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Bacterial Oncotraits Rather than Spatial Organization Are Associated with Dysplasia in Ulcerative Colitis. 细菌性癌性特征而非空间组织与溃疡性结肠炎的发育不良有关。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad092
Carlijn E Bruggeling, Maarten Te Groen, Daniel R Garza, Famke van Heeckeren Tot Overlaer, Joyce P M Krekels, Basma-Chick Sulaiman, Davy Karel, Athreyu Rulof, Anne R Schaaphok, Daniel L A H Hornikx, Iris D Nagtegaal, Bas E Dutilh, Frank Hoentjen, Annemarie Boleij

Background and aims: Colonic bacterial biofilms are frequently present in ulcerative colitis [UC] and may increase dysplasia risk through pathogens expressing oncotraits. This prospective cohort study aimed to determine [1] the association of oncotraits and longitudinal biofilm presence with dysplasia risk in UC, and [2] the relation of bacterial composition with biofilms and dysplasia risk.

Methods: Faeces and left- and right-sided colonic biopsies were collected from 80 UC patients and 35 controls. Oncotraits [FadA of Fusobacterium, BFT of Bacteroides fragilis, colibactin [ClbB] and Intimin [Eae] of Escherichia coli] were assessed in faecal DNA with multiplex quantitative polymerase chain reaction [qPCR]. Biopsies were screened for biofilms [n = 873] with 16S rRNA fluorescent in situ hybridiation. Shotgun metagenomic sequencing [n = 265], and ki67-immunohistochemistry were performed. Associations were determined with a mixed-effects regression model.

Results: Biofilms were highly prevalent in UC patients [90.8%] with a median persistence of 3 years (interquartile range [IQR] 2-5 years). Biofilm-positive biopsies showed increased epithelial hypertrophy [p = 0.025] and a reduced Shannon diversity independent of disease status [p = 0.015], but were not significantly associated with dysplasia in UC: adjusted odds ratio [aOR] 1.45, 95% confidence interval [CI] 0.63-3.40. In contrast, ClbB independently associated with dysplasia [aOR 7.16, 95% CI 1.75-29.28], and FadA and Fusobacteriales were associated with a decreased dysplasia risk in UC [aOR 0.23, 95% CI 0.06-0.83, p <0.01].

Conclusions: Biofilms are a hallmark of UC; however, because of their high prevalence are a poor biomarker for dysplasia. In contrast, colibactin presence and FadA absence independently associate with dysplasia in UC and might therefore be valuable biomarkers for future risk stratification and intervention strategies.

