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TGF-β-mediated Endothelial to Mesenchymal Transition EndMT and the Functional Assessment of EndMT Effectors using CRISPR/Cas9 Gene Editing
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Gut microbe-derived metabolite trimethylamine N-oxide activates PERK to drive fibrogenic mesenchymal differentiation

Seok-Jo Kim1,2, Swarna Bale1, Priyanka Verma1

  • 1Division of Rheumatology, Department of Internal Medicine, The University of Michigan, Suite 7C27, 300 North Ingalls Building, Ann Arbor, MI, USA.

Iscience
|July 20, 2022
PubMed

Insights

Gut bacteria metabolite trimethylamine N-oxide (TMAO) reprograms cells in systemic sclerosis (SSc). This FMO3-TMAO-PERK pathway links gut health to SSc fibrosis and vascular damage, offering a potential therapeutic target.

Area of Science:

  • Microbiology
  • Immunology
  • Gastroenterology

Background:

  • Systemic sclerosis (SSc) is characterized by microvascular injury and fibrosis.
  • Intestinal dysbiosis is common in SSc, but its role in disease pathogenesis is unclear.
  • Trimethylamine N-oxide (TMAO), produced from gut microbial trimethylamine (TMA), is linked to cardiovascular and metabolic diseases.

Purpose of the Study:

  • To investigate the role of the FMO3-TMAO-PERK axis in SSc pathogenesis.
  • To determine if TMAO contributes to microvascular injury and fibrosis in SSc.

Main Methods:

  • Utilized cell culture systems with skin fibroblasts, vascular endothelial cells, and adipocytic progenitor cells.
  • Analyzed patient biopsies from SSc and healthy individuals.
  • Investigated the expression of FMO3 and the effects of TMAO on cellular reprogramming via PERK.

Main Results:

  • TMAO reprograms skin fibroblasts, vascular endothelial cells, and adipocytic progenitor cells into myofibroblasts through the PERK pathway.
  • Flavin-containing monooxygenase (FMO3) was detected in skin fibroblasts and its expression was upregulated by TGF-β1.
  • FMO3 expression was elevated in SSc skin biopsies and SSc fibroblasts compared to controls.

Conclusions:

  • A meta-organismal pathway involving the gut microbiome, FMO3, TMAO, and PERK may link gut dysbiosis to vascular remodeling and fibrosis in SSc.
  • The FMO3-TMAO-PERK axis represents a potential therapeutic target for SSc.
Keywords:
Cell biologyMicrobial metabolismMicrobiome

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