Chronic exposure to excessive environmental fluoride has caused fluorosis to become a major public health problem worldwide. Although studies on stress pathways, signaling pathways, and apoptosis induced by fluoride have provided an in-depth understanding of the mechanism of this disease, its exact pathogenesis remains unclear. We hypothesized that the human gut microbiota and metabolome are associated with the pathogenesis of this disease. To get further insight into the profiles of intestinal microbiota and metabolome in coal-burning-induced endemic fluorosis patients, we conducted 16S rRNA sequencing of the intestinal microbial DNA and carried out non-targeted metabolomics of fecal samples from 32 patients with skeletal fluorosis and 33 matched healthy controls in Guizhou, China. We found that the gut microbiota of coal-burning endemic fluorosis patients displayed significant differences in composition, diversity, and abundance compared with healthy controls. This was characterized by an increase in the relative abundance of Verrucomicrobiota, Desulfobacterota, Nitrospirota, Crenarchaeota, Chloroflexi, Myxococcota, Acidobacteriota, Proteobacteria, and unidentified_Bacteria, and a significant decrease in the relative abundance of Firmicutes and Bacteroidetes at the phylum level. Additionally, at the genus level, the relative abundance of some beneficial bacteria, such as Bacteroides, Megamonas, Bifidobacterium, and Faecalibacterium, was significantly reduced. We also demonstrated that, at the genus level, some gut microbial markers, including Anaeromyxobacter, MND1, oc32, Haliangium, and Adurb.Bin063_1, showed potential for identifying coal-burning endemic fluorosis. Moreover, non-targeted metabolomics and correlation analysis revealed the changes in the metabolome, particularly the gut microbiota-derived tryptophan metabolites such as tryptamine, 5-hydroxyindoleacetic acid, and indoleacetaldehyde. Our results indicated that excessive fluoride might cause xenobiotic-mediated dysbiosis of human gut microbiota and metabolic disorders. These findings suggest that the alterations in gut microbiota and metabolome play vital roles in regulating disease susceptibility and multi-organ damage after excessive fluoride exposure.

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