Metabolites derived from the gut microbiome, such as short chain fatty acids, serotonin and tryptophan, are thought to be key players in the signalling between the Central Nervous System (CNS) and the gut. Furthermore, the infant microbiome is significantly correlated with fine motor and social skills. Previous animal studies have suggested that absence of a microbiome adversely affects the integrity of the blood–brain barrier and leads to physiological changes to the prefrontal cortex, hippocampus and amygdala.

Liu et al. established a gut dysbiosis mouse model using selected antibiotics for four weeks. Two weeks after the final dose, faecal matter underwent 16S rDNA high-throughput sequencing to determine microbiome composition. The mice were the subjected to a series of behavioural tests focussed on spatial learning/memory deficits and behavioural impairments including anxiety. Specifically, Firmicutes were reduced whilst proteobacteria increased. Oher bacteria, which negatively correlated with cognition, were also found to be elevated. Long Term Potentiation (LTP), the process underpinning learning and memory, was found to be impaired in antibiotic treated mice as compared to controls, indicating a reduction in synaptic plasticity. Further reinforcing this was an observed change on dendritic spine morphology in the antibiotic-treated mice. In addition, by labelling hippocampal progenitor cells with relevant antibodies, gut dysbiosis was shown to impair adult neurogenesis as compared to control.

Hippocampal transcriptomic analysis also revealed impaired expression of Immediate Early Genes (IEGs) in the dentate gyrus of antibiotic-treated mice associated with adverse effects in plasticity, learning and memory. Gene expression of LCN2 and LRG1 associated with impaired plasticity and memory were significantly increased. The researchers also found that faecal transplantation to restore the microbiome of the treatment group resulted in significant improvement of behavioural deficits, neurogenesis and LTP and that expression of IEGs appeared restored.

Investigating another bacterial metabolite, naïve mice were treated with 4-methylphenol for 2 weeks. Exposure to this metabolite downregulated IEGs whilst increasing expression of LCN2 and LRG1, inhibiting spine maturation of hippocampal neurons. In addition, upregulated inflammatory/apoptotic signals led to neuronal death in the dentate gyrus and CA1 region of the hippocampus.

Comment: The authors show that there is a critical neurodevelopmental window shortly after birth, where dysbiosis can have severe long-term consequences to hippocampal function and so learning and memory via altered microbiomes and their metabolites. This suggests a potential avenue of therapeutic intervention for neurodevelopmental disorders.

Liu G et al. Gut Microbes. 2022 Jan–Dec;14(1):2104089. https://doi.org/10.1080/19490976.2022.2104089. PMID: 35876011; PMCID: PMC9327780.