Gut dysbiosis leads to cognitive decline through CNTF-mediated activation of microglia in mice

BACKGROUND: The gut microbiota is essential for maintaining host homeostasis through its influence on metabolism, immunity, and neural signalling. Disruption of this microbial balance, known as gut dysbiosis, can alter gut-brain communication and has been associated with cognitive decline, with impairments in learning and memory. However, the cellular and molecular factors that lead to cognitive decline are not well understood. In this study we used an antibiotic-induced gut dysbiosis model. RESULTS: We observed that the animals with antibiotic-induced gut dysbiosis showed deficits in cognition, especially long-term memory consolidation. There was an increase in astrocytes and microglial activation in the CA1 subregion of the hippocampus. The microglia were observed to engage in synaptic pruning at the presynaptic terminals. This aberrant pruning might have disrupted synaptic plasticity and connectivity, contributing to the observed cognitive deficiency. CNTF was also observed to be elevated along with activation of the JAK/STAT3 pathway. CNTF can activate microglia. Our findings revealed that astrocytes, microglia, and CNTF form an inflammatory activation loop within the CA1 region of the hippocampus following antibiotic-induced gut dysbiosis. CONCLUSIONS: In summary, our study demonstrates that antibiotic-induced gut dysbiosis triggers a cascade of neuroinflammatory events in the hippocampus, involving the elevation of CNTF, microglial pruning at presynaptic terminals, and reciprocal activation of glial cells, resulting in cognitive deficits. These findings highlight the critical role of gut-brain communication in maintaining neural homeostasis and identify CNTF as a potential therapeutic target for dysbiosis-associated cognitive disorders.