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Chronic Excessive Exposure to Fluoride Impairs the Intestinal Mucosal Barrier to Cause Inflammatory Response and Microbiome Dysbiosis in Rats.
| Biological Trace Element Research | Zhang JR, Li YW, Chen HX, Luo Y, Liu RM, Wang JB, Liu NN, Xiao JH. |
Chronic fluorosis Gastrointestinal Immune System Animal Study

Abstract

Original abstract online at
https://link.springer.com/article/10.1007/s12011-026-05050-4

Highlights

• Fluoride exposure directly compromises the integrity of the intestinal barrier.

• Intestinal barrier damage triggers local and systemic inflammatory responses.

• Inflammatory responses may provoke mucosal immune dysregulation.

• Dysregulated mucosal immune may induce the dysbiosis of intestinal microbiome.

• Microbiome dysbiosis induces metabolic alterations and further exacerbates fluorosis.

Fluoride exposure compromises intestinal barrier integrity at both cellular and animal levels. This damage triggers local and systemic inflammatory responses, leading to mucosal immune dysregulation, which in turn perturbs gut microbiota homeostasis. The resulting microbial dysbiosis and associated metabolic alterations ultimately exacerbate the pathogenesis of fluorosis.

Chronic excessive exposure to fluoride is known to cause dental fluorosis, skeletal fluorosis, and even disability. We previously demonstrated that chronic fluorosis contributes to dysbiosis of the gut microbiota and metabolic disturbances in human; however, the underlying mechanisms remain unclear. In this study, cellular and rat models of chronic fluorosis were utilized to investigate the mechanistic interactions between fluoride exposure and the intestinal barrier, mucosal immunity, and gut microbiome. Exposure to sodium fluoride disrupted intercellular connections in intestinal epithelial cells by downregulating key tight junction proteins, including ZO-1 and Occludin, and impaired the structure integrity of Caco-2 monolayers. In a rat model of chronic fluorosis, we observed a significant downregulation of ZO-1, Occludins, and mucin MUC-2 at both mRNA and protein levels, and a consequent increase in intestinal permeability, indicating a compromised intestinal barrier. Additionally, a pronounced increase in inflammatory responses suggested dysregulated mucosal immunity. Integrated microbiome and metabolomic analyses revealed dysbiosis in both oral and gut microbiota, which was significantly correlated with altered levels of quinate, ethylmethylacetic acid, cholesterol sulfate, L-phenylalanine, and indole. Collectively, these results demonstrate that chronic excessive fluoride exposure directly impairs the intestinal barrier, triggers inflammatory response, and the resulting inflammation disrupts gut microbiota homeostasis in rats. Our findings provide new insights into fluoride-induced toxicity within intestinal environment and highlights the intestinal barrier as a potential therapeutic target for the prevention and treatment of chronic fluoriosis.

Graphic Abstract

Data Availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank Ministry of Science and Technology of the People’s Republic of China (grant number: GKFZ-2018-29), National Natural Science Foundation of China (grant number: 82260158), Department of Education of Guizhou Province (grant number: QJJ [2023] 020), Guizhou Provincial Department of Science and Technology(grant numbers: QKHPT-RC-GCC [2022]001-2; QKHJC-ZK[2025]ZD-031; QKHJ-ZK[2021]485), and the Science and Technology Bureau of Zunyi City(grant numbers: ZSKH-SYS[2025]-03; ZSKHHZ-[2023]-198), PR China for the funding supports.

Author information

Authors and Affiliations

  1. Institute of Medicinal Biotechnology & Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China

    Jia-Rong Zhang, Yi-Wen Li, Hong-Xuan Chen, Yi Luo, Ru-Ming Liu, Jian-Bin Wang, Ning-Ning Liu & Jian-Hui Xiao

  2. Guizhou Provincial Key Laboratory of Medicinal Biotechnology & Research Center for Translational Medicine in Colleges and Universities, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China

    Yi Luo, Ru-Ming Liu, Jian-Bin Wang & Jian-Hui Xiao

  3. School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ning-Ning Liu

Contributions

Conceptualization, J.H.X.; Investigation, J.R.Z., Y.W.L., and H.X.C.; Methodology, J.R.Z., and Y.L.; Formal analysis, J.R.Z.,Y.W.L., H.X.C., and Y.L.; Validation, J.R.Z.; Data curation, J.R.Z.; Writing-original draft, J.R.Z.; Writing-review & editing, J.H.X., N.N.L., and J.B.W.; Funding acquisition, J.H.X., and J.B.W.; Project adminstration, J.H.X.; Supervision, J.H.X., N.N.L., and R.M.L. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jian-Bin Wang, Ning-Ning Liu or Jian-Hui Xiao.

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Competing interests

The authors declare no competing interests.

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