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OP06 Comparison between Crohn and coeliac diseases small intestine transcriptomics and microbial data define similarities and divergent pathways linked to pathogenesis
Journal of Crohn's and Colitis ( IF 8 ) Pub Date : 2020-01-15 , DOI: 10.1093/ecco-jcc/jjz203.005
Y Haberman Ziv 1 , N Loberman-Nachum 1 , S Katya 1 , A Di Segni 1 , G Efroni 1 , T Braun 1 , M BenShoshan 1 , D Shouval 1 , L A Denson 2 , A Amir 1 , R Unger 3 , B Weiss 1
Affiliation  

Background
Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations.
Methods
We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance.
Results
A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls.
Conclusion
We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.


中文翻译:

OP06克罗恩病和腹腔疾病的比较小肠转录组学和微生物数据确定了与发病机制相关的相似性和不同途径

背景
克罗恩病和腹腔疾病是已知引起小肠炎症的两种炎性疾病。使用高通量转录组学,微生物学和生物信息学方法,我们旨在捕获与发病机制相关的差异和相似性,以及与那些慢性表现有关的未来潜在干预措施。
方法
我们使用临床病理标本对55名小儿新发乳糜泻患者和对照进行了高通量转录组学和16S微生物鉴定,并将这些特征与我们先前报道的248例新诊断的克罗恩病风险进行了比较。使用ToppGene / ToppCluster和ClueGO平台进行功能注释富集分析,使用MaAsLin进行微生物差异丰度分析。
结果
在两项研究中,大量(> 90%)基因通过了表达过滤标准,从而可以进行比较。在354个腹腔下调的基因中,有59%(209/354)与克罗恩信号减少重叠。共有的减少的签名和功能包括上皮脂质代谢,氧化还原酶活性和刷状边界转运签名的减少。相比之下,腹腔疾病524个上调基因中的比例要小得多[19%(97/427,卡方p <0.001]]与诱导的克罗恩病特征重叠,我们注意到适应性免疫相关途径具有共享的丰富特征以及乳糜泻和克罗恩病中的γ-干扰素,但是,克罗恩病的病原体表现出与先天免疫途径相关的病原体更丰富的特异性富集,并且对粒细胞有很强的信号,细胞外基质签名和CXCR趋化因子信号,而腹腔上调的签名显示细胞周期和有丝分裂的独特富集。与以前以克罗恩病为特征的健壮性异位症相反,我们仅能发现乳糜泻患者与对照组相比,细菌类群明显富集。
结论
我们强调了克罗恩病和腹腔疾病之间重要的生物学差异,强调了克罗恩病中先天性粒细胞激活信号的增强和腹腔疾病中特定的上皮增殖信号。不同于与克罗恩病相关的强烈的营养不良,腹腔病人与对照​​组相比,仅显示了几种拟杆菌类的适度富集。克罗恩病中的微生物改变可能触发粒细胞活化,并且该信号抑制上皮细胞的增殖/更新,最终导致在克罗恩病而不是乳糜泻中引起的上皮损伤。抑制先天免疫激活或逆转克罗恩病,可能是克罗恩病的一种有益的未来治疗方法。
更新日期:2020-01-17
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