Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells.

Recently, the intricate relationship between Trimethylamine N-oxide (TMAO) and inflammatory bowel disease (IBD) is of growing interest. The NLRP3 inflammasome plays crucial roles in gut homeostasis and determining the severity of inflammation in IBD, however, the precise roles of the NLRP3 inflammasome in IBD are still debated. ATG16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with IBD. Whether TMAO prime NLRP3 inflammasome via ATG16L1-induced autophagy remains unclear. This study observed the expression of ATG16L1, LC3-II and p62 and activation of NLRP3 inflammasome stimulated by TMAO in fetal human colon cells (FHCs), aiming to elucidate the mechanism by which the TMAO may contribute to colonic epithelial inflammation. Our results demonstrated that TMAO significantly inhibited ATG16L1, LC3-II and p62 expression, and triggered the activated NLRP3 inflammasome and production of ROS in a dose- and time-dependent manner. Furthermore, TMAO-mediated effects were observably reversed by over-expression ATG16L1 and siRNA-mediated knockdown NLRP3.The present results support the hypothesis that TMAO may be involved in the pathogenesis of IBD by impacting ATG16L1-induced autophagy and activating NLRP3 inflammasome, suggesting a potential therapeutic targets for the treatment of IBD and TMAO-associated complications.