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1、马 雄 上海市消化疾病研究所 上海交通大学医学院附属仁济医院 胆汁酸代谢、肠道菌群 与自身免疫性肝病 自身免疫性肝病自身免疫性肝病 Hirshfield GM, et al. Gastroenterology 2010;139:1481 自身免疫性肝炎 （Autoimmune Hepatitis, AIH） 原发性胆汁性胆管炎 （Primary Biliary Cholangitis, PBC ） 原发性硬化性胆管炎 (Primary Sclerosing Cholangitis, PSC) IgG4相关硬化性胆管炎（IgG4 related-Sclerosing cholangitis ）
2、重叠综合征(Overlap Syndrome) OLIGOGENIC POLIGENIC Familial Sporadic ENVIRONMENT GENETICS CFTR, ABCB4 INFCETIONS Autoimmunity 自身免疫性疾病发病机制 “Common Ground” Hypothesis of Pathogenesis Caused by Dysbiotic Gut Microbiota Lynch SV, Pedersen O. N Engl J Med. 2016;375:2369-2379. Study Year Patients Controls Repli
3、cation case/cont Population Loci implicated Karlsen, et al. 2010 285 298 766/2935 Scandinavian, German HLA Melum, et al. 2011 715 2962 1025/2174 Scandinavian, German HLA, BCL2L11, MST1 Folseraas, et al 2012 715 2962 1221/3508 Scandinavian, German discovery; Scandinavian, Central European and US repl
4、ication MMEL1-TNFRSF14 Srivastava, et al. 2012 992 5162 N/A UK Caucasians MST1, IL2RA Ellinghaus, et al 2013 392 2977 1012/2694 German, Scandinavian GPR35, TCF4 Liu, et al 2013 3789 25079 Pan-European, N America HLA, MMEL1-TNFSF14, CD28, MST1, IL2/IL21, BACH2, IL2RA, SIK2, HDAC7, SH2B3, CD226, FUT2,
5、 PSMG1 Ellinghaus, et al 2016 3408 34213 Pan-European CCL20,NFKB1, RIC8B,LOC107984859 Ji, et al 2016 2871 12019 1925/7936 Pan-European, N America, Africa, Chinese, Japanese CCDC88B,CLEC16A, FOXP1,UBASH3A PSC全基因组关联分析研究 Study Year Patients Controls Replication case/cont Population Loci implicated Hirs
6、chfield et al. 2009 536 1536 526/1206 White N American HLA, IL12A, IL12RB2 Hirschfield et al. 2010 494 1502 857/3198 White N American IRF-TNPO3, MMEL1, IZF3 Liu, et al 2010 453 945 None Italian and meta N American SPIB, IKZF3, IRF5-TNPO3 Mells, et al. 2011 1840 5163 620/2514 N European DENND1B, STAT
7、4, CD80, NFKB1, IL7R, CXCR5, TNFRSF1A, RAD51L1, CLEC16A, MAP3KK71P1; PLCL2, RPS6KA4, TNFAIP2 Cordell, et al 2015 2745 9802 3616/4261 N European, Italian, N American IL1R1, CCL20, DGKQ, C5ORF30, IL12B, TNFAIP3 Nakamura, et al 2012 487 476 787/615 Japanese HLA, TNFSF15, POU2AF1 Qiu, et al 2017 1122 40
8、74 900/1200 Chinese Han IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A, IL16 6 PBC全基因组关联分析研究 Qiu F, , Liu X, Ma X. Nature Communications 2017. Stage 1：1122 cases：4074 controls Stage 2：907 cases：2127 controls PBC全基因组关联分析研究 中国汉族人群 A Genome-Wide Association Study Identifies Six Novel Risk Loci for PBC Tfh
