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.