Metabolic comorbidities in schizophrenia pose a significant public health concern, reducing life quality and expectancy1. Glucose metabolism impairments are prevalent in these patients2, though the underlying causes remain unclear. Although antipsychotics contribute to metabolic alterations3, glucose dysregulation is also found in drug-naive first-episode cases2, suggesting other factors like genetics and gut-brain axis disruptions4.

Gut-brain axis disturbances are found in several mental illnesses5, including altered microbiota composition and metabolites, and gut permeability6. Increased permeability facilitates translocation of lipopolysaccharides from Gram-negative bacteria into systemic circulation to bind lipopolysaccharide-binding protein (LBP), recognized by immune cells through soluble cluster of differentiation 14 (sCD14), triggering inflammation7. LBP, with long half-life and endotoxin exposure link, is a reliable biomarker of gut permeability, whereas sCD14 reflects downstream immune activation8. Both are elevated in patients with schizophrenia compared with healthy controls9; however, the role of increased gut permeability in glucose metabolism dysregulation in schizophrenia remains unclear despite independent associations with this disorder10 and insulin resistance (IR)11.

We hypothesized that IR in schizophrenia may be influenced by altered gut permeability and therefore: (1) described patient profiles (sociodemographic, clinical, lifestyle, LBP/sCD14) by IR status; (2) examined associations between these biomarkers and clinical variables; and (3) built a model to identify factors, especially gut permeability, linked to IR.

Our sample included 91 patients with schizophrenia (mean age=40.9 ± 12.3, 40.7% women), with IR estimated through the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)4, using a ≥ 3.0 threshold.

Fifty-one patients had IR, while 40 did not. Individuals with HOMA-IR ≥ 3.0 had higher LBP (U = 554.0, p < 0.001) and C-reactive protein (CRP) (U = 615.0, p = 0.001) levels, higher body mass index (BMI) (t = −5.640, p < 0.001) and a lower prevalence of vigorous/moderate physical activity assessed with the International Physical Activity Questionnaire (IPAQ)12 (X2 = 6.873, p = 0.009). We found no differences in other demographic and clinical variables, including toxic habits and adherence to Mediterranean diet (Table 1).

Table 1 Characteristics of the sample compared by presence of insulin resistance.
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There was positive association between HOMA-IR and LBP (rho = 0.357, p < 0.001), CRP (rho = 0.320, p = 0.002) and BMI (rho = 0.614, p < 0.001). Age, years of evolution, chlorpromazine equivalent doses (CPZ-ED) and clinical severity by CGI-SCH were not correlated (Fig. 1).

Fig. 1: Spearman’s rho heatmap for variables associated with HOMA-IR.
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* p < 0.05, ** p < 0.01, *** p < 0.001. BMI body mass index, CGI-SCH Clinical Global Impression-Schizophrenia, CPZ-ED chlorpromazine equivalent doses for antipsychotics, CRP C-reactive protein, HOMA-IR Homeostasis Model Assessment of Insulin Resistance, LBP lipopolysaccharide-binding protein, sCD14 soluble cluster of differentiation 14.

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No patients exhibited elevated sCD14 (>5 µg/dL)7, so as sCD14 levels did not differ by IR or correlate with HOMA-IR, no further analyses were performed on this biomarker.

Considering the previous results, we performed a stepwise logistic regression for IR with LBP, CRP, BMI and IPAQ as covariates. The regression was significant (Cox-Snell R2 = 0.397, p = 0.012), including LBP (OR = 1.203, p = 0.004), BMI (OR = 1.278, p < 0.001) and vigorous/moderate physical activity (OR = 0.242, p = 0.016). Full data available in the Supplementary material.

This is the first study to directly assess the relationship between gut permeability biomarkers and IR in schizophrenia, despite recent hypotheses about this association13. IR prevalence was high (56%), in line with the literature14, even after excluding patients with diabetes and despite the cohort’s young age. The proportion of patients with elevated LBP (37.4%) was lower than in other studies10. Our results showed elevated LBP levels despite normal sCD14 concentrations, a pattern reported in other studies9, possibly indicating an early stage of gut barrier alteration, with endotoxin exposure without sustained immune activation. Alternatively, individual variability in microbiota composition or metabolic status could influence sCD14 independently of LBP7. These observations highlight the value of assessing both markers together to better understand gut permeability.

Our findings not only align with prior evidence of gut permeability disturbances7,10 and glucose metabolism impairments14 in schizophrenia but also suggest that gut permeability may play a key role in the metabolic dysregulation observed in these patients. The association between LBP and IR persisted even after adjusting for BMI in the logistic regression analysis, highlighting gut permeability as an independent factor in glucose metabolism. Nonetheless, cross-sectional design precludes causal inference, so longitudinal or interventional studies are needed to examine their temporal relationship.

Furthermore, reduced physical activity emerged as an additional risk factor for IR in our population, consistent with literature15.

Although low-grade inflammation was initially associated with LBP (as in previous findings7), the multivariate analysis did not support definitive conclusions. This may reflect the close association between BMI and inflammatory processes16, with BMI overshadowing CRP’s independent contribution.

Overall, these findings represent a step forward in understanding the pathophysiological mechanisms underlying metabolic impairments in schizophrenia, highlighting the role of gut permeability in insulin resistance and reinforcing healthy lifestyle promotion13 as well as providing a basis for future research.

Methods

This observational, cross-sectional study is a secondary analysis of a larger project examining the role of inflammatory and gut permeability biomarkers in 146 patients with schizophrenia and bipolar disorder.

For this study, we included 91 adult, clinically stable patients diagnosed with schizophrenia according to DSM-5 criteria, without diabetes or antidiabetic treatment. Exclusion criteria addressed comorbid acute and chronic medical conditions and recent pharmacological or dietary interventions. A detailed description of these procedures, applied in the same cohort framework, has been previously published6.

Mental health clinics in Oviedo, Spain recruited the participants. The local Ethics Research Committee approved the protocol (Ref. CEImPA 2021.345).

Plasma measurements: glucose (mg/dL), insulin (μU/mL), LBP (μg/mL), C-reactive protein (CRP; mg/dL). Psychometric evaluations: Clinical Global Impression-Schizophrenia (CGI-SCH), IPAQ, Mediterranean Diet Adherence Screener (MEDAS)17. We also documented antipsychotic treatment, CPZ-ED18, toxic habits, and anthropometric measurements.

Statistical analyses used IBM SPSS v29.0. Normality was assessed with the Kolmogorov-Smirnov test. We applied Spearman’s correlation (rho), Student’s t test, Mann–Whitney U, Chi-square, and stepwise logistic regression.