Journal of Crohn's & colitis最新文献

Background and aims: The gut microbiome is closely associated with pediatric Crohn's disease (CD), while the multidimensional microbial signature and their capabilities for distinguishing pediatric CD are underexplored. This study aims to characterize the microbial alterations in pediatric CD and develop a robust classification model.

Methods: A total of 1,175 fecal metagenomic sequencing samples, predominantly from three cohorts of pediatric CD patients, were re-analyzed from raw sequencing data using uniform process pipelines to obtain multidimensional microbial alterations in pediatric CD, including taxonomic profiles, functional profiles, and multi-type genetic variants. Random forest algorithms were used to construct classification models after comparing multiple machine learning algorithms.

Results: We found pediatric CD samples exhibited reduced microbial diversity and unique microbial characteristics. Pronounced abundance differences in 45 species and 1,357 KO genes. Particularly, Enterocloster bolteae emerged as a pivotal pediatric CD-associated species. Additionally, we identified a vast amount of microbial genetic variants linked to pediatric CD, including 192 structural variants, 1,256 insertions/deletions (InDels), and 3,567 single nucleotide variants, with a considerable portion of these variants occurred in non-genic regions. The InDel-based model outperformed other predictive models against multidimensional microbial signatures, achieving an AUC of 0.982. The robustness and disease specificity were further confirmed in an independent CD cohort (AUC=0.996) and five other microbiome-associated pediatric cohorts.

Conclusions: Our study provided a comprehensive landscape of microbial alterations in pediatric CD and introduced a highly effective diagnostic model rooted in microbial InDels, which contributes to the development of the non-invasive diagnostic tools and targeted therapies.

Background & aims: Epithelial muscarinic acetylcholine receptor subtype 3 (M3R) signaling modulates intestinal stem and progenitor cell function, yet its impact on colonic homeostasis remains unclear. Hence, this study explores sex-specific effects of epithelial genetic M3R ablation and muscarinic receptor agonism on murine colonic Lgr5-EGFP+ progenitor cells and epithelial homeostasis.

Methods: Genetic ablation of M3R was achieved using Vil-Cre x M3R fl/fl mice. The effects on Lgr5-expressing progenitor cells, epithelial homeostasis and response to intestinal injury were assessed, with attention to sex-specific differences. Effects of cholinergic, muscarinic agonism on epithelial cell homeostasis were evaluated employing murine and human colonoids.

Results: Genetic epithelial ablation of the M3R employing Vil-Cre x M3R fl/fl mice interestingly resulted in the prominent reduction in Lgr5-expressing progenitor cells in male tissues, contrasting an expansion of Lgr5-expressing cells in female colonic epithelia. This difference showed abrogated in young female Vil-Cre x M3R fl/fl mice, which harbor reduced circulating sex hormone levels. Genetic M3R ablation further induced changes to epithelial differentiation. Importantly, male Vil-Cre x M3R fl/fl mice developed severe inflammation following induction of acute experimental colitis, which did almost not affect female Vil-Cre x M3R fl/fl mice. Moreover, sex-specific effects of modulations of cholinergic, muscarinic signaling on epithelial cells could be corroborated in murine and human colonoids.

Conclusions: Our data reveal sex differences in the modulation of intestinal, colonic epithelial cells by cholinergic, muscarinic signaling and highlight the potential for therapeutic strategies targeting cholinergic receptor signaling in colonic inflammatory diseases.

Background and aim: Intestinal ultrasound (IUS) potentially spares patients from repeated endoscopies under sedation and eliminates the need for alternative imaging modalities like magnetic resonance enterography and computed tomography enterography scans. However, interpreting IUS images is challenging for physicians due to the time-intensive process of identifying markers indicative of inflammatory bowel disease (IBD). This study aims to fully automate the analysis of pediatric IBD to distinguishing between abnormal and normal cases.

