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 Markowitz; Marian 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

doi:10.1038/s41467-018-07841-3

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

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186 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 language	English (US)
Article number	38
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07841-3
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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), Article 38. https://doi.org/10.1038/s41467-018-07841-3

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, MD, 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

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title = "Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-018-07841-3",

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T1 - Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response

AU - Haberman, Yael

AU - Karns, Rebekah

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 D.

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.

PY - 2019/12/1

Y1 - 2019/12/1

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.

AB - 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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JO - Nature communications

JF - Nature communications

IS - 1

M1 - 38

ER -

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

Abstract

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