Gut Microbiota Mediates Prenatal METH Exposure-Induced Anxiety- and Depression-Like Behaviors by Modulating the Wnt Signaling Pathway

Background: Prenatal methamphetamine (METH) exposure poses a significant threat to offspring health, including anxiety and depression-like behaviors. This study investigated the neurotoxicity of prenatal METH exposure in offspring and explored the underlying mechanisms. Results: Our results showed that prenatal METH exposure induced anxiety- and depression-like behaviors in offspring, accompanied by increased hippocampal inflammation and decreased hippocampal neurogenesis. Importantly, offspring exposed to prenatal METH exhibited gut microbiota dysbiosis, characterized by a reduced abundance of beneficial bacteria and an increased abundance of pro-inflammatory bacteria. To assess the involvement of the gut microbiota, we conducted cross-fostering and inulin supplementation experiments. Cross-fostering with control dams partially reversed METH-induced behavioral deficits, suggesting a role for maternal microbiota transmission. Inulin supplementation, both during pregnancy and in offspring, effectively remodeled the gut microbiota composition and alleviated anxiety and depression-like behaviors. This effect was associated with reduced hippocampal inflammation and increased hippocampal neurogenesis, potentially mediated by activation of the canonical Wnt signaling pathway. Conclusions: Gut microbiota mediates prenatal METH exposure-induced anxiety- and depression-like behaviors by modulating the WNT signaling pathway. This study provides evidence for the critical role of the gut microbiota in mediating the neurodevelopmental consequences of prenatal METH exposure, and highlights the potential of inulin supplementation as a promising therapeutic strategy.