Trimethylamine-N-oxide and cerebral stroke risk: A review

• Published in: Neurobiology of disease 2024-03, Vol.192, p.106423-106423, Article 106423
• Main Authors: Dolkar, Phurbu, Deyang, Tenzin, Anand, Nikhilesh, Rathipriya, Annan Gopinath, Hediyal, Tousif Ahmed, Chandrasekaran, Vichitra, Krishnamoorthy, Naveen Kumar, Gorantla, Vasavi Rakesh, Bishir, Muhammed, Rashan, Luay, Chang, Sulie L., Sakharkar, Meena Kishore, Yang, Jian, Chidambaram, Saravana Babu
• Format: Article
• Language: English
• Subjects: Gut dysbiosis; Gut microbiota; Inflammation; Stroke; Trimethylamine-N-oxide
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2024.106423

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono‑oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications. [Display omitted] •Gut dysbiosis is associated with stroke pathogenesis and detrimental outcomes.•TMAO is a gut microbiota-derived metabolite produced from dietary nutrients.•TMAO contributes to vascular dysfunction, resulting in an increased risk of stroke.•TMAO induces neuroinflammation through the NLRP3 inflammasome activation pathway.•Prebiotic and probiotic interventions lowers TMAO level, thereby managing stroke.