scholarly journals Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1349
Author(s):  
Kibrom M. Alula ◽  
Dakota N. Jackson ◽  
Andrew D. Smith ◽  
Daniel S. Kim ◽  
Kevin Turner ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Lipid Metabolism ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Mitochondrial Damage ◽  
Paneth Cells ◽  
Cell Phenotype ◽  
Type I ◽  
Targeted Therapeutics ◽  
Gene Signatures

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.

P109 SMOKING NEGATIVELY AFFECTS DISEASE COURSE REGARDLESS OF SMOKING AMOUNT AND MAY BE ASSOCIATED WITH PANETH CELL PHENOTYPE IN JAPANESE CROHN’S DISEASE PATIENTS

2018 ◽  
Vol 154 (1) ◽  
pp. S56
Author(s):  
Takeo Naito ◽  
Ta-Chiang Liu ◽  
Yoichi Kakuta ◽  
Rintaro Moroi ◽  
Masatake Kuroha ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Cell Phenotype ◽  
Disease Course

Sa529 PANETH CELL MITOCHONDRIAL DAMAGE AND ILEAL CROHN'S DISEASE

2021 ◽  
Vol 160 (6) ◽  
pp. S-537
Author(s):  
Kibrom M. Alula ◽  
Dakota N. Jackson ◽  
Andrew D. Smith ◽  
Daniel S. Kim ◽  
Themistocles Dassopoulos ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Mitochondrial Damage

321 Paneth Cell Phenotype is Associated With Novel Genetic Determinants and Clinical Outcome in Japanese Crohn's Disease Patients

2016 ◽  
Vol 150 (4) ◽  
pp. S75
Author(s):  
Takeo Naito ◽  
Ta-Chiang Liu ◽  
Yoichi Kakuta ◽  
Richard Head ◽  
Zhenqiu Liu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Outcome ◽  
Paneth Cell ◽  
Cell Phenotype ◽  
Genetic Determinants

Tu1165 Evolution of Paneth Cell Phenotype in Crohn's Disease: Implications for Disease Etiopathogenesis

2014 ◽  
Vol 146 (5) ◽  
pp. S-772
Author(s):  
Ta-Chiang Liu ◽  
Nita H. Salzman ◽  
Christina A. Arnold ◽  
Thaddeus S. Stappenbeck
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Cell Phenotype

scholarly journals Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice

2020 ◽  
Vol 3 (6) ◽  
pp. e201900592
Author(s):  
Yu Shimizu ◽  
Kiminori Nakamura ◽  
Aki Yoshii ◽  
Yuki Yokoi ◽  
Mani Kikuchi ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Er Stress ◽  
Disease Progression ◽  
Intestinal Microbiota ◽  
Disulfide Bonds ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Lumen ◽  
Reduced Form

Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

AN AUTOPHAGY PROTEIN ATG16L1 PREVENTS NECROPTOSIS BY REGULATING INTERFERON SIGNALING IN THE INTESTINAL EPITHELIUM

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S24-S25
Author(s):  
Yu Matsuzawa ◽  
Ken Cadwell
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Epithelium ◽  
Paneth Cell ◽  
Type I ◽  
Murine Norovirus ◽  
Interferon Signaling ◽  
Protein Kinase R ◽  
Risk Alleles ◽  
Intestinal Organoids

Abstract Introduction ATG16L1, an essential component of autophagy, is one of the susceptibility genes of Crohn’s disease. We previously showed mice with decreased expression of Atg16L1 and Crohn’s disease patients homozygous for ATG16L1T300A risk alleles develop Paneth cell abnormalities in the intestinal epithelium. Moreover, the abnormalities were dependent on murine norovirus (MNV) infection in mice. Most recently, we reported mice with deletion of ATG16L1 in the intestinal epithelial cells (Atg16L1ΔIEC) are more susceptible to disease following intestinal injury than wild type mice when they are infected with MNV. Also, we revealed intestinal organoids derived from Atg16L1ΔIEC mouse are susceptible to TNFa-induced necroptosis. However, how ATG16L1 protects IECs against TNFa, and whether the susceptibility is preserved in human IECs harboring ATG16L1T300A risk alleles remains unclear. Aims In this study, we first examined the mechanism by which ATG16L1-deficiency renders IECs susceptible to necroptosis. Next, we investigated whether a specific ISG might be involved in the increased susceptibility. Finally, we tested whether human intestinal organoids harboring ATG16L1T300A risk alleles are susceptible to TNFa-induced necroptosis. Methods & Results We performed RNA-Seq analysis using small intestinal organoids derived from Atg16L1ΔIEC and control mouse, and found 49 genes were upregulated in naïve Atg16L1ΔIEC organoids (Figure 1). Interestingly, most of them were the genes known as interferon-stimulated genes (ISGs) representing a type I IFN (IFN-I) signature. Importantly, we found Atg16L1ΔIEC organoids pretreated with JAK-STAT inhibitor Ruxolitinib displayed better viability and decreased level of necroptosis-related proteins when they were stimulated with TNFa. Moreover, we found protein kinase R (PKR) was increased in naïve Atg16L1ΔIEC organoids, and inhibition of PKR significantly protected Atg16L1ΔIEC organoids from TNFa. Finally, we generated human intestinal organoids using biopsy specimens mostly collected from Crohn’s disease patients. We compared the viability between individuals with 2 copies vs 0 or 1 copy of ATG16L1T300A risk allele, and found organoids derived from ATG16L1T300A homozygous individuals exhibited heightened susceptibility to TNFa (Figure 2 A and B). Moreover, we tested the effect of Ruxolitinib as well as multiple necroptosis inhibitors on human organoids, and found all the inhibitors successfully protected ATG16L1T300A homozygous organoids from TNFa-induced cell death. Conclusion Our data indicate ATG16L1 prevents necroptosis by regulating interferon signaling in both mouse and human IECs, and suggest inhibition of JAK-STAT as well as necroptosis pathway could be promising therapeutic options for Crohn’s disease patients with ATG16L1T300A risk alleles.

scholarly journals Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis

Gut ◽  
2020 ◽  
Vol 69 (11) ◽  
pp. 1928-1938 ◽  
Author(s):  
Dakota N Jackson ◽  
Marina Panopoulos ◽  
William L Neumann ◽  
Kevin Turner ◽  
Brandi L Cantarel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Epithelial Cell ◽  
Crohn's Disease ◽  
Mitochondrial Dysfunction ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Inner Mitochondrial Membrane ◽  
Bowel Diseases ◽  
The Impact ◽  
Prohibitin 1

ObjectiveAlthough perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD.DesignMale and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1iΔIEC) or Paneth cell-specific deletion of Phb1 (Phb1ΔPC) and Phb1fl/fl control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1iΔIEC or Phb1ΔPC mice.ResultsPhb1iΔIEC mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1iΔIEC ileum. Deletion of Phb1 specifically in Paneth cells (Phb1ΔPC) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1iΔIEC or Phb1ΔPC mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo.ConclusionOur results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

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