多组学分析在炎症性肠病中的应用与研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2020-1032

摘要/Abstract

摘要：

炎症性肠病（IBD）是一种累及回肠、直肠和结肠的特发性慢性肠道炎症性疾病,主要包括溃疡性结肠炎和克罗恩病,在临床表现、病程和治疗反应等方面具有高度异质性。目前,关于IBD的发病机制尚未明确,治疗方法相对有限。由遗传、环境、肠道微生态以及宿主免疫失衡在内的多因素共同导致了过度活跃的炎症反应并最终引发患者的肠道粘膜屏障受损和管腔菌群紊乱。单一组学的分析无法全面揭示IBD发病过程中复杂的相互协同作用机制,更无法挖掘潜在的治疗靶点和开发有效的干预策略。因此需要运用多组学关联分析技术以帮助研究者从多个维度解析IBD的发病机制。回顾和分析了多组学技术在IBD相关研究领域中的应用,并且讨论了使用这些方法在IBD分型、早期诊断和个性化医疗等领域的潜力,以期为进一步研究IBD发病机制奠定良好基础。

关键词: 炎症性肠病, 多组学关联分析, 基因组学, 微生物组学, 诊疗策略

Abstract:

Inflammatory bowel disease（IBD）,comprising ulcerative colitis（UC）and Crohn’s disease（CD）,is an idiopathic inflammatory disease most commonly affecting the ileum,rectum,and colon. It shows highly heterogeneous in terms of clinical manifestation,disease’s progression and therapeutic response. Currently,there is no consensus on the pathogenesis underlying IBD,while the treatment options are quite limited. Overactive inflammatory responses are leading to the damage of intestinal mucosal barrier and disorder of intestinal flora disturbance,which is caused by genetic factors,environmental factors,intestinal micro-ecology and host immunological imbalance. Revealing the complex interaction mechanism in the pathogenesis of IBD,excavating potential therapeutic targets,and developing effective intervention strategies cannot be achieved via mono-omics analysis. Thus,there is a need to apply multi-omics association analysis techniques in further elucidating the pathogenesis of IBD at multiple dimensions. In this review,we retrospect and analyze the application of multi-omics techniques in fields related to IBD research. Moreover,we discuss their potential in the fields of individualized diagnosis and treatment,early diagnosis,and IBD typing,which is aimed to lay a foundation in further investigation of IBD.

Key words: inflammatory bowel disease, muliti-omics association analysis, genomics, microbiome, diagnosis and treatment strategy

张立兴, 王丽娜, 康广博, 黄鹤. 多组学分析在炎症性肠病中的应用与研究进展[J]. 生物技术通报, 2021, 37(1): 155-167.

ZHANG Li-xing, WANG Li-na, KANG Guang-bo, HUANG He. Application and Advances of Multi-omics Analysis in Inflammatory Bowel Disease[J]. Biotechnology Bulletin, 2021, 37(1): 155-167.

