185 Mucosal host-microbe interactions in IBD Introduction Inflammatory bowel diseases (IBD), which encompass Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract.1 The pathogenesis of IBD is thought to be caused by a complex interplay between inherited and environmental factors, gut microbiota and the host immune system.2,3 Alterations in gut microbiota composition and functionality are commonly observed in patients with IBD, including decreased microbial diversity, decreased abundances of butyrate-producing bacteria and increased proportions of pathobionts.4-8 Interactions between host genetics and the gut microbiome have been studied in both healthy subjects and patients with IBD. For example, we previously focused on host genome– gut microbiota interactions in the context of IBD.9 However, in order to disentangle disease mechanisms that might underlie the etiology and progression of IBD, there should be a greater focus on mucosal gene expression studies.10 Modulation of host mucosal gene expression by gut microbiota or effects of gene expression on microbial fitness may expose mechanisms that contribute to IBD pathogenesis, knowledge that could be utilized to explore novel therapeutic targets.11,12 Most studies, however, employ fecal sampling for microbiota characterization, which precludes analysis of local interactions and their immediate impact on host intestinal expression signatures. Such studies examining mucosal gene expression–microbiome associations in the context of IBD previously identified microbial groups associated with host transcripts from immune-mediated and inflammatory pathways.12-15 In a longitudinal host–microbe interaction study, the chemokine genes CXCL6 and CCL20 were negatively associated with the relative abundances of Eubacterium rectale and Streptococcus, suggesting that these bacteria are more susceptible to the actions of these chemokines.13 Another study found an inverse association between host expression of DUOX2, which produces reactive oxygen species (ROS), and the relative abundance of Ruminococcaceae, an association that may suggest ROS-mediated antibacterial effects.6 However, few studies to date have been able to carry out comprehensive integrated analysis of IBD-associated interaction factors among mucosa-attached microbiota and host intestinalgene expression. Here we analyzed 696 fresh-frozen intestinal biopsies derived from 337 patients with IBD and 16 non-IBD controls for which we generated both mucosal transcriptomic and microbial characterization using bulk RNA-sequencing and 16S rRNA gene sequencing, respectively. We further combined both datasets to comprehensively investigate mutual mucosal host-microbe interactions and integrated these with the extensive clinical characteristics collected. Following this approach, we aimed to investigate mucosal host–microbe interactions while disentangling disease-, location- and inflammation-specific associations (a graphical representation of the study workflow is presented in Figure 1). Most importantly, we could study the associations between mucosal host– microbe interactions and clinical phenotypes of patients with IBD. Finally, we also sought to replicate our main results in data froma smaller independent, publicly available cohort.13
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