L‐arginine metabolism ameliorates age‐related cognitive impairment by Amuc_1100‐mediated gut homeostasis maintaining

Abstract Aging‐induced cognitive impairment is associated with a loss of metabolic homeostasis and plasticity. An emerging idea is that targeting key metabolites is sufficient to impact the function of other organisms. Therefore, more metabolism‐targeted therapeutic intervention is needed to improve cognitive impairment. We first conducted untargeted metabolomic analyses and 16S rRNA to identify the aging‐associated metabolic adaption and intestinal microbiome change. Untargeted metabolomic analyses of plasma revealed L‐arginine metabolic homeostasis was altered during the aging process. Impaired L‐arginine metabolic homeostasis was associated with low abundance of intestinal Akkermansia muciniphila ( AKK ) colonization in mice. Long‐term supplementation of AKK outer membranes protein‐Amuc_1100, rescued the L‐arginine level and restored cognitive impairment in aging mice. Mechanically, Amuc_1100 acted directly as a source of L‐arginine and enriched the L‐arginine‐producing bacteria. In aged brain, Amuc_1100 promoted the superoxide dismutase to alleviated oxidation stress, and increased nitric oxide, derivatives of L‐arginine, to improve synaptic plasticity. Meanwhile, L‐arginine repaired lipopolysaccharide‐induced intestinal barrier damage and promoted growth of colon organoid. Our findings indicated that aging‐related cognitive impairment was closely associated with the disorders of L‐arginine metabolism. AKK ‐derived Amuc_1100, as a potential postbiotic, targeting the L‐arginine metabolism, might provide a promising therapeutic strategy to maintain the intestinal homeostasis and cognitive function in aging.