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 journalArticle

18 Scopus citations

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 (US)
Article number38
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

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

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    Haberman, Y., Karns, R., Dexheimer, P. J., Schirmer, M., Somekh, J., Jurickova, I., Braun, T., Novak, E., Bauman, L., Collins, M. H., Mo, A., Rosen, M. J., Bonkowski, E., Gotman, N., Marquis, A., Nistel, M., Rufo, P. A., Baker, S. S., Sauer, C. G., ... Denson, L. A. (2019). Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nature communications, 10(1), [38]. https://doi.org/10.1038/s41467-018-07841-3