Methods: We used dataset of 260 pediatric patients, consisting of 4,565 IUS images with 1,478 abnormal and 3,087 normal cases. Meticulous annotation of the region between the lumen/mucosa and the muscularis/serosa interfaces in a subset of 612 images were performed. An artificial intelligent (AI) algorithm was trained to delineate the region between these interfaces. The boundaries of these regions were extracted, and the average bowel wall thickness (BWT) was calculated and analysed using cut-off values ranging between 1.5 mm and 3 mm.

Results: This study showed promising segmentation performance in accurately identifying the lumen/mucosa and muscularis/serosa interfaces. In a separate test set of 3,953 images, the classification performance at the 2 mm BWT cut-off showed the highest sensitivity of 90.29% and a specificity of 93.70%. The AI method showed strong agreement, with an inter-class correlation of 0.942 (95% CI: 0.938-0.946), compared to manual clinical measurements.

Conclusion: This study demonstrates an AI approach to automate the analysis of pediatric IBD IUS images, providing a reliable tool for early detection, precise characterization, and monitoring of the disease.

Methods: We included 121,148 UK Biobank participants without IBD at baseline, and collected dietary information from a validated web-based 24-hour dietary recall questionnaire. Overall dietary glycemic index and glycemic load was estimated. Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Substitution analyses were conducted to test associations after replacing medium or high glycemic index foods with low glycemic index foods.

Results: During a median follow-up of 10.6 years, 133 incident CD and 335 incident UC cases were identified. Dietary glycemic index was associated with UC but not CD. The HR of UC was 1.13 (95% CI 1.01-1.27) per 1 standard deviation increment and 1.46 (95%CI 1.07-1.99) for the highest versus lowest quartile of glycemic index. Replacing medium or medium and high glycemic index foods with low glycemic index foods was associated with a lower risk of UC. No significant associations were found between dietary glycemic load with risk of CD and UC.

Conclusion: A higher dietary glycemic index, but not glycemic load, is associated with an increased risk of UC, underscoring the importance of considering glycemic index in dietary recommendations for UC prevention.

Background and aims: There is a paucity of literature that comprehensively investigates risk factors for inflammatory bowel disease (IBD) readmissions on a national scale. In this study, we look to identify independent risk factors for readmission, including psychosocial factors, in patients admitted with a primary diagnosis of Ulcerative colitis (UC) or Crohn's disease (CD).

Methods: We performed a retrospective cohort study using data from the Nationwide Readmissions Database (NRD). We identified cohorts of adult patients (n=28,473) who required inpatient admission for UC or CD in the US in the year 2020. Multivariate logistic regression models controlling for confounding variables were used to identify independent predictors of 90-day readmission.

Results: Patients were identified who required hospitalization for UC (n=11,476) and CD (n=16,997). In patients with UC, younger age, male sex, and transfusion requirement during index hospitalization were all independently predictive of increased 90-day readmission (all p < .05). Psychosocial factors predictive of readmission include alcohol use disorder, drug abuse, and poverty (all p < .05). In patients with CD, younger age and chronic pain were both predictive of increased readmissions (all p < .05). Psychosocial factors predictive of readmission include lower income quartile, uninsured status, depression, drug abuse, nicotine dependence, and opioid use disorder (all p < .05).

Conclusions: This study identifies several risk factors for readmission in patients with IBD, many of which are potentially modifiable psychosocial factors. Closer follow-up, possibly via virtual modalities, as well as alternative treatment strategies, should be considered in patients with IBD at higher risk of readmission.

Background and aims: This study assesses the prognostic role of intestinal ultrasound (IUS) in determining the disease course of ulcerative colitis (UC) in the first year after diagnosis.

Methods: A prospective, multicenter population-based inception-cohort study was conducted on patients newly diagnosed with UC. Patients with left-sided or extensive UC underwent IUS assessments at diagnosis, three months, and 12 months, alongside symptomatic, biochemical, and endoscopic evaluations. Transmural remission was defined as bowel wall thickness ≤ 3 mm without color Doppler signal in all segments.

