The Aged Gut Microbiome Harms the Brain

The balance of microbial species making up the gut microbiome has been shown to change with age. Inflammatory microbes grow in number at the expense of species that generate beneficial metabolites such as butyrate. Patients with neurodegenerative conditions, diseases that are characterized by chronic inflammation and immune dysfunction, have been shown to exhibit a distinctly dysfunctional gut microbiome. In human populations, there remain the questions on direction of causation, but in animal models researchers can quite readily demonstrate that transplanting a young gut microbiome into an old animal improves health, while the reverse happens when an old gut microbiome is transplated into a young animal.

Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by the early hallmark of 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 mouse recipients. Multi-omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum (B.p) and indoleacetic acid (IAA), a metabolite of tryptophan, in the periphery and brain. These features were also reproduced in young mouse recipients that were transplanted with aged gut microbiota.

In human patients, 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 human patients who had fewer B.p abundances into mice yielded worse cognitive behavior in the mice than transplants from human patients with higher B.p abundances.

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 5xFAD 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 microbiome and their tryptophan metabolites.