Manganese-induced Sex-specific Gut Microbiome Perturbations in C57BL/6 Mice

Overexposure to manganese (Mn) leads to toxic effects, such as promoting the development of Parkinson's-like neurological disorders. The gut microbiome is deeply involved in immune development, host metabolism, and xenobiotics biotransformation, and significantly influences central nervous system (CNS) via the gut-brain axis, i.e. the biochemical signaling between the gastrointestinal tract and the CNS. However, it remains unclear whether Mn can affect the gut microbiome and its metabolic functions, particularly those linked to neurotoxicity. In addition, sex-specific effects of Mn have been reported, with no mechanism being identified yet. Recently, we have shown that the gut microbiome is largely different between males and females, raising the possibility that differential gut microbiome responses may contribute to sex-selective toxicity of Mn. Here, we applied high-throughput sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics to explore how Mn exposure affects the gut microbiome and its metabolism in C57BL/6 mice. Mn exposure perturbed the gut bacterial compositions, functional genes and fecal metabolomes in a highly sex-specific manner. In particular, bacterial genes and/or key metabolites of neurotransmitter synthesis and pro-inflammatory mediators are significantly altered by Mn exposure, which can potentially affect chemical signaling of gut-brain interactions. Likewise, functional genes involved in iron homeostasis, flagellar motility, quorum sensing, and Mn transportation/oxidation are also widely changed by Mn exposure. Taken together, this study has demonstrated that Mn exposure perturbs the gut microbiome and its metabolic functions, which highlights the potential role of the gut microbiome in Mn toxicity, particularly its sex-specific toxic effects.