图/表 6

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项目名称	UC/CD	数量	基因组学	转录组学	代谢组学	蛋白质组学	微生物组学	文献
HMP	0/10	12	——	——	——	宏蛋白质组/粪便标本	宏基因组鸟枪法测序/ 粪便标本	[67]
iHMP	36/36	90	宿主基因组DNA甲基化分析/ 外周血标本	宏转录组测序/粪便标本宿主RNA-Seq/结肠活检标本	非靶向代谢组/粪便标本	宿主蛋白质组/粪便标本	16S rRNA扩增子测序/ 粪便标本和活检标本宏基因组鸟枪法测序/粪便标本	[5]
IBDMDB	38/67	132	宿主外显子组测序/血液标本甲基化分析/活检和血液标本	宏转录组测序/粪便标本宿主RNA-Seq/活检标本	非靶向代谢组/粪便匀浆	宿主蛋白质组/粪便标本	16S rRNA扩增子测序/活检标本宏基因组鸟枪法测序/粪便标本	[64]
1000 IBD Project	495/615	1 215	全外显子组测序和IBD易感位点靶向重测序/外周血标本	宿主RNA-Seq/肠道活检标本	——	——	16S rRNA扩增子测序/ 粪便和肠道活检标本	[48]
Med into Grad	0/3	6	全基因组DNA甲基化分析/ 人肠成纤维细胞	宿主RNA-Seq/ 人肠成纤维细胞	——	——	——	[49]
IBDGC	67/115	182	基因分型	——	——	——	16S rRNA扩增子测序/粪便标本	[50]
The GEM Project	0/1561	1 561	人外显子芯片和免疫芯片/ 外周血标本	——	——	——	16S rRNA扩增子测序/粪便标本	[51]
Inflammation at Interfaces	17/19	63	——	RNA-Seq/活检标本	——	——	16S rRNA扩增子测序/ 肠粘膜活检标本	[52]
——	82/50	183	——	——	非靶向代谢组/粪便标本	——	宏基因组鸟枪法测序/粪便标本	[53]
——	9/0	9	——	——	非靶向代谢组/粪便标本靶向代谢组（SCAFs）/粪便标本	——	16S rRNA扩增子测序/粪便标本宏基因组鸟枪法测序/粪便标本	[54]
——	15/9	34	——	RNA-Seq/结肠组织标本	——	宿主蛋白质组/结肠组织标本	——	[55]
——	——	——	甲基化GWAS分析/ 全血白细胞标本	基因表达芯片/全血标本	——	——	——	[56]

项目名称	UC/CD	数量	基因组学	转录组学	代谢组学	蛋白质组学	微生物组学	文献
HMP	0/10	12	——	——	——	宏蛋白质组/粪便标本	宏基因组鸟枪法测序/ 粪便标本	[67]
iHMP	36/36	90	宿主基因组DNA甲基化分析/ 外周血标本	宏转录组测序/粪便标本宿主RNA-Seq/结肠活检标本	非靶向代谢组/粪便标本	宿主蛋白质组/粪便标本	16S rRNA扩增子测序/ 粪便标本和活检标本宏基因组鸟枪法测序/粪便标本	[5]
IBDMDB	38/67	132	宿主外显子组测序/血液标本甲基化分析/活检和血液标本	宏转录组测序/粪便标本宿主RNA-Seq/活检标本	非靶向代谢组/粪便匀浆	宿主蛋白质组/粪便标本	16S rRNA扩增子测序/活检标本宏基因组鸟枪法测序/粪便标本	[64]
1000 IBD Project	495/615	1 215	全外显子组测序和IBD易感位点靶向重测序/外周血标本	宿主RNA-Seq/肠道活检标本	——	——	16S rRNA扩增子测序/ 粪便和肠道活检标本	[48]
Med into Grad	0/3	6	全基因组DNA甲基化分析/ 人肠成纤维细胞	宿主RNA-Seq/ 人肠成纤维细胞	——	——	——	[49]
IBDGC	67/115	182	基因分型	——	——	——	16S rRNA扩增子测序/粪便标本	[50]
The GEM Project	0/1561	1 561	人外显子芯片和免疫芯片/ 外周血标本	——	——	——	16S rRNA扩增子测序/粪便标本	[51]
Inflammation at Interfaces	17/19	63	——	RNA-Seq/活检标本	——	——	16S rRNA扩增子测序/ 肠粘膜活检标本	[52]
——	82/50	183	——	——	非靶向代谢组/粪便标本	——	宏基因组鸟枪法测序/粪便标本	[53]
——	9/0	9	——	——	非靶向代谢组/粪便标本靶向代谢组（SCAFs）/粪便标本	——	16S rRNA扩增子测序/粪便标本宏基因组鸟枪法测序/粪便标本	[54]
——	15/9	34	——	RNA-Seq/结肠组织标本	——	宿主蛋白质组/结肠组织标本	——	[55]
——	——	——	甲基化GWAS分析/ 全血白细胞标本	基因表达芯片/全血标本	——	——	——	[56]

