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Epigenetic and Metabolic Reprogramming of Fibroblasts in Crohn's Disease Strictures Reveals Histone Deacetylases as

Amy Lewis1, David T Humphreys2,3, Belen Pan-Castillo1

  • 1Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London E1 2AT, UK.

Journal of Crohn'S & Colitis
|December 9, 2023
PubMed
Abstract

Insights

Histone deacetylase (HDAC) inhibitors like valproic acid may reverse epigenetic changes in Crohn's disease (CD) fibrosis. This study found distinct HDAC profiles and metabolic priming in stricturing CD fibroblasts, suggesting a new therapeutic avenue.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Epigenetics

Background:

  • Crohn's disease (CD) intestinal fibrosis lacks effective treatments.
  • Fibroblast dysfunction is central to CD fibrosis pathogenesis.

Purpose of the Study:

  • Characterize fibroblast subtypes, epigenetic modifications, metabolic alterations, and signaling pathways in CD fibrosis.
  • Identify potential therapeutic targets for CD-related intestinal fibrosis.

Main Methods:

  • Immunohistochemistry, epigenetic analysis (Transposase-Accessible Chromatin using sequencing), and metabolic assays were performed on intestinal fibroblasts.
  • Fibroblasts were isolated from stricturing CD (SCD) and non-stricturing CD (NSCD) patients and treated with TGFβ and valproic acid (VPA).

Main Results:

  • SCD fibroblasts exhibited distinct histone deacetylase (HDAC) expression profiles (HDAC1, HDAC2, HDAC7) and reduced H3K27ac levels compared to NSCD.
  • SCD fibroblasts showed increased glycolytic activity (lactate production) and collagen production (hydroxyproline), indicating metabolic priming.
  • VPA, an HDAC inhibitor, reversed TGFβ-induced metabolic effects and altered chromatin accessibility at Collagen-I gene promoters (COL1A1, COL1A2).

Conclusions:

  • Stricturing CD-derived fibroblasts are characterized by altered HDAC expression, hypoacetylation, a glycolytic phenotype, and metabolic priming.
  • Epigenetic regulation, particularly involving HDACs, plays a novel role in TGFβ-mediated Collagen-I production and CD fibrosis.
  • HDAC inhibitors represent a potential therapeutic strategy to 'reset' epigenetic changes driving CD fibrosis.
Keywords:
Collagen-ICrohn’s diseasefibrosishistone deacetylasevalproic acid

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