Gut microbial modulation of 3-hydroxyanthranilic acid and dopaminergic signalling influences attention in obesity

<h4>Background</h4>Obesity-related alterations in the gut microbiota have been linked to cognitive decline, yet their relationship with attention remains poorly understood.<h4>Objective</h4>To evaluate the possible relationships among gut metagenomics, plasma metabolomics and attention.<h4>Design</h4>We conducted faecal shotgun metagenomics and targeted plasma tryptophan metabolomics across three independent cohorts (n=156, n=124, n=804) with functional validations in preclinical models, including three faecal microbiota transplantation (FMT) experiments in mice and <i>Drosophila melanogaster</i>.<h4>Results</h4>Obesity was consistently associated with reduced attention. Metagenomics analyses identified <i>Proteobacteria</i> species and microbial functions related to tryptophan biosynthesis from anthranilic acid (AA) as negatively associated with attention in obesity. Plasma tryptophan metabolic profiling and machine learning revealed that 3-hydroxyanthranilic acid (3-HAA) was positively associated with attention, particularly in obesity, while AA showed a negative association. Bariatric surgery improved attention and enriched microbial species linked to attention. In mice, diet-induced obesity (DIO) and microbiota depletion reduced 3-HAA and 5-hydroxy-indole acetic acid (5-HIAA) concentrations in the prefrontal cortex (PFC), which were restored by FMT. Global metabolic profiling (>600 metabolites) of PFC from the FMT group identified 3-HAA and the tryptophan and tyrosine pathways among the most significant in mice receiving microbiota from high-attention donors. A second FMT experiment also revealed a consistent enrichment of the tryptophan and tyrosine metabolism at the transcriptional level in the PFC, with <i>Haao</i> (3-hydroxyantrhanilic acid dioxygenase) and <i>Aox4</i> (aldehyde oxidase 4), key in 3-HAA and 5-HIAA degradation, among the significantly regulated genes. In a third FMT study, attentional traits were transmitted from humans to mice alongside modulation of serotonergic and dopaminergic pathways. In <i>Drosophila</i>, mono-colonisation with <i>Enterobacter cloacae</i> and DIO induced attention deficit-like behaviours, which were mitigated by 3-HAA supplementation.<h4>Conclusions</h4>We have identified the microbiota and 3-HAA as potential therapeutic targets to improve attention, especially in obesity.