Hepatotoxicity induced by polylactic acid microplastics: The mediating role of gut microbiota and uric acid metabolism.

Introduction: The increasing use of biodegradable plastics has led to the inevitable human consumption of biodegradable microplastics (MPs). These MPs can be degraded and absorbed into various organs and tissues via the gastrointestinal tract, with the liver being the primary target for digestion and absorption.

Objectives: This study aimed to investigate the toxic effects and mechanisms of biodegradable MPs on the liver following gastrointestinal degradation.

Methods: Polylactic acid (PLA) was used as a representative bioplastic. We simulated pristine and partially degraded states using polymeric and oligomeric PLA MPs. Mice were exposed to these MPs via 28-day repeated gavage administration at environmentally realistic concentrations. In vivo multi-omics analyses, combined with in vitro studies, were employed to explore underlying mechanisms.

Results: Exposure to PLA oligomers and polymers disrupted gut microbiota, triggering an increase in plasma and hepatic uric acid levels in the mice. Elevated uric acid levels, in turn, upregulated the Hsd17b13 mRNA expression in the liver. This cascade was linked to an accumulation of hepatic triglycerides, triggering liver inflammation and promoting the progression of fibrosis. The clearance of the intestinal microbiota mitigated PLA MP-induced liver injury in mice. In HepG2 cells, PLA oligomers and polymers did not enhance the HSD17B13 mRNA expression or increase cellular lipid droplet formation. Conversely, the presence of uric acid upregulated the HSD17B13 and augmented lipid droplet production. Furthermore, simultaneous exposure to PLA particles and uric acid did not intensify lipid accumulation or lipid droplet formation within these cells.

Conclusion: Our findings demonstrate that PLA MP-induced liver damage is mediated by gut microbiota-driven elevation of uric acid. This highlights the critical role of systemic factors, particularly gut microbiota, in assessing the hepatotoxicity of PLA MPs.