Faculty Collaboration Database

Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 2019 Jan 03;10(1):38

Date

01/04/2019

Pubmed ID

30604764

Pubmed Central ID

PMC6318335

DOI

10.1038/s41467-018-07841-3

Scopus ID

2-s2.0-85059496889 (requires institutional sign-in at Scopus site)   191 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-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.

Author List

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

Author

Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Anti-Inflammatory Agents, Non-Steroidal
Child
Colitis, Ulcerative
Feces
Female
Gene Expression Profiling
Genes, Mitochondrial
Glucocorticoids
Humans
Integrins
Intestinal Mucosa
Male
Mesalamine
Microbiota
Mitochondria
Mitochondrial Diseases
Precision Medicine
Prospective Studies
Rectum
Remission Induction
Sequence Analysis, RNA
Severity of Illness Index
Transcriptome
Treatment Outcome
Tumor Necrosis Factor-alpha