Alterations in inflammasome-related immunometabolites in individuals with severe psychiatric disorders

Abstract

Introduction: Psychiatric disorders are common and significantly impact the quality of life. Inflammatory processes are proposed to contribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been observed in individuals with different psychiatric disorders. A suggested key player in the interaction between inflammation and metabolism is the Nod-like receptor 3 (NLRP3) inflammasome, and NLRP3 is known to react to a number of specific metabolites. However, little is known about the interplay between these immunometabolites and the NLRP3 inflammasome in mental health disorders.

Aim: To assess the interplay between immunometabolites and inflammasome function in a transdiagnostic cohort of individuals with severe mental disorders.

Methods: Mass spectrometry-based analysis of selected immunometabolites, previously known to affect inflammasome function, were performed in plasma from low-functioning individuals with severe mental disorders (n = 39) and sex and aged-matched healthy controls (n = 39) using a transdiagnostic approach. Mann Whitney U test was used to test differences in immunometabolites between psychiatric patients and controls. To assess the relationship between inflammasome parameters, disease severity, and the immunometabolites, Spearman's rank-order correlation test was used. Conditional logistic regression was used to control for potential confounding variables. Principal component analysis was performed to explore immunometabolic patterns.

Results: Among the selected immunometabolites (n = 9), serine, glutamine, and lactic acid were significantly higher in the patient group compared to the controls. After adjusting for confounders, the differences remained significant for all three immunometabolites. No significant correlations were found between immunometabolites and disease severity.

Conclusion: Previous research on metabolic changes in mental disorders has not been conclusive. This study shows that severely ill patients have common metabolic perturbations. The changes in serine, glutamine, and lactic acid could constitute a direct contribution to the low-grade inflammation observed in severe psychiatric disorders.

Keywords: Comorbidity; Inflammasomes; Inflammation; Mental Disorders; Metabolic pathways; Psychoneuroimmunology.

Fig. 1

Spearman’s correlation analysis between the eight quantified metabolites. The correlation matrix shows correlation coefficients (r) between two metabolites in controls (A) and patients (B), with blue color indicating negative correlations and green color indicating positive correlations. Significant correlations are denoted with *

Fig. 2

Circulating levels of serine, lactic acid, and glutamine quantified with mass spectrometry. Univariate analyses showed significant differences in plasma levels of in individuals with psychiatric disorders (green), n = 39, and healthy controls (blue), n = 39. P-values, serine (p = 0.01), glutamine (p = 0.01), and lactic acid (p < 0.01)

Fig. 3

PCA plot of inflammasome related genes, cytokines and the immunometabolites lactic acid, serine, and glutamine in the patient group (n = 39) from the four primary diagnostic groups (SSD, ASD, OCD, NSSID).The first and second dimension explains 41.9% and 17.2% of the variance, respectively