Targeting mitochondrial damage as a therapeutic for ileal crohn’s disease

Kibrom M. Alula, Dakota N. Jackson, Andrew D. Smith, Daniel S. Kim, Kevin Turner, Elizabeth Odstrcil, Benny A. Kaipparettu, Themistocles Dassopoulos, K. Venuprasad, Linda A Feagins, Arianne L. Theiss

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD in-flammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

Original languageEnglish (US)
Article number1349
JournalCells
Volume10
Issue number6
DOIs
StatePublished - Jun 2021

Keywords

  • Antioxidant
  • Epithelial cells
  • Inflammatory bowel diseases
  • Type I Paneth cell phenotype

ASJC Scopus subject areas

  • Medicine(all)

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