Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease.
An inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the defective crosstalk and its consequences for intestinal metabolic and immunological networks are lacking. We assessed the mucosal transcript levels, splicing architecture and mucosa-attached microbial communities of patients with IBD to obtain a comprehensive view of the underlying, hitherto poorly characterised interactions, and how these are altered in IBD.



Mucosal biopsies from Crohn's disease and patients with UC, disease controls and healthy individuals (n=63) were subjected to microbiome, transcriptome and splicing analysis, employing next-generation sequencing. The three data levels were integrated by different bioinformatic approaches, including systems biology-inspired network and pathway analysis.



Microbiota, host transcript levels and host splicing patterns were influenced most strongly by tissue differences, followed by the effect of inflammation. Both factors point towards a substantial disease-related alteration of metabolic processes. We also observed a strong enrichment of splicing events in inflamed tissues, accompanied by an alteration of the mucosa-attached bacterial taxa. Finally, we noted a striking uncoupling of the three molecular entities when moving from healthy individuals via disease controls to patients with IBD.



Our results provide strong evidence that the interplay between microbiome and host transcriptome, which normally characterises a state of intestinal homeostasis, is drastically perturbed in Crohn's disease and UC. Consequently, integrating multiple OMICs levels appears to be a promising approach to further disentangle the complexity of IBD.
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Robert
R
Häsler
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Raheleh
R
Sheibani-Tezerji
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Anupam
A
Sinha
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Matthias
M
Barann
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Ateequr
A
Rehman
Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.
Daniela
D
Esser
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Konrad
K
Aden
Institute of Medical Informatics and Statistics, Christian Albrechts University of Kiel, Kiel, Germany.
Carolin
C
Knecht
Department of General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
Berenice
B
Brandt
Department of General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
Susanna
S
Nikolaus
Language and Information Engineering Lab, Friedrich-Schiller-University Jena, Jena, Germany.
Sascha
S
Schäuble
Institute for Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.
Christoph
C
Kaleta
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Andre
A
Franke
Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany.
Christoph
C
Fretter
Faculty of Life Sciences, University of Manchester, Manchester, UK.
Werner
W
Müller
Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany.
Marc-Thorsten
MT
Hütt
Institute of Medical Informatics and Statistics, Christian Albrechts University of Kiel, Kiel, Germany.
Michael
M
Krawczak
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.|Department of General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
Stefan
S
Schreiber
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Philip
P
Rosenstiel
D001706:Biopsy; D016022:Case-Control Studies; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*; D008297:Male; D012326:RNA Splicing / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000235:genetics / Q000276:immunology
D012333:RNA, Messenger
BACTERIAL INTERACTIONS; CROHN'S DISEASE; GENE EXPRESSION; INFLAMMATORY BOWEL DISEASE; INTESTINAL GENE REGULATION
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