Disruption of the core intestinal microbiota contributes to fluoride-induced neurotoxicity in the host organisms

Fluoride is a potential environmental toxic substance associated with dental fluorosis, skeletal fluorosis, and neurotoxic effects. However, the underlying mechanisms remain poorly understood, especially concerning the potential role of fluoride-induced intestinal microbiota dysbiosis in modulating the nervous system via the gut-neuraxis. In this study, an interspecies insect model of fluoride-induced neuronal damage was established to investigate the underlying mechanisms. The results showed markedly elevated malondialdehyde levels, along with reduced glutathione content and decreased catalase and acetylcholinesterase activity in the hemolymph, while histopathological analysis further confirmed the extent of oxidative damage in the nervous tissues caused by fluoride exposure. Using 16S rRNA amplicon sequencing, we found that fluoride decreased the relative abundance of core intestinal microbiota such as Enterococcus, Staphylococcus, and Delftia, while increasing the abundance of unclassified norank_o_Chloroplast and norank_f_Mitochondria taxa. Additionally, the intestinal microbiome exhibited significant heterogeneity, a reduced gut microbiome health index, and an elevated microbial dysbiosis index under fluoride exposure. Metabolomics results indicated that metabolic pathways such as D-amino acid metabolism, aminoacyl-tRNA biosynthesis, ABC transporters, and purine metabolism were enriched following fluoride treatment. Fluoride exposure also significantly altered the levels of several neurotransmitter-related metabolites, including L-glutamate, L-glutamic acid, N-acetyl-L-glutamic acid, L-glycine, spermidine, and serotonin (P < 0.05). Pearson's correlation analysis revealed a relationship between intestinal microbiota dysbiosis and disruptions in neurotransmitter metabolites. These findings provide new insights into the mechanisms of fluoride-induced neurotoxicity, improving the understanding of neurological pathology in fluorosis-endemic areas.