背景和目的:结肠细菌生物膜经常出现在溃疡性结肠炎[UC]中,并可能通过表达癌共征的病原体增加发育不良的风险。本前瞻性队列研究旨在确定[1]癌性状和纵向生物膜存在与UC发育不良风险的关系,[2]细菌组成与生物膜和发育不良风险的关系。方法:收集80例UC患者的粪便和左右结肠活检,对照组35例。采用多重定量聚合酶链式反应(qPCR)对粪便DNA中的癌性状(梭杆菌FadA、脆弱拟杆菌BFT、大肠杆菌colibactin [ClbB]和内膜素[Eae])进行评估。采用16S rRNA荧光原位杂交技术对活检组织进行生物膜筛选[n = 873]。散弹枪宏基因组测序[n = 265], ki67免疫组化。通过混合效应回归模型确定相关性。结果:生物膜在UC患者中非常普遍[90.8%],中位持续时间为3年(四分位数间距[IQR] 2-5年)。生物膜阳性活检显示上皮肥大增加[p = 0.025], Shannon多样性减少与疾病状态无关[p = 0.015],但与UC的发育不良无显著相关性:调整优势比[aOR] 1.45, 95%可信区间[CI] 0.63-3.40。相比之下,ClbB与不典型增生独立相关[aOR 7.16, 95% CI 1.75-29.28], FadA和Fusobacteriales与UC不典型增生风险降低相关[aOR 0.23, 95% CI 0.06-0.83, p]。然而,由于它们的高患病率是一个不良的生物标志物。相比之下,大肠杆菌素的存在和FadA的缺乏与UC的发育不良独立相关,因此可能是未来风险分层和干预策略的有价值的生物标志物。
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引用次数: 0
Autoimmune Pancreatitis in Patients with Inflammatory Bowel Disease: A Real-World Multicentre Collaborative ECCO CONFER Study. 炎症性肠病患者的自身免疫性胰腺炎:一项真实世界多中心ECCO协作研究
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad097
Piotr Eder, Bram Verstock, Emma Culver, Gabriele Dragoni, Lea Isabell Kredel, Joanna Wypych, Ana Garcia Garcia de Paredes, Magdalena Kaniewska, Haim Leibovitzh, Triana Lobaton, Marie Truyens, Grzegorz Oracz, Davide Giuseppe Ribaldone, Teresa Starzyńska, Abdenor Badaoui, Jean-Francois Rahier, Cristina Bezzio, Peter Bossuyt, Katherine Falloon, Daniela Pugliese, Catherine Frakes Vozzo, Tine Jess, Lone Larsen, Søren Schou Olesen, Partha Pal, María Chaparro, Dikla Dror, Pierre Ellul, Iga Gromny, Maria Janiak, Katarzyna Maciejewska, Noam Peleg, Ariella Bar-Gil Shitrit, Łukasz Szwed, Renata Talar-Wojnarowska, Yifat Snir, Roni Weisshof, Eran Zittan, Izabela Miechowicz, Idan Goren

Background: Autoimmune pancreatitis [AIP] is rarely associated with inflammatory bowel disease [IBD]. The long-term outcomes of AIP and IBD in patients with coexisting AIP-IBD and predictors of complicated AIP course have rarely been reported.

Methods: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collected cases of AIP diagnosed in patients with IBD. Complicated AIP was defined as a composite of endocrine and/or exocrine pancreatic insufficiency, and/or pancreatic cancer. We explored factors associated with complicated AIP in IBD.

Results: We included 96 patients [53% males, 79% ulcerative colitis, 72% type 2 AIP, age at AIP diagnosis 35 ± 16 years]. The majority of Crohn's disease [CD] cases [78%] had colonic/ileocolonic involvement. In 59%, IBD preceded AIP diagnosis, whereas 18% were diagnosed simultaneously. Advanced therapy to control IBD was used in 61% and 17% underwent IBD-related surgery. In total, 82% of patients were treated with steroids for AIP, the majority of whom [91%] responded to a single course of treatment. During a mean follow-up of 7 years, AIP complications occurred in 25/96 [26%] individuals. In a multivariate model, older age at AIP diagnosis was associated with a complicated AIP course (odds ratio [OR] = 1.05, p = 0.008), whereas family history of IBD [OR = 0.1, p = 0.03], and CD diagnosis [OR = 0.2, p = 0.04] decreased the risk of AIP complications. No IBD- or AIP-related deaths occurred.

Conclusions: In this large international cohort of patients with concomitant AIP-IBD, most patients have type 2 AIP and colonic IBD. AIP course is relatively benign and long-term outcomes are favourable, but one-quarter develop pancreatic complications. Age, familial history of IBD, and CD may predict uncomplicated AIP course.

