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

Abstract

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 cobalamindependent 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.

Berberine-microbiota interplay: orchestrating gut health through modulation of the gut microbiota and metabolic transformation into bioactive metabolites

“…In vitro , B. coccoides efficiently converted berberine into thalifendine, as well as did E. limosum to a lesser extent. Blautia producta , a phylogenetically close relative of B. coccoides , and E. limosum are known to demethylate dietary methyl ethers ( Possemiers et al, 2008 ; Burapan et al, 2017 ; Rich et al, 2022 ). Both bacteria are acetogens which use corrinoid-dependent methyltransferase systems to funnel both the methyl group of this substrate and CO 2 into the production of acetate through the Wood-Ljundahl pathway.…”

“…Selection was based on Maaslin2 associations, showing that OTUs belonging to the genus Blautia and Anaerostipes were correlated with berberrubine or thalifendine, and availability in-house, including B. coccoides (DSM 935) , Blautia hansenii (DSM 20583) , Blautia hydrogenotrophica (DSM 10507), Blautia luti (DSM 14534) and Anaerostipes butyraticus (35–7 ( Eeckhaut et al, 2011 )) . Eubacterium limosum (LMG 28910) was also included as it previously showed to carry O-demethylation ( Possemiers et al, 2008 ; Rich et al, 2022 ), a reaction involved in the transformation of berberine to berberrubine or thalifendine. Strains were sub-cultured overnight in M2GSC medium pH 6.…”