Effect of early neonatal exposure to lipopolysaccharide (LPS) with subsequent exposure to antibiotic-induced dysbiosis (double hit theory in a model of schizophrenia) on metabolomics
Abstract
Infections and stress in early life during a vulnerable development period of the cns, are related to an increased risk of the development of neuropsychiatric disorders such as schizophrenia. Based on a dual hit theory of schizophrenia hypothetically a second insult, of various modality, is necessary to trigger the disorder.
Neonatal lipopolysaccharide (LPS, also known as endotoxin) treatment in rats is an acknowledged model for the behavioral deficits and neurocognitive impairments caused by an early-life immune challenge and used as a neurodevelopmental model of psychosis. In the present work we studied in the rat model how the neonatal LPS administration along with dysbiosis induced by chronic antibiotic treatment as a second hit based on the dual hit theory will affect metabolic pathways by an untargeted metabolomic analysis.
We have evaluated differences between the metabolome of control and test groups (exposed to LPS and/or antibiotic treatment) to determine differences between their metabolite profiles. The LPS-treated group samples have exhibited notable metabolomic changes compared to the control subjects. the most affected divergent pathways were determined as Pyrimidine metabolism and Pantothenate and coenzyme a (CoA) biosynthesis pathways (the gamma-adjusted p-value are 0.04275 and 0.04278, respectively).
The ATB treatment did not result in any changes in metabolome and on the contrary masked the effects induced by LPS treatment. Referring to these data, we are able to suggest that a neonatal LPS challenge plays a significant role in the discomposing Pyrimidine metabolism and Pantothenate and CoA biosynthesis pathways, which could be identified as metabolism pathways involved in schizophrenia pathogenesis.
Due to preliminary nature of our study it is necessary to confirm our findings in future schizophrenia research.