Abstract Body: Introduction
The human gut microbiome plays a critical role in cardiovascular health. Previous studies have identified a strong link between high plasma levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut-produced trimethylamine (TMA), and cardiovascular disorders. Despite numerous efforts, effective strategies to lower plasma TMAO levels have yet to be developed. This study sought to discover a commensal microbe capable of degrading TMA and thereby reducing plasma TMAO levels.
Methods
Human fecal suspensions were screened under conditions designed to selectively grow bacteria with methylotrophic properties. Bacterial identification was performed through 16S rRNA gene sequencing. Whole genome sequencing of the final candidate strain was conducted using PacBio Sequel and Illumina NovaSeq 6000 platforms. Genome assembly, gene annotation, and phylogenetic analyses were carried out using tools such as SMRTlink, Prokka, InterProScan, and psiblast with EggNog DB. TMA and TMAO levels were quantified using liquid chromatography-mass spectrometry. To assess in vivo effects, a nutrient-fed chronic mouse model was established, and the strain was delivered orally.
Results
A novel methylotrophic bacterial strain, BM109, was isolated using a targeted enrichment method. BM109 completely degraded TMA during aerobic and anaerobic growth in the presence of additional nutrients, without producing toxic byproducts. Genome sequencing revealed that BM109 possesses unique genes encoding enzymes for the complete breakdown of TMA and TMAO into CO2, a feature not observed in related strains. In mice fed a high-choline diet, oral administration of BM109 significantly reduced fecal TMA and TMAO levels, demonstrating the strain's ability to metabolize these harmful compounds in the host gut. Plasma TMAO levels were also markedly decreased after treatment with BM109.
Conclusion
Effective approaches to lower blood TMAO levels are highly desirable for the prevention and treatment of cardiovascular diseases. BM109 was identified as a unique bacterial strain capable of degrading TMA and TMAO through its specialized enzyme systems. Delivering BM109 as a live biotherapeutic product holds promise for reducing cardiovascular risks by targeting and neutralizing harmful metabolites in the gut.