Trimethylamine N-oxide participates in human diseases by causing endoplasmic reticulum stress

The gut metabolite trimethylamine N-oxide (TMAO) is found to be elevated at high levels not only in the serum but also in the cerebrospinal fluid of humans. Elevated TMAO levels are associated with several human diseases, including cardiovascular complications, cognitive impairment, acute pancreatitis, cancer, and chronic kidney disease. Research on TMAO has also received significant attention due to its association with sudden cardiac arrest. Therefore, understanding the common molecular insight into the association of TMAO with these diseases has been an important intellectual curiosity. Although inflammation and oxidative stress are commonly regarded as hallmarks of TMAO-induced pathology, recent advances have further opened up a new dimension of its role in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). In the present manuscript, we attempted to present a novel mechanism wherein TMAO-UPR axis may underlie the pathogenesis of various human diseases by influencing specific signaling molecules (FOXO1, CREB, TLR4, SIRT1 and mTOR). These studies highlight strategies aimed at targeting TMAO-UPR axis could be promising for the therapeutic intervention of diseases caused by elevated TMAO.