An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

We compared RNA expression of ACE2 and TMPRSS2 in blood (paired-end sequencing), ileal, and colonic mucosal biopsies (microarray) from 138 patients with treatment-naïve IBD (cases) and 154 controls, predominantly with functional gastrointestinal disorders (Supplementary Table 1). They were recruited at 6 European centers, between 2012 and 2015, as part of the IBD-Character program (EU Character reference no. 305676). Demographics and further details are given in the supplementary information.

Although vitamin K deficiency has been implicated in adult inflammatory bowel disease (IBD), its prevalence in pediatric IBD remains unknown. We carried out a cross-sectional study in 63 children with Crohn's disease (CD) and 48 with ulcerative colitis (UC) to assess the prevalence of vitamin K deficiency and to search for potential correlation between vitamin K status and pediatric IBD activity. Vitamin K status was assessed using protein induced by vitamin K absence-II (PIVKA-II; ELISA). Prevalence of vitamin K deficiency was 54.0% in CD and 43.7% in UC. Vitamin K deficiency was more common in patients with higher CD activity, in CD patients with higher mass Z-scores, and less common among children with CD treated with infliximab. Relation of vitamin K deficiency to pediatric IBD clinical course and treatment demand further research.

To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD]. We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log₂-fold change [LFC] = 4.63, p = 4.05 × 10^-118), MCEMP1 [LFC = 2.45, p = 7.37 × 10^-109], and S100A12 [LFC = 2.31, p = 2.15 × 10^-93]. Significantly over-represented pathways included IL-1 [p = 1.58 × 10^-11], IL-4, and IL-13 [p = 8.96 × 10^-9]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3–102.0). Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.

Despite technological progress, we lack a consensus on the method of conducting automated bowel sound (BS) analysis and, consequently, BS tools have not become available to doctors. We aimed to briefly review the literature on BS recording and analysis, with an emphasis on the broad range of analytical approaches. Scientific journals and conference materials were researched with a specific set of terms (Scopus, MEDLINE, IEEE) to find reports on BS. The research articles identified were analyzed in the context of main research directions at a number of centers globally. Automated BS analysis methods were already well developed by the early 2000s. Accuracy of 90% and higher had been achieved with various analytical approaches, including wavelet transformations, multi-layer perceptrons, independent component analysis and autoregressive-moving-average models. Clinical research on BS has exposed their important potential in the non-invasive diagnosis of irritable bowel syndrome, in surgery, and for the investigation of gastrointestinal motility. The most recent advances are linked to the application of artificial intelligence and the development of dedicated BS devices. BS research is technologically mature, but lacks uniform methodology, an international forum for discussion and an open platform for data exchange. A common ground is needed as a starting point. The next key development will be the release of freely available benchmark datasets with labels confirmed by human experts.