# Computational Identification of Blood–Brain Barrier-Permeant Microbiome Metabolites with Binding Affinity to Neurotransmitter Receptors in Neurodevelopmental Disorders

## TL;DR

This study identifies microbiome metabolites that can cross the blood-brain barrier and bind to neurotransmitter receptors linked to neurodevelopmental disorders.

## Contribution

A novel computational framework combining rule-based and neural network models identifies BBB-permeant microbiome metabolites with receptor binding affinity.

## Key findings

- Fungal metabolites from Ascomycota were the most abundant high-affinity ligands for neurotransmitter receptors.
- Menaquinone MK-7 showed broad phylogenetic conservation across phyla.
- Complementary BBB prediction methods revealed distinct sets of permeant metabolites.

## Abstract

The gut microbiome produces thousands of metabolites with potential to modulate central nervous system function through peripheral or direct neural mechanisms. Tourette syndrome, attention-deficit/hyperactivity disorder, and autism spectrum disorder exhibit shared neurotransmitter dysregulation and microbiome alterations, yet mechanistic links between microbial metabolites and receptor-mediated neuromodulation remain unclear. We screened 27,642 microbiome SMILES metabolites for blood–brain barrier permeability using rule-based SwissADME classification and a PyTorch 2.0 neural network trained on 7807 experimental compounds (test accuracy 86.2%, AUC 0.912). SwissADME identified 1696 BBB-crossing metabolites following Lipinski’s criteria, while PyTorch classified 2484 metabolites with expanded physicochemical diversity. Following 3D conformational optimization (from SMILES) and curation based on ≤32 rotatable bonds, molecular docking was performed against five neurotransmitter receptors representing ionotropic (GABRA2, GRIA2, GRIN2B) and metabotropic (DRD4, HTR1A) receptor classes. The top 50 ligands across five receptors demonstrated method-specific BBB classification (44% SwissADME-only, 44% PyTorch-only, 12% overlap), validating complementary prediction approaches. Fungal metabolites from Ascomycota dominated high-affinity top ligands (66%) and menaquinone MK-7 showed broad phylogenetic conservation (71.4% of phylum). Our results establish detailed receptor–metabolite interaction maps, with fungal metabolites dominating high-affinity ligands, challenging the prevailing bacterial focus of the microbiome and providing a foundation for precision medicine and a framework for developing microbiome-targeted therapeutics to address clinical needs in neurodevelopmental disorders.