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 and Lee A. Denson ()
Additional contact information
Yael Haberman: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Rebekah Karns: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Phillip J. Dexheimer: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Melanie Schirmer: Broad Institute of MIT and Harvard University
Judith Somekh: Technion
Ingrid Jurickova: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Tzipi Braun: Tel Hashomer, affiliated with the Tel Aviv University
Elizabeth Novak: Children’s Hospital of Pittsburgh
Laura Bauman: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Margaret H. Collins: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Angela Mo: Georgia Institute of Technology
Michael J. Rosen: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Erin Bonkowski: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Nathan Gotman: University of North Carolina
Alison Marquis: University of North Carolina
Mason Nistel: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Paul A. Rufo: Harvard—Children’s Hospital Boston
Susan S. Baker: Women & Children’s Hospital of Buffalo WCHOB
Cary G. Sauer: Emory University
James Markowitz: Cohen Children’s Medical Center of New York
Marian D. Pfefferkorn: Riley Hospital for Children
Joel R. Rosh: Goryeb Children’s Hospital—Atlantic Health
Brendan M. Boyle: Nationwide Children’s Hospital
David R. Mack: Children’s Hospital of East Ontario, Ottawa
Robert N. Baldassano: The Children’s Hospital of Philadelphia
Sapana Shah: Children’s Hospital of Pittsburgh of UPMC
Neal S. Leleiko: Hasbro Children’s Hospital
Melvin B. Heyman: University of California at San Francisco
Anne M. Grifiths: Hospital for Sick Children
Ashish S. Patel: UT Southwestern
Joshua D. Noe: Medical College of Wisconsin
Bruce J. Aronow: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine
Subra Kugathasan: Emory University
Thomas D. Walters: Hospital for Sick Children
Greg Gibson: Georgia Institute of Technology
Sonia Davis Thomas: University of North Carolina
Kevin Mollen: Children’s Hospital of Pittsburgh
Shai Shen-Orr: Technion
Curtis Huttenhower: Broad Institute of MIT and Harvard University
Ramnik J. Xavier: Broad Institute of MIT and Harvard University
Jeffrey S. Hyams: Connecticut Children’s Medical Center
Lee A. Denson: Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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-α4β7 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.

Date: 2019
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DOI: 10.1038/s41467-018-07841-3

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