Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response

Yael Haberman, Rebekah Karns, Phillip J. Dexheimer, Melanie Schirmer, Judith Somekh, Ingrid Jurickova, Tzipi Braun, Elizabeth Novak, Laura Bauman, Margaret H. Collins, Angela Mo, Michael J. Rosen, Erin Bonkowski, Nathan Gotman, Alison Marquis, Mason Nistel, Paul A. Rufo, Susan S. Baker, Cary G. Sauer, James MarkowitzMarian D. Pfefferkorn, Joel R. Rosh, Brendan M. Boyle, David R. Mack, Robert N. Baldassano, Sapana Shah, Neal S. Leleiko, Melvin B. Heyman, Anne M. Grifiths, Ashish S. Patel, Joshua D. Noe, Bruce J. Aronow, Subra Kugathasan, Thomas D. Walters, Greg Gibson, Sonia Davis Thomas, Kevin Mollen, Shai Shen-Orr, Curtis Huttenhower, Ramnik J. Xavier, Jeffrey S. Hyams, Lee A. Denson

Research output: Contribution to journalArticlepeer-review

Abstract

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α 4 β 7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Original languageEnglish
Article number38
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
Support for this study was provided by NIDDK 5U01DK095745 and P30 DK078392, Gene Analysis and Integrative Morphology Cores, NIDDK DK101753 and DK114464, and NIDDK DK043351 and AT009708, CSIBD DK043351, Center for Microbiome Informatics and Therapeutics at Massachusetts Institute of Technology. This work was also supported in part by the Israel Science Foundation (Y.H., grant no 908/15), the I-CORE program (Y.H., grants no. 41/11), and the ERC starting grant (Y.H., grant no 758313). The authors thank Frank Hamilton, MD, Dana Anderson, MD, James Everhart, PhD, Jose Serrano, MD, PhD, and Stephen James, MD from NIDDK for their guidance, and William Faubion, MD for his role as safety monitor. The authors thank PROTECT site investigators Maria Oliva-Hemker, MD, Jennifer Strople, MD, David Ziring, MD, Stephen L. Guthery, MD, Boris Sudel, MD, Keith Benkov, MD, Prateek Wali, MD, Dedrick Moulton, MD, Jonathan Evans, MD, Michael D. Kappelman, MD, and Marla Dubinsky, MD, for patient recruitment and data gathering. The study investigators are deeply indebted to Shire Pharmaceuticals for providing Pentasa® for this study, to the research coordinators at the investigative sites for their tireless attention, and to the patients and families who agreed to participate in this important study.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • General
  • Physics and Astronomy (all)

Fingerprint

Dive into the research topics of 'Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response'. Together they form a unique fingerprint.

Cite this