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 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

6 Citations (Scopus)

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

Fingerprint

Ulcerative Colitis
Transcriptome
genes
Genes
therapy
Pediatrics
corticosteroids
signatures
Therapeutics
homeostasis
pathogenesis
Mitochondrial Genes
gene expression
Microbiota
microorganisms
Set theory
Gene expression
Integrins
Adenoma
pretreatment

ASJC Scopus subject areas

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

Cite this

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

In: Nature communications, Vol. 10, No. 1, 38, 01.12.2019.

Research output: Contribution to journalArticle

Haberman, Y, Karns, R, Dexheimer, PJ, Schirmer, M, Somekh, J, Jurickova, I, Braun, T, Novak, E, Bauman, L, Collins, MH, Mo, A, Rosen, MJ, Bonkowski, E, Gotman, N, Marquis, A, Nistel, M, Rufo, PA, Baker, SS, Sauer, CG, Markowitz, J, Pfefferkorn, M, Rosh, JR, Boyle, BM, Mack, DR, Baldassano, RN, Shah, S, Leleiko, NS, Heyman, MB, Grifiths, AM, Patel, AS, Noe, JD, Aronow, BJ, Kugathasan, S, Walters, TD, Gibson, G, Thomas, SD, Mollen, K, Shen-Orr, S, Huttenhower, C, Xavier, RJ, Hyams, JS & Denson, LA 2019, 'Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response', Nature communications, vol. 10, no. 1, 38. https://doi.org/10.1038/s41467-018-07841-3
Haberman, Yael ; Karns, Rebekah ; Dexheimer, Phillip J. ; Schirmer, Melanie ; Somekh, Judith ; Jurickova, Ingrid ; Braun, Tzipi ; Novak, Elizabeth ; Bauman, Laura ; Collins, Margaret H. ; Mo, Angela ; Rosen, Michael J. ; Bonkowski, Erin ; Gotman, Nathan ; Marquis, Alison ; Nistel, Mason ; Rufo, Paul A. ; Baker, Susan S. ; Sauer, Cary G. ; Markowitz, James ; Pfefferkorn, Marian ; Rosh, Joel R. ; Boyle, Brendan M. ; Mack, David R. ; Baldassano, Robert N. ; Shah, Sapana ; Leleiko, Neal S. ; Heyman, Melvin B. ; Grifiths, Anne M. ; Patel, Ashish S. ; Noe, Joshua D. ; Aronow, Bruce J. ; Kugathasan, Subra ; Walters, Thomas D. ; Gibson, Greg ; Thomas, Sonia Davis ; Mollen, Kevin ; Shen-Orr, Shai ; Huttenhower, Curtis ; Xavier, Ramnik J. ; Hyams, Jeffrey S. ; Denson, Lee A. / Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. In: Nature communications. 2019 ; Vol. 10, No. 1.
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AU - Dexheimer, Phillip J.

AU - Schirmer, Melanie

AU - Somekh, Judith

AU - Jurickova, Ingrid

AU - Braun, Tzipi

AU - Novak, Elizabeth

AU - Bauman, Laura

AU - Collins, Margaret H.

AU - Mo, Angela

AU - Rosen, Michael J.

AU - Bonkowski, Erin

AU - Gotman, Nathan

AU - Marquis, Alison

AU - Nistel, Mason

AU - Rufo, Paul A.

AU - Baker, Susan S.

AU - Sauer, Cary G.

AU - Markowitz, James

AU - Pfefferkorn, Marian

AU - Rosh, Joel R.

AU - Boyle, Brendan M.

AU - Mack, David R.

AU - Baldassano, Robert N.

AU - Shah, Sapana

AU - Leleiko, Neal S.

AU - Heyman, Melvin B.

AU - Grifiths, Anne M.

AU - Patel, Ashish S.

AU - Noe, Joshua D.

AU - Aronow, Bruce J.

AU - Kugathasan, Subra

AU - Walters, Thomas D.

AU - Gibson, Greg

AU - Thomas, Sonia Davis

AU - Mollen, Kevin

AU - Shen-Orr, Shai

AU - Huttenhower, Curtis

AU - Xavier, Ramnik J.

AU - Hyams, Jeffrey S.

AU - Denson, Lee A.

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N2 - 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.

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