487. PREBIOTICS RESCUE GUT MICROBIOME DYSREGULATION AND ENHANCE COGNITIVE AND GASTROINTESTINAL FUNCTION IN A MOUSE MODEL OF SCHIZOPHRENIA

Abstract Background Schizophrenia is a devastating psychiatric disorder characterized by positive (e.g. hallucinations) and negative (e.g. reduced motivation) symptoms, and cognitive deficits. Chronic gastrointestinal tract issues exist as comorbid symptoms of schizophrenia. Recent findings indicate the involvement of the microorganisms that inhabit the gut, the microbiota (and the broader microbiome which also includes microbial genomes, etc.) in schizophrenia pathogenesis. Prior discoveries by our group and others have established the metabotropic glutamate receptor 5 (mGlu5) knockout mice as a useful preclinical model of schizophrenia. We have provided evidence of strong face validity with respect to schizophrenia-like endophenotypes, and predictive validity in response to the antipsychotic drug clozapine. We have also previously discovered altered gut microbiota (gut dysbiosis) in this preclinical model of schizophrenia, providing the first evidence of such dysbiosis in any genetic animal model of schizophrenia. This gut dysbiosis exhibits parallels to microbiome profiling reported in clinical studies of schizophrenia, further supporting the validity of this preclinical model. Aims & Objectives We followed up our discovery of gut dysbiosis in this preclinical model with interventions designed to correct the abnormalities in the gut microbiota. We hypothesised that amelioration of gut dysbiosis would be associated with therapeutic effects on schizophrenia-like endophenotypes in this validated mouse model. In the present study, we hypothesized that chronic administration with prebiotics fructooligosaccharide and galactooligosaccharide (FOS and GOS; a combination used clinically for other disorders) would restore gut microbiome composition of the mGlu5 knockout mouse model of schizophrenia, which we previously demonstrated to exhibit gut dysbiosis. Method We assessed the impact of prebiotics on gut microbiome composition and function, as well as the gastrointestinal function and schizophrenia-like phenotype of mGlu5 knockout mice and wildtype littermates. We administered a combination of the prebiotics FOS and GOS, versus vehicle control administration, in both the mouse model of schizophrenia and wildtype littermates. Mice were administered a combination of FOS and GOS (dissolved in drinking water for 0.3-0.4 g/mouse/day) or water from 6 to 14 weeks of age. Duration of treatment and dose of prebiotics were chosen based on previous studies in rodents that showed modulation of the gut microbiome, behavioural outcomes and neurochemical effects. This was followed by detailed investigations of gut and brain function, including extensive behavioural profiling. Results The present study firstly corroborated the altered gut microbiome composition in the mGlu5 KO mouse model of schizophrenia. Importantly we have revealed an altered microbial metabolic profile. We have also shown that the prebiotics we administered were not only able to rescue these gut microbiome changes but furthermore had additional beneficial effects including cognitive enhancement and improved gastrointestinal function. We were able to show, in two independent tests, a promising effect of prebiotics on cognition. Discussion & Conclusions These preclinical findings indicate that prebiotics, such as the combination of FOS and GOS used in the present study, may have therapeutic potential in schizophrenia as an add-on intervention with an exceptional safety profile. Future studies will explore the utility of such prebiotic interventions in other preclinical models, with the ultimate aim to translate these novel findings to clinical trials.