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

Fluoride is an essential trace element critical for maintaining normal physiological activities, yet excessive exposure can lead to significant health challenges, including neuroinflammation and gut microbiota dysregulation (Chen et al., 2017; Yasin et al., 2025). In moderate amounts, fluoride promotes the calcification of teeth and bones, facilitates nerve excitation conduction, and supports enzyme metabolism in the body (Mohammadi et al., 2017; Xin et al., 2023). However, excessive fluoride intake is associated with adverse health effects such as skeletal fluorosis and dental fluorosis (Mumtaz et al., 2015; Solanki et al., 2022; Saha et al., 2024; Chang et al., 2025). Although water improvement and fluoride reduction projects have decreased the prevalence of these conditions, industrial activities such as glass manufacturing and steel smelting continue to produce fluoride-containing byproducts, thereby increasing the risk of human exposure (Wang et al., 2021; Tang et al., 2024).

Excessive fluoride exposure is highly toxic to the intestines, causing damage to the intestinal structure and disrupting both the intestinal microbiota and its microenvironment (Liu et al., 2019; Li et al., 2020). Furthermore, fluoride’s neurotoxic effects cannot be ignored. Excessive fluoride intake has been shown to over-activate microglia in the central nervous system, triggering the secretion of inflammatory cytokines that promote neuronal damage and lead to neuroinflammation (Zhao et al., 2024). Despite these findings, the regulatory relationship between fluoride-induced neuroinflammation and gut microbiome imbalance remains poorly understood. Therefore, exploring the connection between gut microbiome dysregulation and neuroinflammation under fluoride exposure is critically important.

During early nervous system development, the gut microbiome regulates key factors, including brain-derived neurotrophic factor, synaptophysin, and postsynaptic density proteins (Sorboni et al., 2022; Loh et al., 2024). Additionally, the development, maturation, and function of microglia, astrocytes, and boundary-dependent macrophages are influenced by microbial-dependent signaling pathways. Processes such as myelination, neurogenesis, and microglial activation depend on the composition of the gut microbiome (Agirman et al., 2021). Metabolites produced by intestinal flora—such as short-chain fatty acids (SCFAs), tryptophan metabolites, secondary bile acids, and neurotransmitter analogues—serve as signaling molecules that regulate neuronal activity, neuroinflammation, and neurotransmitter synthesis and release (Krautkramer et al., 2020). Germ-free mice exhibited abnormal brain development and increased blood-brain barrier permeability, suggesting that reduced integrity of the blood-brain barrier may allow immune cells and bacterial components to enter the brain and influence neuroinflammation (Cryan et al., 2020). Collectively, these findings underscore the gut microbiota’s critical role in the development, maturation, and maintenance of normal nervous system function (de Vos et al., 2022).

The gut microbiome also forms a protective biological barrier on the surface of the intestinal mucosa, maintaining epithelial cell connections and regulating intestinal permeability (Farré et al., 2020). In states of intestinal inflammation, increased leakage of the intestinal vascular barrier allows bacterial toxins from the intestinal cavity to enter the bloodstream, triggering systemic inflammatory responses. The central nervous system, protected by a complex vascular barrier—including the blood-brain barrier and the blood-cerebrospinal fluid barrier—typically restricts the entry of macromolecules from the blood into the brain, maintaining a stable environment in brain tissue (Carloni et al., 2021; Morales-Soto et al., 2023). However, ecological imbalances in the gut microbiota can impair intestinal barrier function, enabling pathogens, LPS, and intestinal-derived amyloid proteins to reach the peripheral circulation. This disruption reduces the integrity of the blood-brain barrier and contributes to neuroinflammation (Pellegrini et al., 2023). Damage to the intestinal barrier may also lead to the displacement of gut flora, the release of pathogenic metabolites, or the infiltration of pathological proteins associated with the central nervous system into the bloodstream, potentially activating inflammatory responses or spreading to the brain and triggering central nervous system lesions (Ommati et al., 2020).

Fluoride-induced neuroinflammation and its potential regulatory relationship with intestinal microbiota imbalance remain poorly understood in existing literature. While prior studies have explored the individual effects of fluoride exposure on neurotoxicity and gut dysbiosis, the mechanistic link between these phenomena has yet to be fully elucidated. To address this critical gap, this study investigates the regulatory mechanisms of the microbiota-gut-brain axis in fluoride-induced neuroinflammation. It evaluates the therapeutic potential of SCFAs as an intervention strategy in rats.