Why do microplastics aggravate cholestatic liver disease? The NLRP3-mediated intestinal barrier integrity damage...

Microplastics (MPs) are becoming a significant environmental and public health concern because they are present in freshwater and marine environments and are ingested by living organisms. Cholestatic liver disease (CLD) is closely related to intestinal homeostasis, but there are no data investigating the effects of MPs on CLD. In this study, we used Mdr2^-/- mice (a model of CLD) to investigate the effects of polystyrene microplastics (PS-MPs, 0.5 μm) on CLD and the underlying mechanisms. Our data revealed that, compared with Mdr2^-/- mice, PS-MPs (200 μg/day)-challenged Mdr2^-/- mice presented more severe collagen deposition, infiltration of inflammatory cells in liver sections and higher alkaline phosphatase (ALP)/γ-glutamyltransferase (γ-GGT) concentrations in the serum. Furthermore, the number of mucous cells in the colonic tissues of mice with CLD was strongly inhibited by PS-MPs, accompanied by the downregulation of intestinal barrier integrity proteins (ZO-1, Occludin and Claudin-1). Through correlation analysis to further verify the connection between ALP/γ-GGT levels and intestinal barrier integrity genes, as well as a significant positive correlation with IL-1β after PS-MPs exposure. Our results also revealed that PS-MPs exposure accelerated the NOD-like receptor protein 3 (NLRP3)-associated inflammatory response in the colon but did not affect NLRP3 expression in the livers of Mdr2^-/- mice. Further study confirmed that the inhibition of NLRP3 by the MCC950 inhibitor abrogated the exacerbating effects of PS-MPs on hepatobiliary injury and intestinal barrier integrity damage. These findings provide the first evidence that NLRP3-mediated inflammation is an important participant in intestinal barrier integrity damage crosstalk that drives CLD under MPs exposure and identify NLRP3 as a potential therapeutic target.