Chronic cerebral hypoperfusion (CCH) is a crucial mechanism causing vascular cognitive impairment (VCI). Choline is metabolized by gut microbiota into trimethylamine N-oxide (TMAO), a risk factor of cardiovascular diseases and cognitive impairment. However, the impact of choline-TMAO pathway on CCH-induced VCI is elusive. We performed a cross-sectional clinical study to investigate the relationship between the choline-TMAO pathway and cognitive outcome and used a bilateral common carotid artery occlusion rat model to explore the effect of a choline-rich diet on cognition and underlying mechanisms. Plasma choline and TMAO levels were negatively correlated with cognitive scores in CCH patients. A choline-rich diet exacerbated CCH-induced cognitive impairment by encouraging the proliferation of choline-metabolizing bacteria in the gut and subsequent generation of TMAO. The choline-TMAO pathway, mediated by gut microbiota, exacerbates cognitive impairment induced by CCH. Targeted dietary choline regulation based on gut microbiota modulation may ameliorate long-term cognitive impairment.
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