High-dose carboxylated cellulose nanocrystals exacerbate gut dysbiosis and intestinal infection.

Surface functionalization of cellulose nanocrystals (CNCs) is commonly used to improve their dispersibility, functionality, and performance across diverse applications. However, the potential biosafety risks of these modified nanomaterials, particularly within the gastrointestinal tract, remain insufficiently understood. Here, we systematically investigated the physicochemical properties, antibacterial activity, and biological effects of several CNC derivatives. Among these, carboxylated CNCs (CNC-COOH) exhibited the strongest antibacterial activity in vitro, primarily by disrupting bacterial membranes and collapsing intracellular proton gradients. Unexpectedly, oral administration of CNC-COOH at 50 mg/kg markedly exacerbated Salmonella Typhimurium infection in vivo, resulting in intestinal barrier impairment and systemic inflammation. Notably, this dose also induced weight loss and elevated pro-inflammatory cytokines in the absence of infection, suggesting a potential basal toxicity. 16S rRNA gene sequencing indicated that CNC-COOH exposure significantly reduced microbial diversity and promoted the overgrowth of opportunistic pathogens, thereby aggravating gut dysbiosis. Histological evaluation and immunofluorescence analyses further revealed epithelial injury, goblet cell depletion, and substantial downregulation of key mucosal and tight junction markers, including MUC2, Occludin, and ZO-1. Collectively, these results suggest that a high dose of CNC-COOH disrupts intestinal homeostasis and increases vulnerability to enteric infections, raising important safety concerns regarding its biomedical and consumer applications.