Signal Pathways and Intestinal Flora through Trimethylamine N-oxide in Alzheimer's Disease

The current studies show signs of progress in treating Alzheimer's disease (AD) with the "brain-gut axis." Restoring intestinal flora balance can alleviate neurodegeneration in the central nervous system. However, due to the complex mechanisms involved in the brain-gut axis, the neuroprotective mechanism brought by intestinal flora has not been fully understood. Trimethylamine N-oxide (TMAO) is a microbiota-dependent metabolism production; TMAO has been proven to be a major risk factor for atherosclerosis, thrombosis, type II diabetes, and other diseases. Meanwhile, all the above diseases are associated with AD; thus, we speculate that TMAO and AD are also correlated. Microbiota, such as Firmicutes, Ruminococcaceae, Escherichia coli, Bifidobacterium, Akkermansia, etc., correlate with the production process of TMAO. High choline intake and insulin resistance have also been identified as contributors to TMAO synthesis. With the increasing TMAO in plasma, TMAO can enter the central nervous system, causing neuroinflammation and immune responses and damaging the blood-brain barrier. TMAO can increase the expression of A beta and the hyperphosphorylation of tau protein, regulate the signal pathways of NLRP3/ASC/caspase1, SIRT1/p53/p21/Rb, PERK/eIF2 alpha/ER-stress, SIRT3-SOD2-mtROS, TXNIP-NLPR3, and PERK/Akt/mTOR, and stimulate the inflammation, apoptosis, endoplasmic reticulum stress, and the ROS. In this mini-review, we have summarized the diseases induced by TMAO through clinical and signal pathways, and intestinal flora correlated with TMAO. Through the analysis of diseases and mechanisms involved in TMAO, we have concluded TMAO to be a potentially important pathological factor of AD.