模型	转录组学	代谢组学	蛋白质组学	微生物组学	文献
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/冷冻血浆和肝脏标本	宿主蛋白质组/肝脏和结肠标本	——	[57]
DSS诱导结肠炎	基因表达芯片/结肠粘膜标本	——	宿主蛋白质组/结肠粘膜标本	——	[58]
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/肝脏和血浆标本	宿主蛋白质组/肝脏标本	16S rRNA扩增子测序/盲肠内容物	[59]
IL-10基因缺陷小鼠	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠粘膜标本	——	[60]
T细胞转移性肠炎模型	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠标本	——	[61]
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/肝脏标本	宿主蛋白质组/肝和结肠标本	——	[62]
Mdr1a（-/-）大鼠模型	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠标本	——	[63]

模型	转录组学	代谢组学	蛋白质组学	微生物组学	文献
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/冷冻血浆和肝脏标本	宿主蛋白质组/肝脏和结肠标本	——	[57]
DSS诱导结肠炎	基因表达芯片/结肠粘膜标本	——	宿主蛋白质组/结肠粘膜标本	——	[58]
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/肝脏和血浆标本	宿主蛋白质组/肝脏标本	16S rRNA扩增子测序/盲肠内容物	[59]
IL-10基因缺陷小鼠	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠粘膜标本	——	[60]
T细胞转移性肠炎模型	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠标本	——	[61]
DSS诱导结肠炎	基因表达芯片/肝脏和结肠标本	非靶向代谢组/肝脏标本	宿主蛋白质组/肝和结肠标本	——	[62]
Mdr1a（-/-）大鼠模型	基因表达芯片/结肠标本	——	宿主蛋白质组/结肠标本	——	[63]

