Alternative pathway for dopamine production by acetogenic gut bacteria that O-Demethylate 3-Methoxytyramine, a metabolite of catechol O-Methyltransferase

Aims: The gut microbiota modulates dopamine levels in vivo, but the bacteria and biochemical processes responsible remain incompletely characterized. A potential precursor of bacterial dopamine production is 3-methoxytyramine (3MT); 3MT is produced when dopamine is O-methylated by host catechol O-methyltransferase (COMT), thereby attenuating dopamine levels. This study aimed to identify whether gut bacteria are capable of reverting 3MT to dopamine. Methods and Results: Human faecal bacterial communities O-demethylated 3MT and yielded dopamine. Gut bacteria that mediate this transformation were identified as acetogens Eubacterium limosum and Blautia producta. Upon exposing these acetogens to propyl iodide, a known inhibitor of cobalamin-dependent O-demethylases, 3MT O-demethylation was inhibited. Culturing E. limosum and B. producta with 3MT afforded increased acetate levels as compared with vehicle controls. Conclusions: Gut bacterial acetogens E. limosum and B. producta synthesized dopamine from 3MT. This O-demethylation of 3MT was likely performed by cobalamin-dependent O-demethylases implicated in reductive acetogenesis. Significance and Impact of the Study: This is the first report that gut bacteria can synthesize dopamine by O-demethylation of 3MT. Owing to 3MT being the product of host COMT attenuating dopamine levels, gut bacteria that reverse this transformation—converting 3MT to dopamine—may act as a counterbalance for dopamine regulation by COMT.