Assessment of intestinal barrier integrity and associations with innate immune activation and metabolic syndrome in acutely ill, antipsychotic-free schizophrenia patients

Abstract Background: Schizophrenia (Sz), once considered solely a brain disorder, is now recognised as a systemic illness involving immune and metabolic dysregulation. Recently, attention has focused on the intestinal barrier as a potential factor that exerts influence via gut–brain–immune interactions. However, studies on gut permeability markers in early, antipsychotic-free stages remain scarce and often neglect confounders such as smoking and metabolic syndrome. Methods: We measured two complementary markers: lipopolysaccharide-binding protein (LBP), reflecting endotoxin exposure and systemic immune activation, and intestinal fatty acid-binding protein (I-FABP), indicating gut epithelial damage and permeability changes, in blood from 96 acutely ill, antipsychotic-free Sz patients (61 first-episode, 35 relapsed) and 96 matched controls. Associations with innate immune activation, metabolic parameters, smoking, and clinical features were assessed using nonparametric statistics and random forest regression. Group differences were tested with covariate adjustment and separately in non-smokers (Sz: n=42; controls: n=84). Results: Median LBP was higher in Sz (21.96 µg/mL) vs. controls (18.10 µg/mL; FDR-adjusted p=0.021, δ=0.209), but became non-significant after adjusting for smoking (FDR-adjusted p=0.199). In contrast, I-FABP was lower in Sz (218.2 pg/mL) than controls (315.0 pg/mL; FDR-adjusted p=0.021, δ=–0.195), and remained robust across smoking-adjusted analyses. No differences were found between first-episode and relapsed patients for either marker. LBP correlated strongly with CRP (r=0.557, p<0.001) and neutrophils (r=0.468, p<0.001), regardless of smoking, and was predicted moderately by immune models (pseudo-R² = 0.354 full sample; 0.273 Sz; 0.449 controls). Links to waist circumference and blood pressure were weaker (pseudo-R²: 0.048–0.104). I-FABP was less associated with immune markers and uncorrelated with LBP (r=–0.017, FDR-adjusted p=0.819), suggesting distinct underlying mechanisms. Conclusions: Our findings reveal multifaceted gut barrier disruptions in antipsychotic-free Sz. Elevated LBP, associated with CRP and neutrophils, suggests inflammation influenced by smoking and metabolic factors. In contrast, reduced I-FABP, independent of smoking, may indicate epithelial injury. Their lack of correlation highlights distinct pathophysiological dimensions of gut dysfunction. Longitudinal studies, ideally spanning prodromal phases and integrating microbiome, dietary, and permeability assessments, are needed to clarify temporal dynamics and guide stratified treatment approaches.