Results: From May 2021 to April 2023, 193 patients with left-sided or extensive UC were included. Inflammatory findings on IUS at diagnosis were associated with symptomatic, biochemical, and endoscopic markers of inflammation, but not with diagnostic delay. IUS-detected inflammation at diagnosis was an independent predictor for colectomy within the first three months, with bowel wall thickness > 6 mm as the optimal cut-off (OR 38, 95% CI 8-270, p<0.0001). Three months after diagnosis, 59% of patients achieved transmural remission, which was associated with higher rates of steroid-free clinical remission in all subsequent follow-ups, as well as a reduced need for steroids during follow-up (6% vs. 19%, p=0.036). Furthermore, transmural remission at three months increased the likelihood of steroid-free clinical remission, as well as transmural and complete remission, at 12 months.

Conclusions: Findings by intestinal ultrasound at the time of diagnosis predict early colectomy risk in UC. Our results underscore that transmural remission is a feasible treatment target in early UC, and significantly impacts the disease course.

Background and aims: Genome-wide association studies have shown that the most risk-conferring genetic polymorphism for ulcerative colitis outside the human leukocyte antigen locus is the amino acid substitution p.Asp439Glu in the adenylyl cyclase 7 gene (ADCY7). ADCY7 is the main isoform in the hematopoietic system and produces the second messenger cyclic AMP (cAMP) downstream of G protein-coupled receptor signaling. Our aim was to determine the contribution of this polymorphism to UC risk by analyzing its effect on ADCY7 function in cell-based assays.

Methods: We characterized the p.Asp439Glu variant in cell lines using western blots, immunofluorescence, cAMP assay, and luciferase assay. We modeled this variant using siRNA knock-down in human primary CD4+ T cells and characterized them by RNA-seq, viability assay, flow cytometry, cAMP assay, and ELISA.

Results: The p.Asp439Glu variant is deficient in protein expression but retains membrane localization. This results in a 40% reduction in cAMP synthesis and luciferase reporter expression. Knock-down of ADCY7 in T cells reduces the expression of ribosomal proteins and cAMP signaling proteins, while skewing cytokine production towards a T helper 2 pattern and upregulating antigen presentation accompanied by increased surface expression of MHC Class II and CD86.

Conclusions: The ulcerative colitis risk-conferring variant, p.Asp439Glu, in ADCY7 reduces cyclic AMP signaling, leading to modifications in cytokine profile and antigen presentation. Medications that enhance cyclic AMP by direct activation of ADCY7 or by phosphodiesterase inhibition may be beneficial in this disease.

Background and aims: Inflammatory bowel disease (IBD) is associated with a higher risk of developing colorectal cancer, according to the inflammation-dysplasia-cancer (IDC) sequence from inflammation to colitis-associated colorectal cancer (CAC). The objective of this study was to identify and generate a transcriptomic signature and score, related to the IDC sequence, that could ultimately classify dysplasia and cancer in IBD.

Methods: Demographics, clinical parameters, histological characteristics and RNA-sequencing data were evaluated on 134 formalin-fixed paraffin-embedded lesions from 2 independent cohorts of IBD patients with low- or high-grade dysplasia (LGD, HGD) and/or CAC. An ordinal logistic regression screened for significant IDC sequence-associated genes that were computed in a transcriptomic signature score.

Results: Principal component analysis and unsupervised clustering on 1% of the most variable genes showed a good clustering between the 4 lesion groups (Normal Mucosa, Inflamed Mucosa, LGD/HGD, and CAC). A gene signature was identified on 27 genes that correlated with the lesion groups in the exploratory cohort. The most weighted gene in this transcriptomic signature was the long non-coding regulatory RNA KCNQ1OT1, a gate keeper against genomic instability and transposon activation. Based on these 27- genes expression, we built and validated a transcriptomic signature score to classify dysplasia and CAC. The overall accuracy of the transcriptomic signature score was 85.71% in the exploratory cohort and 90.91% in the validation cohort.

Conclusion: We identified a tissue-based transcriptomic score to classify IDC lesions in IBD patients and uncovered some of the pivotal genes in the carcinogenesis related to inflammation in IBD.