背景:自身免疫性胰腺炎[AIP]很少与炎症性肠病[IBD]相关。合并AIP-IBD患者的AIP和IBD的长期预后以及复杂AIP病程的预测因素很少有报道。方法:ECCO异常罕见病例报告合作网络项目[ECCO- confer]收集了IBD患者诊断为AIP的病例。复杂性AIP被定义为内分泌和/或外分泌胰腺功能不全和/或胰腺癌的复合。我们探讨了IBD并发AIP的相关因素。结果:纳入96例患者[男性53%,溃疡性结肠炎79%,2型AIP 72%,诊断年龄35±16岁]。大多数克罗恩病(CD)病例(78%)累及结肠/回结肠。59%的患者IBD先于AIP诊断,18%的患者同时诊断。61%的患者采用了先进的治疗方法来控制IBD, 17%的患者接受了IBD相关手术。总的来说,82%的AIP患者接受了类固醇治疗,其中大多数[91%]对单一疗程的治疗有反应。平均随访7年,25/96例(26%)患者出现AIP并发症。在一个多变量模型中,诊断为AIP时年龄较大与复杂的AIP病程相关(比值比[OR] = 1.05, p = 0.008),而IBD家族史[OR = 0.1, p = 0.03]和CD诊断[OR = 0.2, p = 0.04]降低了AIP并发症的风险。无IBD或aip相关死亡发生。结论:在这个合并AIP-IBD患者的大型国际队列中,大多数患者患有2型AIP和结肠IBD。AIP病程相对良性,长期预后良好,但1 / 4发生胰腺并发症。年龄、IBD家族史和CD可以预测不复杂的AIP病程。
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引用次数: 0
Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease. 早期生活因素,包括母乳成分,对患有和不患有炎症性肠病的母亲所生婴儿的微生物组的影响。
IF 8.3 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad096
João Sabino, Leonid Tarassishin, Caroline Eisele, Kelly Hawkins, Amelie Barré, Nile Nair, Alexa Rendon, Anketse Debebe, Mellissa Picker, Manasi Agrawal, Joanne Stone, James George, Peter Legnani, Elana Maser, Ching-Lynn Chen, Anne Thjømøe, Einar Mørk, Marla Dubinsky, Jianzhong Hu, Jean Frederic Colombel, Inga Peter, Joanna Torres

Background and aims: Herein we analysed the influence of early life factors, including breast milk composition, on the development of the intestinal microbiota of infants born to mothers with and without IBD.

Methods: The MECONIUM [Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome] study is a prospective cohort study consisting of pregnant women with or without IBD and their infants. Longitudinal stool samples were collected from babies and analysed using 16s rRNA sequencing and faecal calprotectin. Breast milk proteomics was profiled using Olink inflammation panel.

Results: We analysed gut microbiota of 1034 faecal samples from 294 infants [80 born to mothers with and 214 to mothers without IBD]. Alpha diversity was driven by maternal IBD status and time point. The major influencers of the overall composition of the microbiota were mode of delivery, feeding, and maternal IBD status. Specific taxa were associated with these exposures, and maternal IBD was associated with a reduction in Bifidobacterium. In 312 breast milk samples [91 from mothers with IBD], mothers with IBD displayed lower abundance of proteins involved in immune regulation, such as thymic stromal lymphopoietin, interleukin-12 subunit beta, tumour necrosis factor-beta, and C-C motif chemokine 20, as compared with control mothers [adjusted p = 0.0016, 0.049, 0.049, and 0.049, respectively], with negative correlations with baby´s calprotectin, and microbiome at different time points.

Conclusion: Maternal IBD diagnosis influences microbiota in their offspring during early life. The proteomic profile of breast milk of women with IBD differs from that of women without IBD, with distinct time-dependent associations with baby's gut microbiome and feacal calprotectin.

