Porphyromonas gingivalis drives trimethylamine-N-oxide accumulation via modulation of gut microbial trimethylamine lyase in mice

Introduction: Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, is linked to cardiovascular, neurodegenerative, and metabolic diseases. Emerging evidence indicates a bidirectional interaction between the periodontal pathogen Porphyromonas gingivalis (Pg) and gut microbiota, potentially influencing host TMAO metabolism. However, whether Pg modulates the choline-trimethylamine (TMA) axis remains unclear.

Methods: Wild-type male C57BL/6J mice received oral Pg under chow or a high-choline diet. Plasma and cecal concentrations of TMA and TMAO were quantified, intestinal barrier function was evaluated via histological analysis, and the determination of ZO-1 and occludin expression was performed. Cecal microbiota composition was profiled by 16S rRNA gene sequencing, and microbial choline-TMA lyase markers (cutC/cutD) were measured.

Results: Pg elevated plasma TMAO under chow, accompanied by reduced α-diversity, altered β-diversity, and decreased expression of intestinal barrier proteins. Under high-choline conditions, the diet itself increased plasma and intestinal levels of TMAO and TMA. Pg co-exposure further amplified these effects, raising plasma TMAO, cecal TMA, and cutC/cutD levels. Microbiome analysis revealed elevated abundances of Lachnoclostridium, Odoribacter, and Colidextribacter, and reduced levels of taxa (Prevotellaceae NK3B31, Anaerostipes, and Ruminococcus) negatively correlated with TMAO-related parameters. Moreover, cutC/cutD levels were positively correlated with Colidextribacter and Lachnoclostridium, but negatively correlated with Anaerostipes and Prevotellaceae NK3B31, consistent with the modulation of TMA/TMAO metabolism by these taxa.

Conclusion: This study demonstrates that oral administration of Pg facilitates systemic TMAO elevation by reshaping gut microbial communities and enhancing choline-TMA lyase function, and compromising intestinal barrier integrity. These findings establish an oral-gut metabolic axis connecting periodontitis to host TMAO metabolism, and highlight promising periodontal and microbiota-targeted strategies for alleviating TMAO-associated systemic disorders.