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Assessment of intestinal barrier integrity and associations with innate immune activation and metabolic syndrome in acutely ill, antipsychotic-free schizophrenia patients
Journal article   Open access   Peer reviewed

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

Kaushiki Mukherjee, Paul C Guest, Madeleine Nussbaumer, Leon Dudeck, Leila Shokati Asl, Gabriela Meyer-Lotz, Henrik Dobrowolny, Katrin Borucki, Hans-Gert Bernstein, Alexander Link, …
Journal of neuroinflammation, Vol.22(1), 232
10/13/2025
DOI: 10.1186/s12974-025-03584-3
PMCID: PMC12519603
PMID: 41084047
url
https://doi.org/10.1186/s12974-025-03584-3View
Published (Version of record) Open Access

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Abstract

Schizophrenia (Sz), once seen solely as a brain disorder, is now recognised as a systemic illness involving immune and metabolic dysregulation. The intestinal barrier has emerged as a key player in gut-brain-immune interactions. However, studies in early, antipsychotic free stages remain scarce and often neglect confounding factors such as smoking and metabolic syndrome. 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 immunity, metabolic parameters, smoking, and clinical features were assessed using nonparametric statistics and random forest regression. Group differences were tested using covariate adjustment, as well as in a separate analysis of non-smokers (Sz: n = 42; controls: n = 84). 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) and was moderately predicted by immune models (pseudo-R  = 0.354 overall; 0.273 Sz; 0.449 controls). Links to waist circumference and blood pressure were weaker (pseudo-R : 0.048-0.104). I-FABP showed fewer immune associations and was not correlated with LBP (r = -0.017, FDR-adjusted p = 0.819), suggesting distinct mechanisms. Our findings suggest separable gut‑related processes in antipsychotic-free Sz. The apparent LBP elevation was not schizophrenia‑specific; its strong correlations with CRP and neutrophils point to smoking related inflammation rather than a schizophrenia specific effect. Accordingly, prior findings of LBP elevations in Sz likely reflect unaccounted smoking. In contrast, reduced I-FABP, independent of smoking, may indicate epithelial injury. The absent correlation between LBP and I-FABP highlights distinct pathophysiological dimensions of gut dysfunction. Longitudinal studies, ideally spanning prodromal phases and integrating microbiome, dietary, smoking, and permeability assessments, are needed to clarify temporal dynamics and guide stratified treatments.
 Acute-Phase Proteins - metabolism Adult Antipsychotic Agents - therapeutic use Biomarkers - blood Carrier Proteins - blood Fatty Acid-Binding Proteins - blood Female Humans Immunity, Innate - physiology Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Male Membrane Glycoproteins - blood Metabolic Syndrome - blood Metabolic Syndrome - immunology Middle Aged Schizophrenia - blood Schizophrenia - complications Schizophrenia - immunology Young Adult

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