Exploring the trimethylamine-degrading genes in the human gut microbiome

Trimethylamine (TMA), produced by gut microbes, is a precursor to a risk factor for cardiovascular diseases. Currently, TMA-degrading bacteria in the human gut have rarely been studied. This study combined TMA-enriched cultures (from 104 young male stool samples) with metagenomic profiling to identify key microbial players of TMA degradation. The results showed that the contribution of Enterococcus to methane metabolism was significantly higher in TMA-enriched culture samples. The 68.58% up-regulation of dmd-tmd (dimethylamine/trimethylamine dehydrogenase) in the TMA-enriched group indicated that the anaerobic dehydrogenase pathway participated in TMA metabolism. Notably, we first identified that taxa containing dmd-tmd belonged to Christensenella timonensis. The up-regulation of genes involved in methanogenesis (M00563) as well as the significant enrichment of M00563 (Reporter Score = 2.223) indicated that the methanogenesis pathway may play a role. We constructed gene databases for genes involved in the anaerobic dehydrogenase pathway (1526 sequences for dmd-tmd, 1319 sequences for mauA, and 326 sequences for mauB, respectively) and the aerobic oxidation pathway (2146 sequences for tmm, 1445 sequences for tdm, and 1519 sequences for dmm, respectively) based on genomes from the Integrated Microbial Genome (IMG) database, most of which belong to Pseudomonadota. Screening gut metagenomes with these databases revealed low sequence identity (< 70%), possibly because of the underrepresentation of gut-specific genomes from IMG. This study links Christensenella timonensis to TMA degradation, providing potential targets for microbiota modulation and a gene-centric framework to advance the characterization of gut microbial TMA metabolism.