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Telomere dysfunction instigates inflammation in inflammatory bowel disease

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  2. IBD metabonomics predicts phenotype, disease course, and treatment response

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  • Deepavali Chakravarti
  • Rumi Lee
  • Asha S Multani
  • Andrea Santoni
  • Zachery Keith
  • Wen-Hao Hsu
  • Kyle Chang
  • Laura Reyes
  • Asif Rashid
  • Chang-Jiun Wu
  • Jun Li
  • Jiexin Zhang
  • Hong Seok Shim
  • Krishna Chandra
  • Pingna Deng
  • Denise J Spring
  • Ole Haagen Nielsen
  • Lene Buhl Riis
  • Kavya Kelagere Mayigegowda
  • Sarah E Blutt
  • Jianhua Zhang
  • Mamoun Younes
  • Andrew DuPont
  • Selvi Thirumurthi
  • Eduardo Vilar
  • Mary K Estes
  • Simona Colla
  • Noah F Shroyer
  • Ronald A DePinho
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Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Original languageEnglish
Article numbere2024853118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number29
ISSN0027-8424
DOIs
Publication statusPublished - 20 Jul 2021

ID: 69747453