Investigating HpaB as a Modulator of Gut-Brain Connectivity through Neurotransmitter Metabolism by Gut Microbiota

The gut-brain axis represents a bidirectional communication network linking the gastrointestinal tract and the central nervous system. A growing body of research implicates gut microbiota in modulating host neurochemistry, largely through microbial metabolism of neurotransmitters. This thesis investigates the flavin-dependent monooxygenase HpaB as a putative microbial enzyme involved in host dopamine metabolism, thereby influencing gut-brain signaling. Traditionally characterized for its role in the homoprotocatechuate (HPC) pathway, HpaB catalyzes the hydroxylation of 4-hydroxyphenylacetate (4-HPA) to 3,4-dihydroxyphenylacetate (3,4-DHPA)—a reaction structurally analogous to eukaryotic dopamine oxidation to DOPAC. This structural and chemical convergence suggests that HpaB may act on host-derived catecholamines. In vivo expression data, phylogenetic analysis, and gut colonization models for strains of human microbiota further the relevance of HpaB homologs in host-associated bacterial taxa. Notably, behavioral phenotypes in animal models resulting from host-associated strains overexpressing HpaB—such as impaired locomotion, altered sensory perception, and reproduction—mirror symptoms associated with dopaminergic imbalance. This work proposes a novel mechanism by which bacterial aromatic monooxygenases may deplete or modify host neurotransmitters in situ, with implications for host gut motility, immune function, and behavior. If validated through biochemical assays and animal models, HpaB could represent a novel enzyme-mediated mechanism at the interface of environmental metabolism and neurochemical regulation. The findings expand the conceptual framework of microbial endocrinology and open new avenues for targeting microbial enzymes to influence host neurological health.