Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

肠道菌群失调与包括糖尿病，肥胖症和心血管疾病在内的代谢疾病密切相关。最近的研究表明，肠内微生物依赖性代谢产物三甲胺N-氧化物（TMAO）与年龄相关的认知能力下降有关。但是，尚未阐明TMAO对神经元功能的影响机制。在当前的研究中，我们通过测量血浆和大脑中的TMAO水平，研究了TMAO与阿尔茨海默病模型（3×Tg-AD）和胰岛素抵抗（瘦素缺陷db / db）小鼠突触可塑性缺陷之间的关系。我们观察到与野生型小鼠相比，db / db和3xTg-AD小鼠的血浆和大脑中TMAO含量增加。此外，随着小鼠年龄的增长，TMAO水平进一步升高。突触可塑性的缺陷 与野生型小鼠相比，两组小鼠中均表现出降低的长期增强（LTP）的形式。为了进一步探讨TMAO对神经元功能的影响，我们利用了离体通过将野生型海马脑片与TMAO一起孵育来建立模型，发现突触传递受损。我们观察到TMAO在TMAO处理中诱导了PERK-EIF2α-ER应力信号转导轴离体切片以及db / db和3xTg-AD小鼠。最后，我们还观察到突触前受体改变和突触后受体表达降低。我们的发现表明，TMAO可能通过内质网应激介导的PERK信号通路诱导突触可塑性的缺陷。我们的结果为TMAO可能通过促进ER压力诱导认知缺陷的机制提供了新颖的见解，并确定了治疗干预的潜在靶标。