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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-TNF? and anti-?4?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.

SUBMITTER: Haberman Y 

PROVIDER: S-EPMC6318335 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Haberman Yael Y   Karns Rebekah R   Dexheimer Phillip J PJ   Schirmer Melanie M   Somekh Judith J   Jurickova Ingrid I   Braun Tzipi T   Novak Elizabeth E   Bauman Laura L   Collins Margaret H MH   Mo Angela A   Rosen Michael J MJ   Bonkowski Erin E   Gotman Nathan N   Marquis Alison A   Nistel Mason M   Rufo Paul A PA   Baker Susan S SS   Sauer Cary G CG   Markowitz James J   Pfefferkorn Marian D MD   Rosh Joel R JR   Boyle Brendan M BM   Mack David R DR   Baldassano Robert N RN   Shah Sapana S   Leleiko Neal S NS   Heyman Melvin B MB   Grifiths Anne M AM   Patel Ashish S AS   Noe Joshua D JD   Aronow Bruce J BJ   Kugathasan Subra S   Walters Thomas D TD   Gibson Greg G   Thomas Sonia Davis SD   Mollen Kevin K   Shen-Orr Shai S   Huttenhower Curtis C   Xavier Ramnik J RJ   Hyams Jeffrey S JS   Denson Lee A LA  

Nature communications 20190103 1


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 i  ...[more]

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