Aged Gut Microbiota Contributes to Cognitive Impairment and Hippocampal Synapse Loss in Mice

ABSTRACT Gut microbiota alteration during the aging process serves as a causative factor for aging‐related cognitive decline, which is characterized by the early hallmark, hippocampal synaptic loss. However, the impact and mechanistic role of gut microbiota in hippocampal synapse loss during aging remains unclear. Here, we observed that the fecal microbiota of naturally aged mice successfully transferred cognitive impairment and hippocampal synapse loss to young recipients. Multi‐omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum ( B.p ) and metabolite of tryptophan, indoleacetic acid (IAA) in the periphery and brain. These features were also reproduced in young recipients that were transplanted with aged gut microbiota. Fecal B.p abundance was reduced in patients with cognitive impairment compared to healthy subjects and showed a positive correlation with cognitive scores. Microbiota transplantation from patients who had fewer B.p abundances yielded worse cognitive behavior in mice than those with higher B.p abundances. Meanwhile, supplementation of B.p was capable of producing IAA and enhancing peripheral and brain IAA bioavailability, as well as improving cognitive behaviors and microglia‐mediated synapse loss in 5 × FAD transgenic mice. IAA produced from B.p was shown to prevent microglia engulfment of synapses in an aryl hydrocarbon receptor‐dependent manner. This study reveals that aged gut microbiota ‐induced cognitive decline and microglia‐mediated synapse loss that is, at least partially, due to the deficiency in B.p and its metabolite, IAA. It provides a proof‐of‐concept strategy for preventing neurodegenerative diseases by modulating gut probionts and their tryptophan metabolites.