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Published on: June 2, 2022

Gut microbiota-derived indole-3-propionic acid alleviates endoplasmic reticulum stress by regulating FMO2 in MASLD

Yue Luo1, Yuefeng Zhang1, Qian Zhang1

  • 1School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China.

Hepatology Communications
|June 11, 2026
PubMed
Abstract

Insights

Indole-3-propionic acid (IPA) supplementation improves metabolic dysfunction-associated steatotic liver disease (MASLD) by restoring gut microbiota and reducing liver fat. IPA targets the FMO2/PERK pathway to alleviate endoplasmic reticulum stress.

Area of Science:

  • Hepatology
  • Microbiome Research
  • Metabolic Diseases

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern with no approved treatments.
  • The role of gut microbiota metabolites, like Indole-3-propionic acid (IPA), in MASLD pathogenesis is not fully understood.
  • Investigating IPA's molecular mechanisms is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the effects of Indole-3-propionic acid (IPA) in the development of metabolic dysfunction-associated steatotic liver disease (MASLD).
  • To evaluate the therapeutic potential of IPA in a mouse model of MASLD.

Main Methods:

  • Comparative metabolomic analysis of serum and fecal samples from MASLD and normal mice.
  • In vivo studies using a MASLD mouse model and in vitro studies using cell models to assess IPA's effects.
  • Transcriptome analysis, flow cytometry, western blotting, RNA interference, and immunoprecipitation for mechanistic validation.

Main Results:

  • Serum and fecal IPA levels were significantly reduced in MASLD mice.
  • IPA supplementation ameliorated hepatic lipid accumulation, insulin resistance, liver damage, and steatosis, while restoring gut microbiota balance.
  • Mechanistically, IPA promotes FMO2 expression, which inhibits the PERK/eIF2α/ATF4/CHOP pathway, reducing endoplasmic reticulum stress, hepatocyte apoptosis, and reactive oxygen species.

Conclusions:

  • IPA enhances FMO2 expression, leading to FMO2-PERK binding in hepatocytes, inhibiting PERK phosphorylation and subsequent ER stress.
  • This mechanism reduces hepatocyte apoptosis and oxidative stress, offering a novel therapeutic approach for MASLD.
  • The IPA/FMO2/PERK axis represents a potential therapeutic target for managing ER stress in MASLD.
Keywords:
FMO2PERK/eIF2α/ATF4/CHOPgut microbiota metaboliteliver diseaseoxidative stress

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