Journal of Crohns & Colitis最新文献

Introduction: Ulcerative colitis [UC] is a chronic disease with rising incidence and unclear aetiology. Deep molecular phenotyping by multiomics analyses may provide novel insights into disease processes and characteristic features of remission states.

Methods: UC pathomechanisms were assessed by proteome profiling of human tissue specimens, obtained from five distinct colon locations for each of the 12 patients included in the study. Systemic disease-associated alterations were evaluated thanks to a cross-sectional setting of mass spectrometry-based multiomics analyses comprising proteins, metabolites, and eicosanoids of plasma obtained from UC patients during acute episodes and upon remission, in comparison with healthy controls.

Results: Tissue proteome profiling indicated colitis-associated activation of neutrophils, macrophages, B and T cells, fibroblasts, endothelial cells and platelets, and hypoxic stress, and suggested a general downregulation of mitochondrial proteins accompanying the establishment of apparent wound healing-promoting activities including scar formation. Whereas pro-inflammatory proteins were apparently upregulated by immune cells, the colitis-associated epithelial cells, fibroblasts, endothelial cells, and platelets seemed to predominantly contribute anti-inflammatory and wound healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulations of gut and gut microbiome-derived metabolites. Upon remission several, but not all, molecular candidate biomarker levels recovered back to normal.

Conclusion: The findings may indicate that microvascular damage and platelet deregulation hardly resolve upon remission, but apparently persist as disease-associated molecular signatures. This study presents local and systemic molecular alterations integrated in a model for UC pathomechanisms, potentially supporting the assessment of disease and remission states in UC patients.

Background: Inflammatory bowel disease [IBD] has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear.

Methods: We identified 41 880 individuals with IBD (Crohn's disease [CD: n = 12 850]; ulcerative colitis [UC]: n = 29 030]) from Sweden matched with 41 880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios [aHRs] for neoplastic colorectal polyps [tubular, serrated/sessile, advanced and villous] defined by histopathology codes.

Results: During follow-up, 1648 [3.9%] IBD patients and 1143 [2.7%] reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10 000 person-years, respectively. This correlated to an aHR of 1.23 (95% confidence interval [CI] 1.12-1.35) with the highest HRs seen for sessile serrated polyps [8.50, 95% CI 1.10-65.90] and traditional serrated adenomas [1.72, 95% CI 1.02-2.91]. aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and at 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD [aHRs 1.31 vs 1.06, respectively], with a 20-year cumulative risk difference of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis.

Conclusions: In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.

Background and aims: Intestinal ultrasound [IUS] is widely accepted as a reliable tool to monitor Crohn's disease [CD]. Several IUS scores have been proposed, but none has been formally accepted by international organizations. Our aim here was to compare the available scores regarding their correlation with endoscopic activity.

Methods: Consenting CD patients undergoing ileocolonoscopy at our Unit between September 2021 and February 2023 were included. Endoscopic activity was defined as SES-CD ≥ 3 or Rutgeerts score ≥ i2b for operated patients. IUS was performed within 6 weeks of endoscopy and scored with IBUS-SAS, BUSS, Simple-US and SUS-CD scores. All correlations were performed using Spearman's rank coefficient [rho = ρ]. Receiver operating characteristic [ROC] curves were compared with the Hanley and McNeil method.

Results: Of 73 CD patients, 45 [61.6%] presented endoscopic activity, of whom 22 were severe [30.1%]. All IUS scores showed a significant positive correlation with endoscopy [p < 0.0001], with IBUS-SAS ranking the highest [ρ = 0.87]. Similarly, IBUS-SAS was the most highly correlated with clinical activity [ρ = 0.58]. ROC analysis of IBUS-SAS for any endoscopic activity showed the highest area under the curve (0.95 [95% confidence interval 0.87-0.99]), with sensitivity of 82.2% and specificity of 100% for a cut-off value of 25.2. IBUS-SAS was statistically superior to all the other scores in detecting severe endoscopic activity [SES-CD ≥ 9 or Rutgeerts i4].