组学	分组	潜在的生物标志物	参考文献
基因组	IBD vs. controls	CARD 9, RER, XBP1, IL23R, JAK2, TYK2, ICOSLG, TNFSF*15, CUL2, MST1, TNFSF8, IL12B, IL23, PRDM1, IL10, CREM, PUS10, ORMDL3, UTS2, PEX13	[73]
	CD vs. controls	NOD2, ITLN1, ATG16L1, STAT3, IRGM, LRRK2, MUC19, CCL11, CCL2, CCL7, CCL8, CCR6, NDFIP1, TAGAP, IL2R, ERAP2, LNPEP, DENND1B, IL27, SBNO2, FASLG, THAA, CPEB4, PRDX5, BACH2, ADO, GPC4, GPX1, SLC22A4, LRRK2	[73]
	UC vs. controls	SLC11A1, FGR2a*/B, IL21, PARK7, DAP, GNA12, HNF4A, CDH1, ERRFI1, IL8RA, IL8RB, TNFRSF9, PIM3, IL/R, TNFSF8, IGNG, IL23, IL1R1, IL1R2, SERNC3, HSPA6, DLD	[73]
表观基因组（甲基化状态）	IBD vs. controls	THRAP2, FANCC, GBGT1, WDR8, ITGB2, CARD9, CDH1（↑）;DOK2, TNFSF4, VMP1, ICAM3（↓）	[73]
表观基因组（甲基化状态）	CD vs. controls	CBGT1, IGFBP4, FAM10A4（↑）;IFITM1（↓）	[73]
转录组	IBD vs. controls	乙状结肠：CYLD、 CDH11等	[74]
	CD vs. controls	结肠粘膜：19个差异表达基因, CXCL1最为显著	[74]
	IBD vs. controls	miRs-3180-3p, miRplus-E1035, miRplusF1159, miR20b, miR-98, miR125b-1, let-7e, miRs-103-2, miR-362-3p, miR-532-3p, miR-98, miR340, miR-484（↑）	[73]
代谢组	UC vs. controls	结肠：精氨酸、葡萄糖、甘油磷酰胆碱、赖氨酸（↑）;丙氨酸、胆碱、甲酸盐、谷氨酸盐、谷氨酰胺、异亮氨酸、亮氨酸、缬氨酸、乳酸盐、肌醇、丁二酸盐（↓）粪便：谷氨酸盐、赖氨酸（↑）甲胺、三甲胺（↓）尿液：柠檬酸盐、甘氨酸、乙醇酸盐、胍基乙酸酯、甲基组氨酸（↑）;马尿酸盐、三甲基赖氨酸（↓）血清：天冬氨酸、甘氨酸、延胡索酸（↑）;天冬酰胺、谷氨酸、谷氨酰胺、组氨酸、色氨酸（↓）	[75-76]
代谢组	CD vs. controls	结肠：葡萄糖、甘油磷酰胆碱（↑）;丙氨酸、胆碱、甲酸盐、谷氨酸盐、谷氨酰氨、异亮氨酸、亮氨酸、缬氨酸、乳酸盐、肌醇、丁二酸盐（↓）粪便：丙氨酸、甘油、异亮氨酸、亮氨酸、缬氨酸、赖氨酸（↑）;乙酸盐、丁酸盐、甲胺、三甲胺（↓）尿液：甲酸盐、甘氨酸、乙醇酸盐、胍基乙酸酯、甲基组氨酸（↑）;4-甲酚硫酸盐、柠檬酸盐、马尿酸盐（↓）血清：天冬氨酸、甘氨酸、蛋氨酸、脯氨酸、延胡索酸、羟基丁二酸、丁二酸（↑）;丙氨酸、谷氨酰胺、组氨酸、色氨酸（↓）	[75-76]
蛋白质组	CD vs. controls	血清：ALCA、 gASCA、 anti-OmpC、 PAB、 S100A12、钙卫蛋白、 TNF-RI、 TNF-RII、 IL-8、 IL-18、半乳糖凝集素-3、 CXCL16、 C-反应蛋白、视黄醇结合蛋白4、胰岛素（↑）;脂连素（↓）粪便：钙卫蛋白、 S100A12、乳铁蛋白（↑）;结肠粘膜：S100A12、钙卫蛋白（↑）	[77]
	UC vs. controls	血清：atypical pANCA、 GAB、 S100A12、钙卫蛋白、 TNF-RI、 TNF-RII、 IL-8、 IL-18、 CXCL16、半乳糖凝集素-3、 C-反应蛋白、视黄醇结合蛋白4、胰岛素（↑）;脂连素（↓）粪便：钙卫蛋白、 S100A12、乳铁蛋白（↑）结肠粘膜：S100A12、钙卫蛋白（↑）	[77]
	CD vs. UC	血清：ALCA、 ACCA、 gASCA、 anti-OmpC、 AMCA、 antichitin、 antilaminarin、 PAB、 IL-18、 CXCL16（↑）	[77]
	UC vs. CD	血清：atypical pANCA、 IL-8（↑）粪便：乳铁蛋白（↑）	[77]
微生物组	IBD vs. controls（上调）	变形菌门Phylum proteobacteria、大肠杆菌Escherichia coli、简明弯曲杆菌Campylobacter concisus、艰难梭菌Clostridium difficil、脆弱拟杆菌Bacteroides fragilis、普通拟杆菌Bacteroides vulgatus、肺炎克雷伯菌Klebsiella pneumoniae、变形梭杆菌Fusobacterium varium、活泼瘤胃球菌Ruminococcus gnavus、产肠毒素性脆弱拟杆菌Enterotoxigenic Bacteroides fragilis 克罗恩病：副结核分枝杆菌Mycobacterium avium paratuberculosis	[75]
微生物组	IBD vs. controls（下调）	厚壁菌门Phylum Firmicutes、产丁酸盐菌（如人罗斯拜瑞氏菌Roseburia hominis和粪杆菌属 Faecalibacterium）、普拉氏梭杆菌Fusobacterium prausnitzii、青春双歧杆菌Bifidobacterium adolescentis、浑浊戴阿利斯特菌Dialister invisus、微生物多样性	[75]