Biomarkers of intestinal permeability in major psychiatric disorders: Distinct biological roles call for a more nuanced application

Abstract

Background: Zonulin, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14) are frequently used as proxy biomarkers of intestinal permeability in studies involving patients with psychiatric disorders. Although often used interchangeably, these biomarkers reflect distinct biological processes. Objective: This review integrates evidence from basic research on the mechanisms of action of zonulin, LBP, and sCD14 with findings from studies on major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders, aiming to refine their application in gut–brain axis research. Findings: Zonulin is consistently elevated in schizophrenia spectrum disorders and appears most closely linked to gut barrier integrity and systemic immune activation. LBP is consistently elevated in major depressive disorder and may reflect underlying alterations in gut permeability, metabolic status, and psychological stress. sCD14 has been primarily studied in schizophrenia spectrum disorders, where findings are more heterogeneous, and is thought to reflect generalized monocyte activation. These biomarkers were largely unrelated to clinical symptom severity, with the exception of sCD14, which showed associations with positive symptoms, aggression, and the number of manic episodes. Conclusions: Zonulin, LBP, and sCD14 each capture unique aspects of gut and immune system function. Their interchangeable use risks misinterpretation. A more nuanced, context-dependent application—tailored to specific research questions or intervention targets—is essential for advancing gut–brain axis research in psychiatry.