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Iron overload exacerbates metabolic dysfunction-associated steatohepatitis via the microbiota-gut-liver axis through

Yu Han1, Yuhui Zhang1, Jianjun Chen1

  • 1Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.

Free Radical Biology & Medicine
|March 29, 2025
PubMed

Insights

Iron overload worsens metabolic dysfunction-associated steatohepatitis (MASH) by altering gut bacteria and increasing lipopolysaccharide (LPS). This promotes liver injury and inflammation via the microbiota-gut-liver axis.

Area of Science:

  • Hepatology
  • Gastroenterology
  • Metabolic Diseases

Background:

  • Iron homeostasis is linked to metabolic dysfunction-associated steatohepatitis (MASH).
  • Mechanisms connecting iron overload and MASH remain unclear.
  • Gut microbiota dysbiosis is implicated in MASH.

Purpose of the Study:

  • To investigate how iron overload influences MASH development.
  • To elucidate the role of gut microbiota in iron overload-induced MASH.
  • To identify molecular pathways linking iron overload, gut microbiota, and MASH.

Main Methods:

  • Utilized HFE knockout mice to model mild iron overload.
  • Induced MASH using a methionine- and choline-deficient (MCD) diet.
  • Performed fecal microbiota transplantation (FMT) and analyzed gut microbiota composition and metabolites (LPS, SCFAs).

Main Results:

  • Iron overload exacerbated MCD-induced MASH, worsening liver injury, lipid accumulation, inflammation, and fibrosis.
  • Iron overload altered gut microbiota composition and increased lipopolysaccharide (LPS) levels.
  • Elevated LPS upregulated aldo-keto reductase family 1 member B8 (Akr1b8) in hepatocytes, promoting lipid accumulation and inflammation.

Conclusions:

  • Iron overload promotes MASH progression via the microbiota-gut-liver axis.
  • LPS-induced Akr1b8 activation is a key mediator in iron overload-driven MASH.
  • Maintaining iron homeostasis and modulating gut microbiota are potential therapeutic strategies for MASH.
Keywords:
Akrlb8Gut microbiotaIron overloadLipopolysaccharideMetabolic dysfunction-associated steatohepatitis

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