Li Siwen, Yuan Yu, Zeng Yuan, Fang Peng, Wang Junchang, Liu Yi, Xiao Fang
Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, 410013, PR China.
Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha, 410013, PR China.
Environ Pollut. 2025 Mar 1;368:125753. doi: 10.1016/j.envpol.2025.125753. Epub 2025 Jan 25.
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.
微塑料（MPs）正成为一个重大的环境和公共卫生问题，因为它们存在于淡水和海洋环境中，并被生物体摄入。胆汁淤积性肝病（CLD）与肠道稳态密切相关，但尚无关于微塑料对CLD影响的研究数据。在本研究中，我们使用Mdr2小鼠（一种CLD模型）来研究聚苯乙烯微塑料（PS-MPs，0.5μm）对CLD的影响及其潜在机制。我们的数据显示，与Mdr2小鼠相比，接受PS-MPs（200μg/天）攻击的Mdr2小鼠肝脏切片中胶原沉积更严重、炎症细胞浸润更多，血清碱性磷酸酶（ALP）/γ-谷氨酰转移酶（γ-GGT）浓度更高。此外，PS-MPs强烈抑制了CLD小鼠结肠组织中黏液细胞的数量，同时伴随着肠道屏障完整性蛋白（ZO-1、闭合蛋白和Claudin-1）的下调。通过相关性分析进一步验证了ALP/γ-GGT水平与肠道屏障完整性基因之间的联系，以及PS-MPs暴露后与IL-1β的显著正相关。我们的结果还显示，PS-MPs暴露加速了结肠中NOD样受体蛋白3（NLRP3）相关的炎症反应，但不影响Mdr2小鼠肝脏中NLRP3的表达。进一步研究证实，MCC950抑制剂对NLRP3的抑制消除了PS-MPs对肝胆损伤和肠道屏障完整性破坏的加剧作用。这些发现提供了首个证据，即NLRP3介导的炎症是肠道屏障完整性损伤串扰中的一个重要参与者，在微塑料暴露下驱动CLD，并将NLRP3确定为一个潜在的治疗靶点。
