Gut-selective integrin-targeted therapy improves metabolic pathways in the early immune activation mouse model of autism spectrum disorder as revealed by untargeted metabolomics

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology, often associated with gastrointestinal dysfunction and immune dysregulation. The microbiota-gut-brain axis is emerging as a crucial pathway in ASD pathogenesis, mediating the communication between gut, immune system, and central nervous system (CNS). We hypothesized that gut inflammation mediates metabolic reprogramming underlying ASD-like behavioral deficits. In this study, we thus evaluated the metabolic changes associated with ASD behavior and investigated their relationship with the presence of gut inflammation in a mouse model of ASD induced by early-life immune activation (EIA), a double-hit model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges in which we previously described gut inflammation. In this model, we demonstrated that inhibition of gut inflammation through a selective blockade of inflammatory monocytes and gut experienced lymphocyte homing to the intestinal lamina propria by the administration of an anti-α4β7 blocking monoclonal antibody rescued the social novelty deficit observed in EIA mice. Here, using untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics, we analyzed serum metabolites in EIA mice and in EIA mice treated with the anti-α4β7 monoclonal antibody. Our findings reveal significant metabolic disturbances in the EIA model, particularly in pathways associated with oxidative stress, mitochondrial dysfunction, and nucleotide metabolism. Notably, treatment with anti-α4β7 antibody restored several metabolic alterations related to gut inflammation, although it did not fully reverse changes in purine and pyrimidine metabolism. These results suggest that, after developmental immune activation, gut inflammation significantly contributes to the ASD phenotype and highlight the potential for targeting gut-immune interactions to modulate metabolic and behavioral outcomes in ASD.