Short-chain fatty acids alleviated fluoride-induced neuroinflammation via the gut-brain axis in rats

Dec 8, 2025Environmental pollution (Barking, Essex : 1987)

Short-chain fatty acids reduce fluoride-caused brain inflammation through the gut-brain connection in rats

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Abstract

Supplementation with short-chain fatty acids (SCFAs) may alleviate fluoride-induced neuroinflammation in rats.

Fluoride exposure disrupted the composition of colonic microbiota in rats at both phylum and genus levels.
Fluoride exposure led to decreased mucin secretion and reduced protein expression of key mucosal barrier proteins in colon tissue.
Increased levels of inflammatory markers, such as IL-1β and TNF-α, were observed in the serum of fluoride-exposed rats.
Fluoride exposure activated the TLR4/NF-κB signaling pathway in both colonic and cerebral cortex tissues, contributing to neuroinflammation.
SCFAs supplementation improved microbial dysbiosis and enhanced tight junction integrity in the colon, decreasing intestinal permeability.
SCFAs restored the blood-brain barrier structure and suppressed activation of neuroinflammatory cells, mitigating fluoride's adverse effects.

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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.

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Short-chain fatty acids alleviated fluoride-induced neuroinflammation via the gut-brain axis in rats

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