Aging is associated with declines in cognitive performance, which are mediated in part by neuroinflammation, characterized by astrocyte activation and higher levels of pro-inflammatory cytokines; however, the upstream drivers are unknown. We investigated the potential role of the gut microbiome–derived metabolite trimethylamine N-oxide (TMAO) in modulating neuroinflammation and cognitive function with aging. Study 1: In middle-aged and older humans (65 ± 7 years), plasma TMAO levels were inversely related to performance on NIH Toolbox Cognition Battery tests of memory and fluid cognition (both r² = 0.07, p < 0.05). Study 2: In mice, TMAO concentrations in plasma and the brain increased in parallel with aging (r² = 0.60), suggesting TMAO crosses the blood-brain barrier. The greater TMAO concentrations in old mice (27 months) were associated with higher brain pro-inflammatory cytokines and markers of astrocyte activation vs. young adult mice (6 months). Study 3: To determine if TMAO independently induces an “aging-like” decline in cognitive function, young mice (6 months) were supplemented with TMAO in chow for 6 months. Compared with controls, TMAO-supplemented mice performed worse on the novel object recognition test, indicating impaired memory and learning, and had increased neuroinflammation and markers of astrocyte activation. Study 4: Human astrocytes cultured with TMAO vs. control media exhibited changes in cellular morphology and protein markers consistent with astrocyte activation, indicating TMAO directly acts on these cells. Our results provide translational insight into a novel pathway that modulates neuroinflammation and cognitive function with aging, and suggest that TMAO might be a promising target for prevention of neuroinflammation and cognitive decline with aging.

衰老与认知能力下降有关，这部分是由神经炎症介导的，其特征是星形胶质细胞激活和更高水平的促炎细胞因子；但是，上游驱动因素未知。我们研究了肠道微生物组衍生的代谢物三甲胺N-氧化物 (TMAO) 在随着衰老调节神经炎症和认知功能中的潜在作用。研究 1：在中老年人（65 ± 7 岁）中，血浆 TMAO 水平与 NIH Toolbox Cognition Battery 记忆和流体认知测试的表现呈负相关（r ²  = 0.07，p  < 0.05）。研究 2：在小鼠中，血浆和大脑中的 TMAO 浓度随着年龄的增长而增加（r ² = 0.60），表明 TMAO 穿过血脑屏障。与年轻成年小鼠（6 个月）相比，老年小鼠（27 个月）中较高的 TMAO 浓度与较高的脑促炎细胞因子和星形胶质细胞活化标志物相关。研究 3：为了确定 TMAO 是否独立诱导认知功能的“老化样”下降，年轻小鼠（6 个月）在食物中补充 TMAO 6 个月。与对照组相比，补充 TMAO 的小鼠在新的物体识别测试中表现更差，表明记忆和学习受损，并且神经炎症和星形胶质细胞活化标志物增加。研究 4：与对照培养基相比，用 TMAO 培养的人类星形胶质细胞表现出与星形胶质细胞活化一致的细胞形态和蛋白质标志物变化，表明 TMAO 直接作用于这些细胞。