Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease

• Published in: Gut Vol. 66; no. 12; pp. 2087 - 2097
• Main Authors: Häsler, Robert, Sheibani-Tezerji, Raheleh, Sinha, Anupam, Barann, Matthias, Rehman, Ateequr, Esser, Daniela, Aden, Konrad, Knecht, Carolin, Brandt, Berenice, Nikolaus, Susanna, Schäuble, Sascha, Kaleta, Christoph, Franke, Andre, Fretter, Christoph, Müller, Werner, Hütt, Marc-Thorsten, Krawczak, Michael, Schreiber, Stefan, Rosenstiel, Philip
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.12.2017; BMJ Publishing Group
• Series: Original article
• Subjects: Biopsy; Case-Control Studies; Colon; Crohn's disease; Female; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - immunology; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Gene regulation; Genomes; Homeostasis; Humans; Inflammation; Inflammatory Bowel Disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - microbiology; Intestinal microflora; Intestine; Male; Metabolism; Microbiota; Mucosa; Next-generation sequencing; Patients; RNA Splicing - genetics; RNA Splicing - immunology; RNA, Messenger - genetics; RNA, Messenger - immunology; Signal transduction; Splicing; Studies; Transcription; Transcriptome - genetics; Transcriptome - immunology; GENE EXPRESSION; BACTERIAL INTERACTIONS; CROHN'S DISEASE; INTESTINAL GENE REGULATION; INFLAMMATORY BOWEL DISEASE
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2016-311651

ObjectiveAn 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.DesignMucosal 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.ResultsMicrobiota, 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.ConclusionsOur 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.