A Systems Hypothesis of Lipopolysaccharide-Induced Vitamin Transport Suppression and Metabolic Reprogramming in Autism Spectrum Disorders: An Open Call for Validation and Therapeutic Translation
Year: 2025
Type: article
Abstract: Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental condition increasingly linked to systemic metabolic dysfunction. In this study, we applied a transcriptomics-based systems framework—Personalized Metabolic Margin Mapping (PM³) - to analyze prefrontal cortex samples from 12 individuals with ASD and 12 neurotypical controls. Differential expression of 158 curated metabolic genes was assessed across pathways related to energy metabolism, redox regulation, one-carbon cycling, and detoxification. Unsupervised machine learning (Isolation Forest and K-means clustering), combined with Euclidean and percentage distance metrics, revealed consistent downregulation of mitochondrial enzymes and transporters - most notably the multivitamin symporters SLC5A6 and SLC19A2, which mediate the uptake of biotin, pantothenic acid, thiamine, and lipoic acid. These alterations were accompanied by upregulation of redox and sulfur-handling genes, indicating compensatory adaptation to metabolic stress. We propose a unifying hypothesis in which chronic microbial lipopolysaccharide (LPS) exposure suppresses vitamin transport, triggering a cascade of mitochondrial dysfunction and metabolic reprogramming in the ASD brain. This transcriptomic signature supports the concept of a “metabolic autism spectrum” and highlights nutrient transport bottlenecks as modifiable targets for precision therapies. The PM³ model offers a mechanistically grounded platform for stratifying ASD by metabolic subtype and guiding future intervention studies. We invite prospective validation of this model using integrated transcriptomic–metabolomic approaches in LPS-exposed systems.
Source: Metabolites
Author: Albion Dervishi
Institution: University of Tübingen
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
Funder: Servier
OpenAlex ID: W4411282101