Nanoplastics exacerbate DSS-induced colitis via histone lactate axis

Nanoplastic pollution is a serious global concern, which has caused great threat to the human health. However, the relationship between nanoplastic exposure and the development and progression of ulcerative colitis (UC) is still unknown. We established a chronic dextran sulfate sodium (DSS)-induced colitis model with exposure to polystyrene nanoplastics (PS-NPs) and evaluated disease severity, gut inflammation, and intestinal barrier function. The immune microenvironment was assessed using fluorescence multiplex immunohistochemistry (mIHC), while histone lactylation modification was analyzed via western blot and Cleavage Under Targets and Tagmentation (CUT&Tag). Additionally, lipopolysaccharide (LPS)-treated RAW264.7 cells were cultured and intervened to further investigate the molecular mechanism of PS-NPs in colitis. Continuous exposure to PS-NPs exacerbated gut inflammation and damage intestinal barrier function in DSS-induced colitis. PS-NPs exposure is closely correlated with increased macrophage infiltration, enhanced the glycolysis and up-regulated the histone H3 lactylation in macrophages. CUT&Tag analysis showed that PS-NPs influenced the expression of GART via histone H3K18la lactylation. Intervention in histone H3K18la lactylation significantly altered the expression of GART and levels of inflammatory factors in LPS-treated RAW264.7 cells. Downregulating GART expression reduced inflammatory factor levels in RAW264.7 cells treated with LPS plus PS-NPs. PS-NPs exposure exacerbates colitis by upregulating histone H3 lactylation. This study reveals a novel mechanism underlying nanoplastic-exacerbated intestinal injury and provides a direction for future risk assessment of nanoplastics.