Objective 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. Design 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. Results 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. Conclusions 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.

中文翻译：

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炎症性肠病中黏膜基因调控、mRNA剪接和粘附微生物群特征的解偶联

目的 宿主对肠道微生物群的反应不足可能导致人类炎症性肠病 (IBD) 的表现和进展。然而，目前还缺乏揭示有缺陷的串扰性质及其对肠道代谢和免疫网络的影响的分子方法。我们评估了 IBD 患者的黏膜转录水平、剪接结构和黏膜附着微生物群落，以获得对潜在的、迄今为止特征不佳的相互作用的全面了解，以及这些在 IBD 中是如何改变的。设计 对来自克罗恩病和 UC 患者、疾病对照者和健康个体（n = 63）的粘膜活检进行微生物组、转录组和剪接分析，采用新一代测序。这三个数据级别通过不同的生物信息学方法进行整合，包括系统生物学启发的网络和通路分析。结果微生物群、宿主转录水平和宿主剪接模式受组织差异的影响最大，其次是炎症的影响。这两个因素都指向与疾病相关的代谢过程的实质性改变。我们还观察到发炎组织中剪接事件的强烈富集，伴随着黏膜附着细菌分类群的改变。最后，当从健康个体通过疾病控制转移到 IBD 患者时，我们注意到三个分子实体的显着解偶联。结论我们的结果提供了强有力的证据，证明微生物组和宿主转录组之间的相互作用，通常表征肠道稳态的特征，在克罗恩病和 UC 中受到严重干扰。因此，整合多个 OMIC 级别似乎是进一步解决 IBD 复杂性的一种有前途的方法。