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

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.

Giuseppina Fanelli and Veronica Lelli contributed equally to the work. Department of Ecological and Biological Sciences, University of Tuscia, 01100, Viterbo, Italy Giuseppina Fanelli, Veronica Lelli & Anna Maria Timperio National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy Rosa Luisa Potenza, Roberta De Simone, Monica Boirivant & Alessia Butera Center for Behavioral Science and Mental Health, Istituto Superiore di Sanità, Rome, Italy Correspondence to Alessia Butera or Anna Maria Timperio. The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.

You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.