Conclusions: All IUS scores provided solid correlation with endoscopy and clinical symptoms. IBUS-SAS outperformed the others due to a more granular description that might help in stratifying different levels of disease activity. Therefore, the use of IBUS-SAS in centres with well-founded expertise in IUS can be suggested.

Background and aims: Patients with inflammatory bowel disease [IBD] have an attenuated response to initial COVID-19 vaccination. We sought to characterize the impact of IBD and its treatment on responses after the third vaccine against SARS-CoV-2.

Methods: This was a prospective multicentre observational study of patients with IBD [n = 202] and healthy controls [HC, n = 92]. Serological response to vaccination was assessed by quantification of anti-spike protein [SP] immunoglobulin [Ig]G levels [anti-SPIgG] and in vitro neutralization of binding to angiotensin-converting enzyme 2 [ACE2]. Peripheral blood B-cell phenotype populations were assessed by flow cytometry. SARS-CoV-2 antigen-specific B-cell responses were assessed in ex vivo culture.

Results: Median anti-SP IgG post-third vaccination in our IBD cohort was significantly lower than HCs [7862 vs 19 622 AU/mL, p < 0.001] as was ACE2 binding inhibition [p < 0.001]. IBD patients previously infected with COVID-19 [30%] had similar quantitative antibody response as HCs previously infected with COVID-19 [p = 0.12]. Lowest anti-SP IgG titres and neutralization were seen in IBD patients on anti-tumour necrosis factor [anti-TNF] agents, without prior COVID-19 infection, but all IBD patients show an attenuated vaccine response compared to HCs. Patients with IBD have reduced memory B-cell populations and attenuated B-cell responses to SARS-CoV-2 antigens if not previously infected with COVID-19 [p = 0.01]. Higher anti-TNF drug levels and zinc levels <65 ng/ml were associated with significantly lower serological responses.

Conclusions: Patients with IBD have an attenuated response to three doses of SARS-CoV-2 vaccine. Physicians should consider patients with higher anti-TNF drug levels and/or zinc deficiency as potentially at higher risk of attenuated response to vaccination.

Background and aims: Treatment adherence is key to the efficacy of exclusive enteral nutrition [100% EN] in active Crohn's disease [CD], but there are no biomarkers to objectively estimate this. We explored faecal parameters as biomarkers of compliance with 100% EN, and subsequently developed and validated the Glasgow Exclusive Enteral Nutrition Index of Compliance [GENIE].

Methods: Healthy adults replaced all [100% EN] or part [85% EN, 50% EN, 20% EN] of their diet with a formula for 7 days. Faecal pH, water content, short chain fatty acids, and branched chain fatty acids [BCFAs] were measured before [D0] and after [D7] each intervention. Optimal biomarkers and threshold values were derived using receiver operating characteristic curve analyses and machine learning to develop the GENIE. The GENIE was then validated in 30 CD children, during and after 100% EN.

Results: In all, 61 adults were recruited. D7 faecal pH and the ratios of BCFAs to either acetate or butyrate performed the best to differentiate between patients on 100% EN from <100% EN. Two models were generated; one included faecal metabolites (Laboratory GENIE, L-GENIE; sensitivity, specificity, and positive predictive value [PPV] of 88%, 94%, and 92%) and a second one [Clinical Genie, C-GENIE] which considers only faecal pH [sensitivity, specificity, and PPV of 84%, 86%, and 81%]. Validation of GENIE in CD children found that C-GENIE outperformed L-GENIE, producing a sensitivity, specificity, and PPV of 85%, 88%, and 88%, respectively.

Conclusions: GENIE can help predict adherence to 100% EN and may complement current conventional dietary assessment.