背景与目的:本文分析了早期生活因素的影响,包括母乳成分对患有和不患有IBD的母亲所生婴儿肠道微生物群发育的影响。从婴儿身上采集纵向粪便样本,并使用16s rRNA测序和粪便钙卫蛋白进行分析。使用Olink炎症小组对母乳蛋白质组学进行了分析。结果:我们分析了294名婴儿1034份粪便样本的肠道微生物群(80份为患有IBD的母亲所生,214份为无IBD的妈妈所生)。阿尔法多样性是由母体IBD状态和时间点驱动的。微生物群总体组成的主要影响因素是分娩方式、喂养和母亲IBD状况。特定的分类群与这些暴露有关,母体IBD与双歧杆菌的减少有关。在312份母乳样本(91份来自IBD母亲)中,与对照母亲相比,患有IBD的母亲表现出较低的参与免疫调节的蛋白质丰度,如胸腺基质淋巴细胞生成素、白细胞介素-12亚单位β、肿瘤坏死因子β和C-C基序趋化因子20(分别调整p=0.0016、0.049、0.049和0.049),与婴儿的钙卫蛋白和不同时间点的微生物组呈负相关。结论:母亲IBD的诊断会影响其后代早期的微生物群。IBD妇女母乳的蛋白质组学特征与非IBD妇女不同,与婴儿肠道微生物组和粪便钙卫蛋白有明显的时间相关性。
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引用次数: 0
Major Adverse Cardiovascular Events by Baseline Cardiovascular Risk in Patients with Ulcerative Colitis Treated with Tofacitinib: Data from the OCTAVE Clinical Programme. 托法替尼治疗的溃疡性结肠炎患者基线心血管风险的主要不良心血管事件:来自OCTAVE临床项目的数据
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad104
Stefan Schreiber, David T Rubin, Siew C Ng, Laurent Peyrin-Biroulet, Silvio Danese, Irene Modesto, Xiang Guo, Chinyu Su, Kenneth K Kwok, Hyejin Jo, Yan Chen, Arne Yndestad, Walter Reinisch, Marla C Dubinsky

Background and aims: Patients with inflammatory bowel disease have increased risk of atherosclerotic cardiovascular [CV] disease [ASCVD]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. We report major adverse CV events [MACE] in the UC OCTAVE programme, stratified by baseline CV risk.

Methods: Rates of MACE were analysed by baseline [first tofacitinib exposure] CV risk profile: prior ASCVD, or 10-year ASCVD risk categories [low, borderline, intermediate, high].

Results: Of 1157 patients [2814.4 patient-years of exposure; ≤7.8 years' tofacitinib treatment], 4% had prior ASCVD and 83% had no prior ASCVD and low-borderline baseline 10-year ASCVD risk. Eight [0.7%] patients developed MACE; one had prior ASCVD. Incidence rates [unique patients with events/100 patient-years of exposure; 95% confidence intervals] for MACE were: 0.95 [0.02-5.27] in patients with prior ASCVD; and 1.81 [0.05-10.07], 1.54 [0.42-3.95], 0.00 [0.00-2.85], and 0.09 [0.01-0.32] in patients without prior ASCVD and with high, intermediate, -borderline, and low baseline 10-year ASCVD risk, respectively. For the 5/7 patients with MACE and without prior ASCVD, 10-year ASCVD risk scores were numerically higher [>1%] prior to MACE versus at baseline, primarily due to increasing age.

Conclusions: Most patients receiving tofacitinib in the UC OCTAVE programme had low baseline 10-year ASCVD risk. MACE were more frequent in patients with prior ASCVD and higher baseline CV risk. This analysis demonstrates potential associations between baseline CV risk and MACE in patients with UC, suggesting CV risk should be assessed individually in clinical practice.

Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

背景和目的:炎症性肠病患者发生动脉粥样硬化性心血管疾病(ASCVD)的风险增加。托法替尼是一种用于治疗溃疡性结肠炎的口服Janus激酶抑制剂[UC]。我们报告了UC OCTAVE项目中的主要不良CV事件(MACE),并按基线CV风险分层。方法:通过基线[首次托法替尼暴露]CV风险概况、既往ASCVD或10年ASCVD风险分类[低、临界、中、高]分析MACE发生率。结果:1157例患者[2814.4患者-年]暴露;≤7.8年托法替尼治疗],4%有ASCVD病史,83%没有ASCVD病史,10年基线ASCVD风险低。8例(0.7%)患者发生MACE;1例既往有ASCVD。发病率[有事件的独特患者/100患者-年暴露;既往ASCVD患者MACE的95%置信区间为:0.95 [0.02-5.27];无ASCVD、基线10年ASCVD高、中、临界和低风险的患者分别为1.81[0.05-10.07]、1.54[0.42-3.95]、0.00[0.00-2.85]和0.09[0.01-0.32]。对于5/7的MACE患者,既往无ASCVD, MACE前的10年ASCVD风险评分比基线时高[>1%],主要是由于年龄的增加。结论:大多数在UC OCTAVE项目中接受托法替尼治疗的患者基线10年ASCVD风险较低。MACE在既往ASCVD和基线CV风险较高的患者中更为常见。该分析表明UC患者基线CV风险与MACE之间存在潜在关联,提示在临床实践中应单独评估CV风险。NCT01465763;NCT01458951;NCT01458574;NCT01470612。
{"title":"Major Adverse Cardiovascular Events by Baseline Cardiovascular Risk in Patients with Ulcerative Colitis Treated with Tofacitinib: Data from the OCTAVE Clinical Programme.","authors":"Stefan Schreiber, David T Rubin, Siew C Ng, Laurent Peyrin-Biroulet, Silvio Danese, Irene Modesto, Xiang Guo, Chinyu Su, Kenneth K Kwok, Hyejin Jo, Yan Chen, Arne Yndestad, Walter Reinisch, Marla C Dubinsky","doi":"10.1093/ecco-jcc/jjad104","DOIUrl":"10.1093/ecco-jcc/jjad104","url":null,"abstract":"<p><strong>Background and aims: </strong>Patients with inflammatory bowel disease have increased risk of atherosclerotic cardiovascular [CV] disease [ASCVD]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. We report major adverse CV events [MACE] in the UC OCTAVE programme, stratified by baseline CV risk.</p><p><strong>Methods: </strong>Rates of MACE were analysed by baseline [first tofacitinib exposure] CV risk profile: prior ASCVD, or 10-year ASCVD risk categories [low, borderline, intermediate, high].</p><p><strong>Results: </strong>Of 1157 patients [2814.4 patient-years of exposure; ≤7.8 years' tofacitinib treatment], 4% had prior ASCVD and 83% had no prior ASCVD and low-borderline baseline 10-year ASCVD risk. Eight [0.7%] patients developed MACE; one had prior ASCVD. Incidence rates [unique patients with events/100 patient-years of exposure; 95% confidence intervals] for MACE were: 0.95 [0.02-5.27] in patients with prior ASCVD; and 1.81 [0.05-10.07], 1.54 [0.42-3.95], 0.00 [0.00-2.85], and 0.09 [0.01-0.32] in patients without prior ASCVD and with high, intermediate, -borderline, and low baseline 10-year ASCVD risk, respectively. For the 5/7 patients with MACE and without prior ASCVD, 10-year ASCVD risk scores were numerically higher [>1%] prior to MACE versus at baseline, primarily due to increasing age.</p><p><strong>Conclusions: </strong>Most patients receiving tofacitinib in the UC OCTAVE programme had low baseline 10-year ASCVD risk. MACE were more frequent in patients with prior ASCVD and higher baseline CV risk. This analysis demonstrates potential associations between baseline CV risk and MACE in patients with UC, suggesting CV risk should be assessed individually in clinical practice.</p><p><strong>Clinicaltrials.gov: </strong>NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.</p>","PeriodicalId":15547,"journal":{"name":"Journal of Crohns & Colitis","volume":" ","pages":"1761-1770"},"PeriodicalIF":8.0,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10110204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Early intervention with biologic therapy in Crohn´s disease: how early is early? 克罗恩病早期干预生物治疗:多早算早?
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad089
Joana Revés, André Mascarenhas, Maria José Temido, Bárbara Morão, Catarina Neto Nascimento, Ana Rita Franco, Raquel R Mendes, Carolina Palmela, Cristina Chagas, Pedro Narra Figueiredo, Luísa Glória, Francisco Portela, Joana Torres

Background: Early biologic therapy within the first 18-24 months after diagnosis is associated with improved clinical outcomes in Crohn's disease [CD]. However, the definition of the best time to initiate biologic therapy remains unclear. We aimed to assess if there is an optimal timing for early biologic therapy initiation.

