Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome

Abstract

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

The Impact of Free Sugar on Human Health—A Narrative Review

“…This low-grade systemic inflammation is known as metabolic endotoxemia and can lead to several chronic inflammatory conditions [ 229 ]. Fructose-induced dysbiosis-triggered hippocampal neuroinflammation and neuronal loss in mice may highlight a potential mechanism for the neurological and psychiatric impairments associated with sugar and obesity [ 224 , 228 , 233 ].…”

The potential of the gut microbiome for identifying Alzheimer’s disease diagnostic biomarkers and future therapies

“…The microbiome is necessary for the normal development of hippocampal and microglial cell morphology ( Luczynski et al, 2016 ). Recently, Liu et al observed microbiome deficiency altered dendritic signaling integration in the Cornu Ammonis1 region of mice ( Liu et al, 2022 ). The presence of activated microglia and reactive astrocytes in the vicinity of amyloid plaques is characteristic of AD neuroinflammation, mainly in the hippocampus ( Crews and Masliah, 2010 ; Cattaneo et al, 2017 ).…”

Faecal microbiota transplantation from Alzheimer’s participants induces impairments in neurogenesis and cognitive behaviours in rats

“…In line with these findings, intra-species FMT (5xFAD to WT mice) reduced the survival and proliferation of neurons (Kim et al, 2021), and the recruitment and dendritic complexity of immature neurons was deficient in a familial AD mouse model (Mishra et al, 2022). Interestingly, recent studies have shown that that transfer of a WT mouse microbiome into APPswe/PSEN1dE9 mice improved spatial memory and synaptic plasticity (Sun et al, 2019), that reconstitution with normal gut flora in newborn mice protected against decreased AHN and cognitive deficits in antibiotic-treated mice (Liu et al, 2022), and that augmentation of AHN restored the dendritic development of new neurons, coupled with an enhancement of spatial recognition memory (Mishra et al, 2022). Thus, future studies should address whether the changes we observed in adult rats that received FMT from AD human donors are reversible, as well as mechanistic pathways that connect the gut microbiome to AHN.…”