Format

Send to

Choose Destination
Nat Commun. 2019 Jan 3;10(1):38. doi: 10.1038/s41467-018-07841-3.

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

Author information

1
Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA.
2
Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel.
3
Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA.
4
Faculty of Medicine, Technion, Haifa, 3109601, Israel.
5
Department of Information Systems, University of Haifa, Haifa, 3498838, Israel.
6
Children's Hospital of Pittsburgh, Pittsburgh, 15224, PA, USA.
7
Department of Pediatrics, University of California at San Diego, La Jolla, 92162, CA, USA.
8
Georgia Institute of Technology, Atlanta, 30332, GA, USA.
9
Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA.
10
Harvard-Children's Hospital Boston, Boston, 02115, MA, USA.
11
Women & Children's Hospital of Buffalo WCHOB, Buffalo, 14222, NY, USA.
12
Emory University, Atlanta, 30322, GA, USA.
13
Cohen Children's Medical Center of New York, 11040, New Hyde Park, NY, USA.
14
Riley Hospital for Children, Indianapolis, 46202, IN, USA.
15
Goryeb Children's Hospital-Atlantic Health, Morristown, 07960, NJ, USA.
16
Nationwide Children's Hospital, Columbus, 43205, OH, USA.
17
Children's Hospital of East Ontario, Ottawa, Ontario, K1P 1J1, Canada.
18
The Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA.
19
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, 15224, PA, USA.
20
Hasbro Children's Hospital, Providence, 02903, RI, USA.
21
University of California at San Francisco, San Francisco, 94143, CA, USA.
22
Hospital for Sick Children, Toronto, M5G 1X8, Canada.
23
UT Southwestern, Dallas, 75390, TX, USA.
24
Medical College of Wisconsin, Milwaukee, 53226, WI, USA.
25
RTI International, Research Triangle Park, 27709, NC, USA.
26
Harvard School of Public Health, Boston, 02115, MA, USA.
27
Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA.
28
Connecticut Children's Medical Center, Hartford, 06106, CT, USA.
29
Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA. lee.denson@cchmc.org.

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.

PMID:
30604764
PMCID:
PMC6318335
DOI:
10.1038/s41467-018-07841-3
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Supplementary concept, Grant support

Publication types

MeSH terms

Substances

Supplementary concept

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center