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

被引：288

作者：

Haberman, Yael ^{[1
,2
,3
]}

Karns, Rebekah ^{[1
,2
]}

Dexheimer, Phillip J. ^{[1
,2
]}

Schirmer, Melanie ^{[4
]}

Somekh, Judith ^{[5
,6
]}

Jurickova, Ingrid ^{[1
,2
]}

Braun, Tzipi ^{[3
]}

Novak, Elizabeth ^{[7
]}

Bauman, Laura ^{[1
,2
,8
]}

Collins, Margaret H. ^{[1
,2
]}

Mo, Angela ^{[9
]}

Rosen, Michael J. ^{[1
,2
]}

Bonkowski, Erin ^{[1
,2
]}

Gotman, Nathan ^{[10
]}

Marquis, Alison ^{[10
]}

Nistel, Mason ^{[1
,2
]}

Rufo, Paul A. ^{[11
]}

Baker, Susan S. ^{[12
]}

Sauer, Cary G. ^{[13
]}

Markowitz, James ^{[14
]}

Pfefferkorn, Marian D. ^{[15
]}

Rosh, Joel R. ^{[16
]}

Boyle, Brendan M. ^{[17
]}

Mack, David R. ^{[18
]}

Baldassano, Robert N. ^{[19
]}

Shah, Sapana ^{[20
]}

Leleiko, Neal S. ^{[21
]}

Heyman, Melvin B. ^{[22
]}

Grifiths, Anne M. ^{[23
]}

Patel, Ashish S. ^{[24
]}

Noe, Joshua D. ^{[25
]}

Aronow, Bruce J. ^{[1
,2
]}

Kugathasan, Subra ^{[13
]}

Walters, Thomas D. ^{[23
]}

Gibson, Greg ^{[9
]}

Thomas, Sonia Davis ^{[10
,26
]}

Mollen, Kevin ^{[7
]}

Shen-Orr, Shai ^{[5
]}

Huttenhower, Curtis ^{[4
,27
]}

Xavier, Ramnik J. ^{[4
,28
]}

Hyams, Jeffrey S. ^{[29
]}

Denson, Lee A. ^{[1
,2
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[2] Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA

[3] Tel Aviv Univ, Sheba Med Ctr, IL-5265601 Tel Aviv, Israel

[4] Broad Inst MIT & Harvard Univ, Cambridge, MA 02142 USA

[5] Technion, Fac Med, IL-3109601 Haifa, Israel

[6] Univ Haifa, Dept Informat Syst, IL-3498838 Haifa, Israel

[7] Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA

[8] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92162 USA

[9] Georgia Inst Technol, Atlanta, GA 30332 USA

[10] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27516 USA

[11] Harvard Childrens Hosp Boston, Boston, MA 02115 USA

[12] WCHOB, Buffalo, NY 14222 USA

[13] Emory Univ, Atlanta, GA 30322 USA

[14] Cohen Childrens Med Ctr New York, New Hyde Pk, NY 11040 USA

[15] Riley Hosp Children, Indianapolis, IN 46202 USA

[16] Goryeb Childrens Hosp Atlantic Hlth, Morristown, NJ 07960 USA

[17] Nationwide Childrens Hosp, Columbus, OH 43205 USA

[18] Childrens Hosp East Ontario, Ottawa, ON K1P 1J1, Canada

[19] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[20] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA

[21] Hasbro Childrens Hosp, Providence, RI 02903 USA

[22] Univ Calif San Francisco, San Francisco, CA 94143 USA

[23] Hosp Sick Children, Toronto, ON M5G 1X8, Canada

[24] UT Southwestern, Dallas, TX 75390 USA

[25] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[26] RTI Int, Res Triangle Pk, NC 27709 USA

[27] Harvard Sch Publ Hlth, Boston, MA 02115 USA

[28] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA

[29] Connecticut Childrens Med Ctr, Hartford, CT 06106 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

以色列科学基金会; 欧洲研究理事会;

关键词：

INFLAMMATORY BOWEL DISEASES; COLORECTAL-CANCER; PRORESOLVING MEDIATORS; RESPIRATORY-CHAIN; CROHNS-DISEASE; RESOLUTION; CHILDREN; PATHOGENESIS; MICROBIOME; EXPRESSION;

D O I：

10.1038/s41467-018-07841-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 alpha and anti-alpha(4)beta(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.

