Prevotella copri-produced 5-aminopentanoic acid promotes pediatric metabolic dysfunction-associated steatotic liver disease.

Abstract

Background: Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD.

Methods: C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro.

Results: In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export.

Conclusions: Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.