Synergistic Toxicity of Combined Exposure to Acrylamide and Polystyrene Nanoplastics on the Gut–Liver Axis in Mice

Acrylamide (AA) and nanoplastics (NPs) are common food toxicants. However, their combined toxicity and health risks call for further studies. This study aimed to investigate the combined toxicity of AA and polystyrene NPs (PS-NPs) in mice through drinking water exposure. Co-exposure to AA and PS-NPs aggravated colon and liver damage, including more severe inflammatory infiltration, higher levels of colonic and hepatic pro-inflammatory cytokines, and elevated serum content of lipopolysaccharide and activities of diamine oxidase, alanine aminotransferase, and aspartate aminotransferase compared to single exposures. Co-exposure also significantly downregulated the expression of colonic tight-junction genes ZO-1 and Claudin-5. Metabolomics revealed that co-exposure induced more profound metabolic disorders in the liver, particularly affecting amino acid and carbohydrate metabolism. 16S amplicon sequencing showed that co-exposure caused more drastic gut microbiota dysbiosis, characterized by a decrease in beneficial bacteria (<i>unclassified_f__Oscillospiraceae</i>, <i>Roseburia</i>, <i>UCG-005</i>, <i>Ruminiclostridium</i>, <i>unclassified_o__Clostridia_UCG-014</i>, <i>Fournierella</i>, and <i>Acetatifactor</i>) and an increase in pathogenic bacteria (<i>Eubacterium_xylanophilum_group</i> and <i>Eubacterium_nodatum_group</i>). Correlation analysis indicated a negative correlation between beneficial bacteria and intestinal-liver toxicity indicators and a positive correlation between pathogenic bacteria and these indicators. Overall, our findings showed that AA and PS-NPs exerted synergistic toxicity to the gut-liver axis in mammals, highlighting the higher health risks of their combined ingestion.