The proposed barrier dysfunction axis in psychiatric disorders: a systematic review and meta-analysis of circulating zonulin and claudin-5

Emerging evidence suggests that disruption of the gut–brain axis, particularly involving intestinal permeability and blood–brain barrier (BBB) integrity, may play a critical role in the pathophysiology of psychiatric disorders. However, existing studies have largely evaluated these mechanisms independently. This study aimed to systematically investigate gut and BBB biomarkers within a unified framework and to evaluate the concept of a “barrier dysfunction axis” across psychiatric conditions. A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines. PubMed/MEDLINE, Web of Science, and Scopus databases were searched for studies published between January 2020 and February 2026. Observational studies assessing serum zonulin and/or claudin-5 levels in psychiatric patients and healthy controls were included. Standardized mean differences were calculated using Hedges’ g, and a random-effects model (DerSimonian–Laird) was applied. Heterogeneity was assessed using the I² statistic. Subgroup, publication bias (funnel plot and Egger’s test), and leave-one-out sensitivity analyses were performed. A total of 15 observational studies met the eligibility criteria. Ten studies contributed to the zonulin meta-analysis, which showed higher assay-reported circulating zonulin levels in psychiatric populations than in healthy controls (Hedges’ g = 0.97, 95% CI: 0.46–1.48; p < 0.001), with substantial heterogeneity (I² = 91.2%). Eight studies contributed to the claudin-5 meta-analysis, which showed a small and statistically non-significant pooled difference (Hedges’ g = 0.25, 95% CI: −0.21–0.71; p = 0.280), also with substantial heterogeneity (I² = 89.2%) and bidirectional study-level estimates. The certainty of evidence was rated as very low for both outcomes. Assay-reported circulating zonulin levels were higher on average across heterogeneous psychiatric populations; however, substantial heterogeneity, very low certainty of evidence, and concerns regarding the analytical specificity of commercial zonulin assays limit interpretation of this finding as direct evidence of increased intestinal permeability. No significant overall alteration in circulating claudin-5 was demonstrated. The proposed barrier dysfunction axis was not directly tested and should be regarded as a hypothesis-generating framework.