TARGETING THE MICROBIOME TO TREAT COGNITIVE IMPAIRMENT AND STRESS SENSITIVITY ASSOCIATED WITH SCHIZOPHRENIA – PRECLINICAL STUDY

Recent studies have found that schizophrenia-associated dysbiosis is linked to higher stress vulnerability and contributes to cognitive dysfunction in patients. This study aimed to investigate the effects of the antipsychotic clozapine (CLO) and/or galactooligosaccharide (GOS) prebiotic treatment on stress vulnerability and behavioral phenotype in association with gut microbiota composition in the triple-hit Wisket rat model of schizophrenia.
Male Wistar (control) and Wisket rats were treated for 3 weeks: CLO (2.5 mg/kg) or its vehicle was administered intraperitoneally, while GOS (15 g/L) or tap water was provided ad libitum in a drinking bottle. Cognition-related parameters were assessed using the food-rewarded Ambitus test, fecal samples were collected for microbiota analysis, and smooth muscle electromyography was performed to record basal and immobilization-induced stress response. Correlation analysis was conducted to investigate the microbiota-behavior network.
Our main results are the following:(1) among the treatments, GOS resulted in the highest improvement in cognitive performance in Wisket animals, and its beneficial effect in controls were also verified; (2) Wisket animals showed increased myoelectric activity during immobilization, indicating elevated stress vulnerability compared to controls; which difference disappeared by treatments, particularly by CLO and GOS combination; (3) dysbiosis in Wisket rats was partially reversed by each treatment. (4) Microbiota-behavior correlation network analysis highlights that the differential abundance of bacterial genera had the greatest influence on cognition-related parameters, most of them responsible for short-chain fatty acid production.
These results suggest that targeting the gut microbiome may represent a promising therapeutic strategy for alleviating schizophrenia-related cognitive deficits and heightened stress sensitivity.