Commensal human gut microbes produce species specific neuroactive compounds

The gut microbiota communicates with multiple organs through neuroactive molecules, but the specific compounds produced remain unclear. We investigated eight commensal gut species, Lactococcus lactis, Enterococcus faecalis, Blautia producta, Clostridium symbiosum, Streptococcus thermophilus, Prevotella copri, Bacteroides fragilis, and Escherichia coli Nissle, using targeted and non-targeted LC-MS/MS. These bacteria differentially consumed glutamine, glutamate, and tryptophan, producing distinct neuroactive metabolites. For example, E. coli and B. producta generated high levels of gamma-aminobutyric acid (GABA), while P. copri was the sole producer of tryptamine. In the tyrosine pathway, E. faecalis synthesized tyramine and dopamine, and L. lactis, B. producta, and E. coli produced L-DOPA. Interestingly, none produced serotonin or its intermediates despite consuming tryptophan. Multiple species also generated short-chain fatty acids (SCFAs). These findings demonstrate that commensal microbes contribute to host neurochemistry by producing diverse neuroactive metabolites and SCFAs, highlighting the therapeutic potential of modulating the gut microbiota to influence human health.