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Prevotella copri-produced 5-aminopentanoic acid promotes pediatric metabolic dysfunction-associated steatotic liver
Qing-Yang Xu1, Tian-Yi Ren1, Yong-Chang Zhou2
1Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Insights
Prevotella copri expansion drives pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) by producing 5-aminopentanoic acid (5-AVA). This metabolite worsens liver steatosis, indicating P. copri and 5-AVA as potential therapeutic targets for pediatric MASLD.
Area of Science:
- Microbiology
- Hepatology
- Pediatric Gastroenterology
Background:
- Emerging evidence links Prevotella copri (P. copri) expansion to increased severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in children.
- The precise role and molecular mechanisms of P. copri in pediatric MASLD remain to be elucidated.
Purpose of the Study:
- To investigate the causative role of P. copri in pediatric MASLD.
- To identify the molecular mechanisms by which P. copri contributes to liver steatosis.
Main Methods:
- C57BL/6 J mice were fed a high-fat diet (HFD) and administered P. copri orally for 5 weeks.
- MASLD features and gut microbiota were assessed. Untargeted metabolomics identified P. copri-derived metabolites, which were tested in vitro.
Main Results:
- P. copri administration exacerbated liver steatosis and upregulated inflammation and fibrosis genes in HFD-fed mice.
- P. copri altered gut microbiota composition and significantly enriched 5-aminopentanoic acid (5-AVA).
- In vitro, 5-AVA aggravated lipid accumulation in liver cells by promoting lipogenesis and fatty acid uptake, while impairing VLDL export.
Conclusions:
- P. copri promotes liver steatosis in juvenile mice via its metabolite 5-AVA.
- These findings highlight P. copri and 5-AVA as potential therapeutic targets for pediatric MASLD management.
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.
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