Critical role of crosstalk through the gut-liver and gut-kidney axes in mediating organ-specific toxicity induced by foodborne and waterborne rare earth elements

The escalating contamination of rare earth elements (REEs) in agricultural soils and rivers from intensive mining activities necessitates urgent investigation into their potential health risks. This study systematically compared the organ-specific toxicological effects of foodborne versus waterborne REE exposure in murine model, focusing on toxicity mechanisms mediated by the gut-liver and gut-kidney axes crosstalk. Elevated REE concentrations were detected in both liver and kidney tissues, as well as feces following exposure, with accumulation dependent on exposure level and duration, indicating that REEs can accumulate in mice despite existing excretion mechanisms. Histopathological analysis and immunofluorescence staining revealed that tissue damage related to inflammation and oxidative stress in the liver and kidney was caused by REE exposure, supported by altered metabolite profiles. Both foodborne and waterborne REEs disrupted hepatic metabolism related to amino acids and arachidonic acid, driving inflammation and oxidative stress. Whereas waterborne REEs preferentially impaired renal tryptophan and riboflavin metabolism associated with oxidative stress. Notably, both pathways disturbed the urea cycle in target organs, impacting nitrogen metabolism. Furthermore, REE exposure triggered a significant shift in intestinal flora composition, characterized by an elevated Firmicutes/Bacteroidota ratio. Correlation network analysis indicated significant crosstalk within the gut-kidney axis (p < 0.01), underscoring the critical role of gut microbiota in mediating REE toxicity. While the gut-liver axis exhibits comparatively weaker interactions. Overall, our study offers new insights into the distinct toxic action mechanisms of REEs through varied exposure patterns and highlights the gut microbiota as a key modulator of host health outcomes.