Methods: This was a multicentre retrospective cohort study including newly diagnosed CD patients who started anti-tumour necrosis factor [TNF] therapy within 24 months from diagnosis. The timing of initiation of biologic therapy was categorised as ≤6, 7-12, 13-18, and 19-24 months. The primary outcome was CD-related complications defined as a composite of progression of Montreal disease behaviour, CD-related hospitalisations, or CD-related intestinal surgeries. Secondary outcomes included clinical, laboratory, endoscopic, and transmural remission.

Results: We included 141 patients where 54%, 26%, 11%, and 9% started biologic therapy at ≤6, 7-12, 13-18, and 19-24 months after diagnosis, respectively. A total of 34 patients [24%] reached the primary outcome: 8% had progression of disease behaviour, 15% were hospitalised, and 9% required surgery. There was no difference in the time to a CD-related complication according to the time of initiation of biologic therapy within the first 24 months. Clinical, endoscopic, and transmural remission was achieved in 85%, 50%, and 29%, respectively, but no differences were found according to the time of initiation of biologic therapy.

Conclusion: Starting anti-TNF therapy within the first 24 months after diagnosis was associated with a low rate of CD-related complications and high rates of clinical and endoscopic remission, although we found no differences with earlier initiation within this window of opportunity.

背景:诊断后18-24个月内的早期生物治疗与克罗恩病的临床预后改善相关[CD]。然而,开始生物治疗的最佳时间的定义仍然不清楚。我们的目的是评估是否存在早期生物治疗开始的最佳时机。方法:这是一项多中心回顾性队列研究,包括在诊断后24个月内开始抗肿瘤坏死因子(TNF)治疗的新诊断的CD患者。开始生物治疗的时间分为≤6个月、7-12个月、13-18个月和19-24个月。主要结局是cd相关并发症,定义为蒙特利尔疾病行为进展、cd相关住院或cd相关肠道手术的复合。次要结局包括临床、实验室、内窥镜和经壁缓解。结果:我们纳入了141例患者,其中54%、26%、11%和9%分别在诊断后≤6个月、7-12个月、13-18个月和19-24个月开始生物治疗。共有34例患者(24%)达到主要结局:8%的患者出现疾病行为进展,15%住院,9%需要手术。根据开始生物治疗的时间,在前24个月内出现cd相关并发症的时间没有差异。临床、内镜和经壁缓解分别为85%、50%和29%,但根据开始生物治疗的时间没有发现差异。结论:在诊断后的前24个月内开始抗tnf治疗与cd相关并发症发生率低,临床和内窥镜缓解率高相关,尽管我们发现在这个机会窗口内早期开始抗tnf治疗没有差异。
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引用次数: 1
Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility. 髓细胞特异性缺失PDGFR-α促进肠道菌群失调,从而增加结肠炎易感性。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad103
Ronja Dörk, Penelope Pelczar, Ahmad M Shiri, Annika Volmari, Elisabeth Zierz, Anastasios Giannou, Marius Böttcher, Lidia Bosurgi, Samuel Huber, Carolin F Manthey

Background and aims: The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance.

Methods: We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models.

Results: Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect.

Conclusions: Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype.

背景与目的:炎症性肠病(IBD)的发病率正在稳步上升,因此寻找新的靶点来改善治疗是一个主要目标。PDGF家族生长因子及其受体在肠道发育早期表达,存在于成人组织的单核细胞和巨噬细胞中。巨噬细胞在IBD的发病机制中起着独特的作用,因为它们的功能对维持耐受性至关重要。方法:我们旨在研究PDGFR-α在小鼠IBD和感染性模型中骨髓表达介导肠道稳态的作用。结果:我们的研究结果表明,髓系PDGFR-α的缺失增加了对葡聚糖硫酸盐诱导的结肠炎的易感性。因此,与对照组小鼠相比,LysM-PDGFR-α-/-小鼠表现出更高的结肠炎评分,抗炎巨噬细胞水平降低。这种效应是通过促结肠炎微生物群介导的,在缺乏髓系PDGFR-α的情况下,促结肠炎微生物群发展,与对照组相比,粪菌群移植后,无菌小鼠结肠炎易感性增加。此外,LysM-PDGFR-α-/-小鼠有漏肠,并伴有吞噬功能受损,导致严重的屏障缺陷。结论:综上所述,我们的研究结果表明髓系PDGFR-α通过促进保护性肠道微生物群和提供抗炎巨噬细胞表型,在维持肠道稳态中起保护作用。
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引用次数: 0
Gut Microbiome-Generated Phenylacetylglutamine from Dietary Protein is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Model Possibly via Platelet Activation. 肠道微生物从膳食蛋白中产生的苯乙酰谷氨酰胺与克罗恩病有关,并可能通过血小板激活加剧小鼠结肠炎
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad098
Rui Feng, Zhenyi Tian, Ren Mao, Ruiqi Ma, Wanrong Luo, Min Zhao, Xiaozhi Li, Yunchong Liu, Kan Huang, Liyuan Xiang, Xiaojun Zhuang, Bitao Huo, Tiantian Yu, Sifan Chen, Minhu Chen, Yijun Zhu

