Assessment of the bacteria-derived metabolite TMAO as a potential factor contributing to the pathophysiology of delirium in elderly patients with hip fracture

BACKGROUND: Trimethylamine N-oxide (TMAO) concentrations are dependent on several factors including gut microbial metabolism of dietary nutrients. High TMAO levels have been implicated in the pathogenesis of age-related cognitive impairment. We hypothesized that TMAO may contribute to the pathophysiology of delirium. METHODS: In this observational study, we analyzed TMAO concentration in blood and cerebrospinal fluid (CSF) samples from 487 hip fracture patients. Delirium status was set according to the DSM-5 criteria, and pre-existing cognitive impairment by the IQCODE. We performed a logistic regression analysis to examine the association between TMAO and delirium, adjusting for age, pre-existing dementia, and renal function. RESULTS: The median TMAO concentration was significantly higher in patients with delirium (3.9 µM, IQR 2.6-6.6 in blood; 2.5 µM, IQR 1.3-4.9 in CSF) than without delirium (3.0 µM, IQR 2.1-5.1 in blood; P = 0.02, and 1.6 µM, IQR 0.9-3.0 in CSF, P < 0.001). After adjusting for confounders, the association between TMAO and delirium remained significant in CSF (OR = 1.5, 95%CI 1.09-2.05, P = 0.01). Analysis stratified by dementia showed the association was significant only for CSF TMAO among patients without pre-existing dementia (OR = 1.6, 95% CI 1.09-2.30, P = 0.02). CONCLUSIONS: The increased concentration of TMAO in CSF is positively associated with delirium among patients without pre-existing dementia. Our finding supports previous observations that the gut derived metabolites may be relevant in delirium, but the pathophysiology may differ in patients with and without pre-existing dementia.