Abstract

Nanoplastics (NPs) exposure can cause severe hepatic injuries. Gut microbiota is considered a contributing factor to multiple hepatic injuries. However, its role in NPs‐induced hepatic injuries remains unclear, and microbial intervention strategies are required. Our results reveal that oral exposure to polystyrene NPs reduces gut probiotic Bifidobacterium pseudolongum ( B.p ) and its metabolite inosine. Gut microbiota from NPs‐administered mice partially reproduces NPs‐related impairment of gut homeostasis and hepatic injury in recipient mice. Moreover, B.p colonization improves NPs‐induced gut homeostasis impairment and hepatic injury, and its protective effects are reproduced by supplementation with inosine. Mechanically, B.p colonization increases hepatic level of inosine and subsequently normalizes the expression of its target A2AR. Meanwhile, increased inosine inhibits the miR155/SOCS1/NF‐κB pathway and represses NPs‐induced M1 macrophage polarization. CGS21680 , an agonist of A2AR, effectively represses lipopolysaccharide (LPS)‐induced M1 macrophage polarization and inhibits the miR155/SOCS1/NF‐κB pathway in vitro. Further, miR155 knockout inhibits NPs‐induced M1 macrophage polarization, but does not influence the suppression of NPs on A2AR. These findings suggest that B.p ‐derived inosine can repress NPs‐induced M1 macrophages polarization by inhibiting the miR155/SOCS1/NF‐κB pathway via targeting A2AR. Altogether, this study further clarifies the role of gut microbiota in NPs‐induced hepatic injury and provides a potential microbial therapeutic strategy. Probiotic B.p colonization elevated gut‐derived inosine level in the liver, while elevated inosine activated A2AR and subsequently blocked NPs‐induced polarization of M1 macrophages by repressing the miR155/SOCS1/NF‐κB pathway. This reduced the release of inflammatory cytokines and thereby, mitigated NPs‐induced hepatic injury.