottawa scale (NOS). Four articles were identified as strong and one as moderate, representing altogether 402 participants providing evidence on IP in children diagnosed with attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive–compulsive disorder (OCD). In ADHD, elevated serum zonulin levels were associated with impaired social functioning compared to controls. Children with ASD may be predisposed to impair intestinal barrier function, which may contribute to their symptoms and clinical outcome compared to controls. Children with ASD, who experience gastro-intestinal (GI) symptoms, seem to have an imbalance in their immune response. However, in children with OCD, serum zonulin levels were not significantly different compared to controls, but serum claudin-5, a transmembrane tight-junction protein, was significantly higher. A meta-analysis of mean zonulin plasma levels of patients and control groups revealed a significant difference between groups (p = 0.001), including the four studies evaluating the full spectrum of the zonulin peptide family. Therefore, further studies are required to better understand the complex role of barrier function, i.e., intestinal and blood–brain barrier, and of inflammation, to the pathophysiology in mental and neurodevelopmental disorders. This review was PROSPERO preregistered, (162208).</jats:p>

The use of biomarkers associated with leaky gut as a diagnostic tool for early intervention in autism spectrum disorder: a systematic review

“…Zonulin has been shown to prompt the disassembly of TJs between the cells of the duodenum and the small intestine, resulting in leaky gut [ 53 ]. Multiple studies indicate that serum zonulin levels are associated with increased intestinal permeability, affecting neural, hormonal, and immunological pathways, and thus, could induce neurological abnormalities in the case of leaky gut [ 54 ]. Zonulin levels and Social Responsiveness Scale scores in patients with attention-deficit hyperactivity disorder (ADHD) differed significantly from those in controls.…”

PapRIV, a BV-2 microglial cell activating quorum sensing peptide

“…Moreover, the intestinal barrier function is affected in several gastro-intestinal disorders such as IBD, IBS, celiac disease and obesity leading to a ‘leaky gut’ and an increased flux of luminal compounds towards the circulation 56 . Also in mental disorders such as ASD, ADHD and bipolar disorder, increased serum zonulin and/or claudin-5 levels are observed which is associated with respectively increased intestinal and BBB permeability 60 , 61 .…”

PapRIV, a BV-2 microglial cell activating quorum sensing peptide

“…Moreover, the intestinal barrier function is affected in several gastro-intestinal disorders such as IBD, IBS, celiac disease and obesity leading to a 'leaky gut' and an increased flux of luminal compounds towards the circulation [65]. Also in mental disorders such as ASD, ADHD and bipolar disorder, increased serum zonulin and/or claudin-5 levels are observed which is associated with respectively increased intestinal and BBB permeability [69,70].…”