2026 Volume 2 Issue 1 Pages 154-168
Background: Schizophrenia is increasingly conceptualized not only through the lens of central monoamin e dysregulation but also as a disorder involving low-grade systemic inflammation and abnormalities of the gut-brain axis. A subset of patients, particularly those with chronic or deficit presentations, shows evidence of intestinal hyperpermeability (leaky gut) and gut-derived immune activation. However, the widespread c linical assumption that barrier leakage directly causes malabsorption of nutrients or orally administered dru gs is physiologically oversimplified and conflates correlation with causation.
Objective: This review critically appraises the evidence and limitations of intestinal barrier dysfunction an d its biomarkers in schizophrenia, examines how mucosal low-grade inflammation, dysbiosis, and gastroint estinal dysmotility may together alter nutrient utilization and psychotropic pharmacokinetics, and outlines a practical, multidisciplinary nutritional psychiatry approach.
Main Text: Biomarkers such as zonulin, lipopolysaccharide-binding protein, intestinal fatty acid-binding p rotein, and the lactulose-to-mannitol ratio reflect distinct biological dimensions and are confounded by sm oking, illness stage, and metabolic syndrome. Paracellular leakage does not equate to transcellular transpor ter failure; nevertheless, pro-inflammatory cytokines may downregulate nutrient transporters and cytochro me P450 enzymes, while dysbiosis shifts microbial metabolism toward protein fermentation and alters neu rotransmitter-precursor availability. Depletion of butyrate-producing bacteria, a Candida-enriched mycobio ta, and faecal microbiota transplantation studies collectively suggest, but do not prove, a causal gut-to-brai n contribution; antipsychotics themselves reshape the microbiome, complicating causal inference. The revi ew further shows how routine markers such as ferritin and transferrin saturation can reveal latent deficienci es within the reference range.
Conclusion: Intestinal barrier dysfunction is reliably observed in an immune-inflammatory subgroup of sc hizophrenia, but it cannot yet be equated with clinically demonstrated malabsorption. To date, no study has directly measured nutrient utilization (bioavailability) or antipsychotic pharmacokinetics in relation to gut barrier dysfunction. Gut-targeted nutritional psychiatry interventions may complement, but should not repl ace, standard antipsychotic treatment, and their efficacy remains to be established in adequately powered l ongitudinal and interventional studies.