Objectives: Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite.

Design: We collected faecal and serum samples from a CD cohort [n = 136] and healthy controls [n = 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [n = 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD.

Results: PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients.

Conclusion: Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.

目的:我们的目的是更好地了解饮食和肠道微生物群在克罗恩病[CD]中的相互作用,利用新发treatment-naïve CD队列。我们关注的是苯乙酰谷氨酰胺[PAGln],这是一种饮食衍生的元有机体血栓前代谢物。设计:我们在治疗前收集了来自CD队列[n = 136]和健康对照[n = 126]的粪便和血清样本,并使用LC-MS/MS定量血清PAGln。使用食物频率问卷对饮食进行评估。小鼠[C57BL/6]饲喂高/低蛋白饲粮,并给予葡聚糖硫酸钠[DSS]检测血浆PAGly、血栓形成潜力和结肠炎严重程度。给dss诱导的结肠炎小鼠注射PAGly或生理盐水,检测结肠炎严重程度和结肠组织基因表达。在PAGln启动后暴露于血小板激动剂后,测定富血小板血浆中p -选择素和CD40L的表达[n = 5-6]。生物信息学分析和细菌培养确定了PAGln在CD中的主要作用。结果:PAGln是一种凝血前代谢产物,与CD有关。在小鼠模型中,PAGly加重了结肠炎,并上调了凝血相关的生物过程。抗血小板药物,双嘧达莫,减轻pagy -增强结肠炎易感性。PAGln增强血小板活化和富血小板血浆中CD40L的表达。进一步的研究表明,高膳食蛋白质摄入和苯丙酮酸脱羧酶介导的产生苯乙酸(PAA)的变形菌群丰度的增加共同导致CD患者的PAGln水平升高。综上所述,膳食蛋白中携带ppdc的变形菌产生的PAGln与CD相关,并可能通过血小板诱导的凝血和炎症加剧结肠炎。这些结果表明,PAGln是CD潜在的早期诊断标志物和治疗靶点。
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引用次数: 0
Results of the Eighth Scientific Workshop of ECCO: Prevention and Treatment of Postoperative Recurrence in Patients With Crohn's Disease Undergoing an Ileocolonic Resection With Ileocolonic Anastomosis. ECCO第八届科学研讨会结果:回肠结肠切除术与回肠结肠吻合术对克罗恩病患者术后复发的预防与治疗
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-24 DOI: 10.1093/ecco-jcc/jjad053
Marc Ferrante, Lieven Pouillon, Míriam Mañosa, Edoardo Savarino, Matthieu Allez, Christina Kapizioni, Naila Arebi, Michele Carvello, Pär Myrelid, Annemarie C De Vries, Pauline Rivière, Yves Panis, Eugeni Domènech

Despite the introduction of biological therapies, an ileocolonic resection is often required in patients with Crohn's disease [CD]. Unfortunately, surgery is not curative, as many patients will develop postoperative recurrence [POR], eventually leading to further bowel damage and a decreased quality of life. The 8th Scientific Workshop of ECCO reviewed the available scientific data on both prevention and treatment of POR in patients with CD undergoing an ileocolonic resection, dealing with conventional and biological therapies, as well as non-medical interventions, including endoscopic and surgical approaches in case of POR. Based on the available data, an algorithm for the postoperative management in daily clinical practice was developed.