Background: Inflammatory bowel disease [IBD] is a major debilitating disease. Recently, the gut microbiota has gained attention as an important factor involved in the pathophysiology of IBD. As a complement to the established bacterial 'enterotypes' associated with IBD, we focused here on viruses. We investigated the intestinal virome of IBD patients undergoing biological therapy for the presence of virome configurations associated with IBD, and to uncover how those configurations are associated with therapeutic success.

Methods: Viral-like particle enrichment followed by deep sequencing was performed on 432 faecal samples from 181 IBD patients starting biological therapy. Redundancy analysis and Dirichlet Multinomial Mixtures were applied to determine covariates of the virome composition and to condense the gut virota into 'viral community types', respectively.

Results: Patients were stratified based on unsupervised clustering into two viral community types. Community type CA showed a low α-diversity and a high relative abundance of Caudoviricetes [non-CrAss] phages and was associated with the dysbiotic Bact2-enterotype. Community type CrM showed a high α-diversity and a high relative abundance of Crassvirales and Malgrandaviricetes phages. During post-interventional analysis, endoscopic outcome was associated with gut virome composition. Remitting UC patients had a high percentage of community type CrM, a high Shannon diversity and a low lysogenic potential. Pre-interventional analyses also identified five novel phages associated with treatment success.

Conclusions: This study proposed two gut virome configurations that may be involved in the pathophysiology of IBD. Interestingly, those viral configurations are further associated with therapeutic success, suggesting a potential clinical relevance.

Background: The traditional long-term treatment goal of Crohn's disease [CD] is maintenance of corticosteroid-free clinical remission. Additional treatment targets, such as biochemical, endoscopic and patient-reported remission, are advocated. The relapsing-remitting nature of CD provides a challenge to the timing of target assessment. Cross-sectional assessment at predetermined moments disregards the health state in between measurements. In this systematic review, we provide an overview of outcomes used to assess long-term efficacy in clinical trials in CD.

Methods: A systematic search of the PubMed and EMBASE databases was performed to identify clinical trials in luminal CD reporting on maintenance treatment [strategies] since 1995. Two independent reviewers selected eligible articles for full text retrieval, and assessed if long-term corticosteroid-free clinical, biochemical, endoscopic or patient-reported efficacy outcomes were used.

Results: The search resulted in 2452 hits and 82 articles were included. Clinical activity was used in 80 studies [98%] as the long-term efficacy outcome, and in 21 [26%] of these concomitant corticosteroid use was taken into account. C-reactive protein was used in 32 studies [41%], faecal calprotectin in 15 studies [18%], endoscopic activity in 34 studies [41%] and patient-reported outcome in 32 studies [39%]. In seven studies, clinical, biochemical, endoscopic activity and the patient's perspective were measured. In most studies cross-sectional measures or multiple measurements over time were used.

Conclusion: In none of the published clinical trials in CD was sustained remission on all treatment targets reported. Cross-sectional outcomes at predetermined times were widely applied, leading to lack of information regarding sustained corticosteroid-free remission for this relapsing-remitting chronic disease.

Background and aims: Exacerbated immune activation, intestinal dysbiosis and a disrupted intestinal barrier are common features among inflammatory bowel disease [IBD] patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment.

Methods: We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2-/- mice by endoscopy, histology and analysis of markers of molecular inflammation. The effects on the intestinal microbiome were determined by 16S rDNA sequencing of mouse faeces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells.

Results: Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 [PTPN2], its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages.

Conclusion: Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome and preserving epithelial barrier integrity in a PTPN2-dependent manner.

Despite the introduction of potent biologic therapies, many patients with Crohn's disease [CD] still require an ileocolonic resection [ICR] during the course of their disease. Furthermore, the need of redo ICR has not decreased over the past few decades, highlighting the need for better strategies to prevent and treat postoperative recurrence [POR]. The first step to develop such a strategy would be to define and standardise the description of POR with adequate diagnostic instruments. In this article, we will describe the different methodologies used to report POR [endoscopic, histological, radiological, biochemical, clinical, and surgical], and review their potential benefits and limitations, as well as the optimal timing of evaluation.