Trimethylamine N-oxide (TMAO) is a metabolite produced by the gut microbiome from dietary nutrients such as choline and carnitine. Recent research has found that TMAO is strongly associated with cardiovascular disease (CVD), chronic kidney disease (CKD) and, more recently, inflammatory bowel disease (IBD). Although TMAO is linked to conditions characterized by inflammation, oxidative stress, fibrosis and gut microbiome imbalances, its exact role in disease development remains unclear. This review examines TMAO's potential role as a key link in the IBD-CKD-CVD disease spectrum. Highlighting the importance of limiting TMAO production, we propose several promising strategies to achieve its reduction. Specifically, we focus on microbiome therapies as innovative methods for managing TMAO levels. This approach offers a hopeful avenue for addressing the complex interplay between gut health and systemic chronic human diseases.