Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn's Disease.

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

doi:10.3390/cells10061349

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 inflammation, 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.

Highlights

Non-inflammatory bowel disease (IBD) control subjects were significantly older than Crohn’s disease (CD) patients (p = 0.0002, Mann–Whitney–Wilcoxon test)
After Paneth cell phenotype analysis, 20 CD patients and 24 non-IBD patients were excluded as the biopsy samples had an inadequate number of crypts (
Independent of inflammaCD Paneth cells, but not goblet cells or enterocytes, exhibited mitochondrial ultrastructural abnormalities with highest proportion in patients stratifying as the Type I phenotype

Summary

Introduction

Several CD susceptibility genes integrate into cellular processes that converge on the homeostasis of Paneth cells, which are long-lived cells residing at the base of the small intestinal crypts interspersed between Lgr5-expressing intestinal stem cells (ISCs). Paneth cells produce and secret important niche factors for neighboring ISCs, thereby promoting crypt homeostasis [2]. Paneth cell abnormalities in CD patients are independent of inflammation, associated with early disease recurrence after resection, gut microbial dysbiosis, and decreased mucosal expression of genes that regulate oxidative phosphorylation, the latter suggesting that these patients may have mitochondrial alterations [3,4,5,6,7,8]. A recent study from our group implicated mitochondrial dysfunction in Paneth cells as a mediator of spontaneous CD-like ileitis in mice [9]

Methods

Results

Conclusion