Improved effect of antibiotic treatments on the hippocampal spatial memory dysfunction of mice induced by high fluoride exposure: Insight from assembly processes and co-occurrence networks of gut microbial community.

High fluoride exposure was widely demonstrated to be related with brain memory impairment. Since the absorption of F- enters the body mainly through the gastrointestinal tract, studying the effects of excessive intake of fluoride on brain memory function in various gut microbiome states might have profound implications for the prevention of fluorosis because growing evidence revealed the significance of the "microbiota-gut-brain" axis (MGBA). In the present study, we aimed to illustrate the potential mechanism of gut microbiota on high fluoride exposure-induced hippocampal lesions and spatial memory dysfunction in mice by the various intestinal microecological environments, which were constructed by antibiotic treatment. Mice fed with normal (CG1 and Exp1 groups) or sodium-fluoride (CG2 and Exp2 groups; 24 mg/kg sodium fluoride per mouse) by gavage administration with or without antibiotic treatments, a combination of metronidazole (1 g/L) and ciprofloxacin (0.2 g/L) in drinking water. Mice gavaged with excessive sodium fluoride alone exhibited reduced weight gain, hippocampal tissue damages, spatial memory levels dysfunction, impaired intestinal permeability, decreased inflammatory cytokines expression and antioxidant capability in the hippocampal and ileal tissues. In contrast, antibiotic intervention significantly reversed these high fluoride exposure-induced hippocampal and ileal changes.16S rRNA high throughput sequencing found that ileal microbiota were dominated by abundant taxa, which is conducive to constructing microbial interaction networks and module communities, and identifying keystone species targeted by high fluoride exposure compared with colonic microbiome. In addition, the microbial community composition and assembly mechanism of ileal microbiome under the effects of antibiotics were suitable for revealing the characteristics of high fluoride environment. In the later analysis, Lactobacillus, Staphylococcus, Muribaculaceae and Robinsoniella were considered as the keystone species targeted by high fluoride-exposed mice based on the analysis of network node properties and niche overlap of ileal microbes. Spearman rank correlation demonstrated that these keystone species had significant effects on hippocampal memory levels and intestinal health, as well as microbial communities functions. Compared to previous researches, this study further revealed intestinal microbial coummunity mediated the underlying mechanism through antibiotic treatment against high fluoride-induce hippocampal spatial memory impairment.