9、cells, IL-21 and B Cell Maturation LSECs Tfh PDC-E2 B BECs T Macrophage CXCL13 Biliary Ducts Hepatic sinusoid NK IL-21 IL-10 IL-4 IL-6 IL-21 Na ve B Breg B B Tfh Bm Bp IL-6 IFN- AMA Na ve B Li Y, et al. Hepatolgy 2015;61:1998-2007. Wang LF, et al. Hepatology 2015;61:627-38. IL-21 produced by Tfh cel
10、ls promotes B-cell maturation and autoantibody production in PBC patients 肠道微生物组：人类第二基因组 肠道细菌重量约1kg 种类1000余种 细胞数量是人体细胞 总数的10倍 基因数量3,300,000， 是人体自身基因组的 150倍 2001年人类基因组 工作草图发表 2010年人体肠道菌群 基因集构建 人体与肠道菌群已形 成了紧密的共生关 系 The gut microbiota in the development and diseases Nicholson JK, et al. Science 2012;33
11、6:1262. A schematic of a conceptual energy landscape harbouring multiple possible stable states of symbiosis and dysbiosis. Levy M, et al. Nat Rev Immunol 2017 Types of dysbiosis: Bloom of pathobionts; Loss of commensals; Loss of diversity. 肠道菌群失调与疾病 Levy M, et al. Nat Rev Immunol 2017 致病菌过度生长 共生菌丢失
12、 微生物多样性降低 Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans Vatanen T, et al. Cell 2016 Ruff WE, Kriegel MA. Trends Mol Med 2015;21:233-44. 肠道菌群参与肠道和肠外自身免疫性疾病的发生发展 表位扩散表位扩散 肠菌抗原肠菌抗原 组织损伤组织损伤 A P C 自身抗原自身抗原 CD 旁观者效应旁观者效应 TLR NLR 超抗原 打破免疫耐受打破免疫耐受 分子模拟分子模拟 自身抗原自身抗原 模拟物模拟物
13、 与肠菌抗原交叉反应 潜在机制潜在机制 肠道菌群 自身免疫性疾病 肠肠肝轴肝轴 肝脏与肠道在解剖位置和生 理功能方面密切联系 肝脏70%血液来自于肠道， 易暴露于肠道细菌及其代谢 产物 肝脏通过分泌胆汁酸等调节 肠道菌群；肠道菌群调控胆 汁酸合成与代谢 脂肪肝、肝硬化患者肠道菌 群均发生改变 炎症细胞 肠菌代谢物 胆汁酸 肝脏肝脏 原发性硬化性胆管炎原发性硬化性胆管炎 Lazaridis KN, et al. N Engl J Med 2016;375:1161-70. PSC 59:571582 The gutliver relationship in PSC OHara SP, et al
14、. Gut 2017. The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation Schrumpf E, et al. J Hepatol 2017;66:382-389. Germ free NOD.c3c4 mice have less CD3, Ly6G and Mac-2 positive cells around their bile ducts compared with conventionally raised NOD.c3c4 mice. Germ free NO
15、D.c3c4 mice have reduced inflammatory portal infiltrates compared with conventionally raised NOD.c3c4 mice at 18 weeks of age. Absence of the intestinal microbiota exacerbates hepatobiliarydisease in PSC modal. Tabibian JH, et al. Hepatology. 2016;63:185-96. Conceptual framework for the role of the
16、microbiota in the etiopathogenesis of PSC Tabibian JH, et al. Hepatology. 2016;63:185-96. 原发性硬化性胆管炎、炎症性肠病、健康人群的肠道微生物差异 Sabino J, et al. Gut 2016. PSC患者肠道菌群组成与健康对照、IBD患 者均有显著差别；无论有无IBD，PSC的 肠道菌群相似 PSC-UC患者菌群多样 性显著降低 52 PSC, 52 HC, 13 UC, 30 CD 16S rRNA 基因测序 Sabino J, et al. Gut 2016. 肠球菌属，链球菌属，乳杆菌属的比例 在PSC患者中特异性上升，与患者是否合 并IBD及服用UDCA无关 梭菌属在PSC和IBD患者中都有显著上升 PSC肠菌标记物肠菌标记物 原发性硬化性胆管炎、炎症性肠病、健康人群的