尽管引入了生物疗法,但在克罗恩病患者中经常需要回肠结肠切除术[CD]。不幸的是,手术不能治愈,因为许多患者会出现术后复发[POR],最终导致进一步的肠道损伤和生活质量下降。ECCO第8届科学研讨会审查了现有的关于在接受回肠结肠切除术的CD患者中预防和治疗POR的科学数据,涉及传统和生物疗法,以及非医疗干预措施,包括在POR情况下的内窥镜和手术方法。在此基础上,提出了一种适用于日常临床实践的术后管理算法。
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引用次数: 0
Obefazimod: A First-in-class Drug for the Treatment of Ulcerative Colitis. 奥贝法齐莫特:治疗溃疡性结肠炎的一流药物。
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-08 DOI: 10.1093/ecco-jcc/jjad067
Séverine Vermeire, Virginia Solitano, Laurent Peyrin-Biroulet, Herbert Tilg, Silvio Danese, Hartmut Ehrlich, Didier Scherrer, Paul Gineste, Laurence d'Agay, Bruce E Sands

Biologic agents and oral small molecules are the mainstays of inflammatory bowel disease [IBD] management. However, an unmet clinical need remains for additional agents with novel mechanism of action which are effective, safe, and disease-modifying; this is due to the substantial proportion of patients who do not respond, lose response, or develop intolerance to currently marketed products. microRNAs [miRNAs] that play a role in the modulation of signal transduction pathways implicated in the development of IBD hold the potential to be used as therapeutic targets. Recently, a novel first-in-class compound, obefazimod, originally conceived as a human immunodeficiency virus [HIV] infection drug, has shown great promise in phase II induction trials for ulcerative colitis [UC] patients. Findings from the maintenance phases of trials showed that long-term obefazimod treatment provides continued improvement in clinical symptoms of disease, with a substantial proportion of patients in clinical remission, and an overall good safety profile. With a novel mechanism of action, obefazimod is an orally available small molecule with anti-inflammatory properties through the specific and selective upregulation of miR-124 expression. The aim of this paper is to critically review the available evidence related to pharmacokinetics and pharmacodynamics, and to discuss the potential clinical implications of this first-in-class oral small molecule.

生物制剂和口服小分子药物是治疗炎症性肠病(IBD)的主要手段。然而,尚未满足的临床需求仍然是具有新的作用机制,有效,安全和改善疾病的其他药物;这是由于相当大比例的患者对目前上市的产品无反应、失去反应或产生不耐受。microrna [mirna]在IBD发展过程中信号转导通路的调节中发挥作用,具有被用作治疗靶点的潜力。最近,一种新型的第一性化合物obefazimod,最初被认为是一种人类免疫缺陷病毒(HIV)感染药物,在溃疡性结肠炎(UC)患者的II期诱导试验中显示出巨大的希望。试验维持阶段的结果表明,长期的奥贝法莫治疗可以持续改善疾病的临床症状,有相当比例的患者处于临床缓解状态,并且总体上具有良好的安全性。obefazimod是一种口服小分子,具有新的作用机制,通过特异性和选择性上调miR-124的表达而具有抗炎特性。本文的目的是批判性地回顾与药代动力学和药效学相关的现有证据,并讨论这种一流的口服小分子的潜在临床意义。
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引用次数: 2
Shifting the Inflammatory Balance in Ulcerative Colitis Through Diet: A Mediterranean Diet Pattern is Associated with Improvements in Dysbiosis and Disease Activity. 通过饮食改变溃疡性结肠炎的炎症平衡:地中海饮食模式与生态失调和疾病活动的改善有关
IF 8 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2023-11-08 DOI: 10.1093/ecco-jcc/jjad095
Steven N Mathews, Dana J Lukin
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引用次数: 0
期刊
Journal of Crohns & Colitis
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