引用

页数：13

共 58 条

[1]

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases [J].

Abraham, Clara ;

Dulai, Parambir S. ;

Vermeire, Severine ;

Sandborn, William J. .

GASTROENTEROLOGY, 2017, 152 (02) :374-+

[2]

The double-edged role of 12/15-lipoxygenase during inflammation and immunity [J].

Ackermann, Jochen A. ;

Hofheinz, Katharina ;

Zaiss, Mario M. ;

Kroenke, Gerhard .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2017, 1862 (04) :371-381

[3]

Psychrophilic proteases dramatically reduce single-cell RNA-seq artifacts: a molecular atlas of kidney development [J].

Adam, Mike ;

Potter, Andrew S. ;

Potter, S. Steven .

DEVELOPMENT, 2017, 144 (19) :3625-3632

[4]

xCell: digitally portraying the tissue cellular heterogeneity landscape [J].

Aran, Dvir ;

Hu, Zicheng ;

Butte, Atul J. .

GENOME BIOLOGY, 2017, 18

[5]

Effect of vedolizumab (anti-α4β7-integrin) therapy on histological healing and mucosal gene expression in patients with UC [J].

Arijs, Ingrid ;

De Hertogh, Gert ;

Lemmens, Bart ;

Van Lommel, Leentje ;

de Bruyn, Magali ;

Vanhove, Wiebe ;

Cleynen, Isabelle ;

Machiels, Kathleen ;

Ferrante, Marc ;

Schuit, Frans ;

Van Assche, Gert ;

Rutgeerts, Paul ;

Vermeire, Severine .

GUT, 2018, 67 (01) :43-52

[6]

Mucosal Gene Expression of Antimicrobial Peptides in Inflammatory Bowel Disease Before and After First Infliximab Treatment [J].

Arijs, Ingrid ;

De Hertogh, Gert ;

Lemaire, Katleen ;

Quintens, Roel ;

Van Lommel, Leentje ;

Van Steen, Kristel ;

Leemans, Peter ;

Cleynen, Isabelle ;

Van Assche, Gert ;

Vermeire, Severine ;

Geboes, Karel ;

Schuit, Frans ;

Rutgeerts, Paul .

PLOS ONE, 2009, 4 (11)

[7]

ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks [J].

Bindea, Gabriela ;

Mlecnik, Bernhard ;

Hackl, Hubert ;

Charoentong, Pornpimol ;

Tosolini, Marie ;

Kirilovsky, Amos ;

Fridman, Wolf-Herman ;

Pages, Franck ;

Trajanoski, Zlatko ;

Galon, Jerome .

BIOINFORMATICS, 2009, 25 (08) :1091-1093

[8]

Histologic Correlates of Clinical and Endoscopic Severity in Children Newly Diagnosed With Ulcerative Colitis [J].

Boyle, Brendan ;

Collins, Margaret H. ;

Wang, Zhu ;

Mack, David ;

Griffiths, Anne ;

Sauer, Cary ;

Markowitz, James ;

LeLeiko, Neal ;

Keljo, David ;

Rosh, Joel ;

Baker, Susan S. ;

Pfefferkorn, Marian ;

Heyman, Melvin ;

Patel, Ashish ;

Baldassano, Robert ;

Noe, Joshua ;

Rufo, Paul ;

Kugathasan, Subra ;

Walters, Thomas ;

Denson, Lee ;

Hyams, Jeffrey .

AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2017, 41 (11) :1491-1498

[9]

Near-optimal probabilistic RNA-seq quantification (vol 34, pg 525, 2016) [J].

Bray, Nicolas L. ;

Pimentel, Harold ;

Melsted, Pall ;

Pachter, Lior .

NATURE BIOTECHNOLOGY, 2016, 34 (08) :888-888

[10]

Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci [J].

Cardinale, Christopher J. ;

Wei, Zhi ;

Li, Jin ;

Zhu, Junfei ;

Gu, Mengnan ;

Baldassano, Robert N. ;

Grant, Struan F. A. ;

Hakonarson, Hakon .

PLOS ONE, 2014, 9 (05)

← 1 2 3 4 5 6 →