From tooth to gut: Proteomic evidence of systemic dysregulation in fluorosis

Excessive fluoride intake during early tooth development causes dental fluorosis, yet chronic high fluoride exposure may also disrupt gastrointestinal physiology and host-microbe interactions. We profiled the host fecal proteome of school-aged children with severe dental fluorosis (PF; TF 5-9; n = 10) and age-matched controls (CF; TF 0; n = 10) from a fluoride-endemic region of Thailand, with systemic exposure confirmed by elevated 24-h urinary fluoride excretion. LC-MS/MS identified 182 proteins (164 retained after filtering), including 24 proteins detected exclusively in PF samples. Differential protein expression revealed six upregulated (C3, FYTTD1, TRIP11, PRDX4, CDH1, SI) and four downregulated (SIAE, ZG16, MUC5AC, GUSB). Enrichment analyses implicated coordinated alterations in epithelial adhesion and barrier regulation, vesicular trafficking/ER proteostasis, oxidative stress responses, carbohydrate metabolism, and innate immune signaling. Knowledge-based interaction mapping (STRING/IntAct) further nominated cystic fibrosis transmembrane conductance regulator (CFTR)-centered epithelial ion-transport and barrier pathways as a convergent axis linking multiple fluoride-responsive proteins. These findings provide human proteomic evidence that fluorosis associates with intestinal epithelial and immune dysregulation extending beyond enamel pathology, supporting a systems-level view of fluorosis as a multisystem condition.