Trimethylamine-N-oxide: the microbial cue in immune-mediated disorders

Trimethylamine-N-oxide (TMAO), a gut microbial metabolite derived from dietary choline and carnitine, has emerged as a pivotal link between diet, microbial metabolism, and host immunity. Beyond its historical role as a marine osmolyte, TMAO engages core immune pathways-driving oxidative stress, inflammasome activation, and type I interferon signaling-to shape macrophage polarization, T cell responses, and systemic immune tone. These actions place TMAO at the intersection of chronic diseases, exacerbating cardiovascular, metabolic, renal, and neurodegenerative pathology while paradoxically enhancing antitumor immunity in pancreatic and breast cancers. Such duality underscores its significance as both a biomarker and a therapeutic target. We discuss current advances in TMAO biology, immune mechanisms, and strategies to modulate its activity through diet, microbiome interventions, and enzymatic inhibition.