Neuroinflammation is a hallmark of central nervous system injury caused by fluorosis; however, the regulatory relationship between intestinal microbial and fluoride-induced neuroinflammation remains unclear. Here, we aimed to evaluate the alleviating effect of short-chain fatty acids (SCFAs) on fluoride exposure-induced neuroinflammation in rats. In this study, it is demonstrated that the composition of colonic microbiota was disrupted in fluoride-exposed rats at both phylum and genus levels, and fluoride exposure decreased the number of positive cells per crypt, inhibited mucin secretion, and reduced the protein expression of MUC2 and TFF3, and tight junction proteins (Occludin and ZO-1) in the colon tissue, leading to colonic mucosal barrier damage. Additionally, the content of IL-1β, TNF-α and LPS in the serum of fluoride-exposed rats was increased, and the TLR4/NF-κB pathway was also activated in the colon tissue. Moreover, the expression of Occludin and ZO-1 in the cerebral cortex was decreased by fluoride exposure, resulting in neuronal damage, astrocyte and microglial activation and the activation of the TLR4/NF-κB signaling pathway, which subsequently induced neuroinflammation. However, these adverse effects were mitigated by supplementation with SCFAs. It was observed that supplementation with SCFAs improves microbial dysbiosis in the colon, and SCFAs enhance tight junction integrity between intestinal epithelial cells, decrease intestinal permeability and the content of IL-1β, TNF-α and LPS in the serum, inhibit colonic inflammation. Additionally, SCFAs restored the damaged blood-brain barrier structure, suppressed astrocyte and microglial activation, and relieved fluoride-induced neuroinflammation by inhibiting the activation of the TLR4/NF-κB signaling pathway. In conclusion, SCFAs supplementation alleviates fluoride-induced colonic barrier damage and microbial disturbances, thereby mitigating fluoride-induced neuroinflammation in rats through the microbiota-gut-brain axis.
