Understanding the role of the gut-brain axis in modulating Cadmium neurotoxicity

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PROJECT SUMMARY Cadmium (Cd) is a heavy metal with major public health concern around the world. Increasing studies suggest that Cd is a neurotoxicant, and the Cd exposure is associated with learning and memory deficits, and various neurodegenerative diseases in humans. My previous study has found that environmental relevant Cd exposure can impair learning and memory in animals. However, the current knowledge about the mechanisms of Cd neurotoxicity is still very limited. There is an increasing recognition that the gut-brain axis, a communication pathway between the central nervous system and the gut microbiome, is important for regulating neurological functions. Since the gut microbiome is a target of Cd toxicity, I hypothesized that the gut-brain axis mechanistically contributes to Cd neurotoxicity. This project aims to determine if the gut microbiome contributes to Cd neurotoxicity on learning and memory and identify specific microbiomes and microbial metabolites that mechanistically contribute to Cd neurotoxicity. The K99 mentored phase proposes to (1) examine the changes of the gut microbiome and microbial metabolites according to the onset of Cd-induced learning and memory deficits, and further (2) determine if the gut microbiome is both necessary and sufficient for Cd neurotoxicity by using antibiotics-treated mice to determine how depletion of the gut microbiome modulates the Cd-induced learning and memory deficits in mice, and conducting fecal microbiota transplant in antibiotics-treated mice inoculated with intestinal content collected from Cd-treated mice with impaired memory to determine how a “diseased microbiome” itself contributes to cognitive deficits. During this time, the candidate will complete mentored training and courses in the microbiome, bioinformatics, second-generation sequencing, and other professional development training in preparation for the independent R00 phase. In the independent phase, with the findings from the K99 phase, this project will further identify specific microbiomes and microbial neuroactive metabolites that contribute to Cd toxicity in learning and memory. Regarding the expected outcomes, this project will determine for the first time the importance of the gut-brain axis in Cd-induced neurotoxicity, enhance the understanding of the mechanisms concerning the neurotoxicity of Cd and other environmental neurotoxicants, and provide translational insights for the design of prevention and intervention strategies to mitigate Cd neurotoxicity by reprogramming the gut microbiome.