Gut Microbiota Taxon-Dependent Transformation of Microglial M1/M2 Phenotypes Underlying Mechanisms of Spatial Learning and Memory Impairment after Chronic Methamphetamine Exposure

Methamphetamine (METH) exposure may lead to cognitive impairment. Currently, evidence suggests that METH exposure alters the configuration of the gut microbiota. However, the role and mechanism of the gut microbiota in cognitive impairment after METH exposure are still largely unknown. Here, we investigated the impact of the gut microbiota on the phenotype status of microglia (microglial phenotypes M1 and microglial M2) and their secreting factors, the subsequent hippocampal neural processes, and the resulting influence on spatial learning and memory of chronically METH-exposed mice. We determined that gut microbiota perturbation triggered the transformation of microglial M2 to M1 and a subsequent change of pro-brain-derived neurotrophic factor (proBDNF)-p75(NTR)-mature BDNF (mBDNF)-TrkB signaling, which caused reduction of hippocampal neurogenesis and synaptic plasticity-related proteins (SYN, PSD95, and MAP2) and, consequently, deteriorated spatial learning and memory. More specifically, we found that Clostridia, Bacteroides, Lactobacillus, and Muribaculaceae might dramatically affect the homeostasis of microglial M1/M2 phenotypes and eventually contribute to spatial learning and memory decline after chronic METH exposure. Finally, we found that fecal microbial transplantation could protect against spatial learning and memory decline by restoring the microglial M1/M2 phenotype status and the subsequent proBDNF-p75(NTR)/mBDNF-TrkB signaling in the hippocampi of chronically METH-exposed mice.IMPORTANCE Our study indicated that the gut microbiota contributes to spatial learning and memory dysfunction after chronic METH exposure, in which microglial phenotype status plays an intermediary role. The elucidated specific microbiota taxa-microglial M1/M2 phenotypes-spatial learning and memory impairment pathway would provide a novel mechanism and elucidate potential gut microbiota taxon targets for the no-drug treatment of cognitive deterioration after chronic METH exposure. Our study indicated that the gut microbiota contributes to spatial learning and memory dysfunction after chronic METH exposure, in which microglial phenotype status plays an intermediary role. The elucidated specific microbiota taxa-microglial M1/M2 phenotypes-spatial learning and memory impairment pathway would provide a novel mechanism and elucidate potential gut microbiota taxon targets for the no-drug treatment of cognitive deterioration after chronic METH exposure.

Automated summary

This study reveals that Methamphetamine (METH) exposure causes cognitive impairment and alters the gut microbiota. The disruption of gut microbiota triggers the transformation of microglial M2 to M1, leading to changes in hippocampal neural processes and impairments in spatial learning and memory. Understanding the interaction between the gut microbiota and microglia has important implications for the treatment of cognitive deterioration after chronic METH exposure.