寄生虫及其相关物治疗炎症性肠病转归进展

doi:10.12140/j.issn.1000-7423.2024.03.018

摘要/Abstract

摘要：

炎症性肠病（IBD）是一种病因尚未完全明确、以肠道症状为主的肠道疾病。该病迁延难愈，为国内外肠道疾病的疑难病，严重影响患者生存质量。近年研究发现，寄生虫及其相关物作用宿主后，可诱导一系列免疫应答，调节免疫微环境及改善肠道菌群，减轻炎症症状。本文就寄生虫及其相关物实验治疗IBD的最新研究进展进行综述，以期为治疗IBD的新型药物研发提供参考。

关键词: 寄生虫, 炎症性肠病, 实验治疗

Abstract:

Inflammatory bowel disease (IBD) is a type of intestinal disease whose etiology has not been completely defined and is mainly characterized by intestinal symptoms. This disease is protracted and difficult to cure, making it a challenging medical condition both domestically and internationally, and seriously affects the life quality of the patients. Recently, it has been found that parasites and their related agents can regulate the immune microenvironment, improve intestinal flora and reduce inflammatory symptoms by inducing a series of immune responses after acting on the host. In this paper, the latest research advances in the experimental treatment of IBD with parasites and related agents are reviewed to provide a reference for developing new drugs for the treatment of IBD.

Key words: Parasite, Inflammatory bowel disease, Experimental treatment

中图分类号:

徐凯, 陈力, 林登峰. 寄生虫及其相关物治疗炎症性肠病转归进展[J]. 中国寄生虫学与寄生虫病杂志, 2024, 42(3): 407-412.

XU Kai, CHEN Li, LIN Dengfeng. Advances in the treatment of inflammatory bowel disease with parasites and their agents[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2024, 42(3): 407-412.

图/表 1

表1

寄生虫及其相关物治疗IBD转归表

物种		相关物	诱导物		作用机制		转归	文献
旋毛虫 Trichinella spiralis		细胞外囊泡	三硝基苯磺酸（TNBS）		辅助型T细胞2（Th2）和Treg细胞（Treg）因子增加		肠上皮屏障损伤减轻，促炎细胞因子中性粒细胞浸润较少，免疫调节细胞因子表达上调	[6]
		重组旋毛虫成虫丝氨酸蛋白酶7 （rTs-ADSP-7）	TNBS		抑制了Th1和Th17免疫应答，同时增强Th2和Treg免疫应答		体内CD4+、CD25+、Foxp3+ T细胞的百分比明显增高	[7]
		旋毛虫粗蛋白(TsCP)	右旋糖酐硫酸钠（DSS）		抑制炎性小体（NLRP3）的激活和消皮素D（GSDMD）介导的细胞焦亡		髓过氧化物酶（MPO）、NLRP3、GSDMD、半胱氨酸天冬氨酸蛋白酶1（caspase-1）、caspase-1 p10、GSDMD-N、白细胞介素1β（IL-1β）、IL-1β p17和核因子κB（NF-κB）的蛋白表达水平下调，DAI和组织学损伤均减轻	[8]
		旋毛虫重组丝氨酸蛋白酶（TsSP）	DSS		抑制了肿瘤坏死因子-α（TNF-α）的产生，并且提高IL-10的表达		临床表现好转，结肠内巨噬细胞浸润明显减少	[9]
		旋毛虫副肌球蛋白（TsPMY）	DSS		上调了Th2环境下Foxp3⁺ Treg中GATA结合蛋白3（GATA3）的表达		促炎细胞因子IL-17A、IL-17F和IL-6减少，而IL-10和转化生长因子β（TGF-β）显著增加	[10]
多形螺旋线虫 Heligmosomoides polygyrus		多形螺旋线虫TGF-β模拟物（HpTGM）	-		CD4⁺ T细胞有效地诱导FOXP3的表达，Treg细胞更好地抑制CD4+和CD8⁺ T细胞增殖		减少了干扰素γ（IFN-γ）、IL-2、IL-4、IL-13和肿瘤坏死因子（TNF）的表达	[11]
		-	-		激活了肠道中IFN-γ肠神经胶质细胞（EGC）信号轴，EGC中趋化因子10（CXCL10）表达上调		CXCL10基因消融后小鼠肠道内肉芽肿的大小、数量以及炎症浸润较对照明显增加	[13]
		-	DSS		IBD小鼠模型中的分泌产物出现了膜联蛋白、溶菌酶-2、腺苷三磷酸双磷酸酶和半乳糖凝集素等百余种独特的蛋白		-	[14]
鼠管状线虫 Syphacia obvelata		鼠管状线虫卵（Egg）	DSS		促炎因子IFN-γ、TNF-α、IL-17较正常组明显降低，抗炎因子IL-10及Treg细胞中Foxp3⁺水平增高		小鼠疾病活动度（DAI）及存活率明显升高，组织学上发现炎症细胞浸润显著减少	[15]
钩虫 Hookworm		大分子抗炎蛋白（AIP）	TNBS		保守的螺旋区域在一定程度上起着抗炎作用		其中一些肽在与人外周血单核细胞共培养时表现出抗炎作用，结肠炎小鼠模型中可发现具有治疗效果	[16]
日本血吸虫 Schistosoma japonicum		日本血吸虫尾蚴（mSjci）	DSS		抑制促炎Th1细胞因子及促进IL-10、CD4⁺、CD25⁺、Treg的产生来调节Th1/Th2的平衡		肠道微生态趋于平衡，临床症状缓解	[18]
		可溶性虫卵抗原（SEA）	DSS、 TNBS		Th1反应（IFN-γ）下调、Th2反应（IL-4）上调		DAI评分降低，结肠长度增加，组织学发现炎性细胞浸润程度降低，促进肠道内益生菌生长；CD4+ IFNγ+明显降低，CD4+ IL-4+表达升高	[19]
		可溶性虫卵抗原（SEA）	DSS、 TNBS		Th1反应（IFN-γ）下调、Th2反应（IL-4）上调			[20]
		日本血吸虫分泌蛋白16（rSj16）	DSS		促凋亡蛋白Bax降低，抗凋亡蛋白Bcl-2升高，miR-217-5p表达降低，肝细胞核因子1β（HNF1B）表达升高，抑制凋亡发生		组织病理学可见炎症减轻，临床表现减轻	[21]
华支睾吸虫 Clonorchis sinensis		华支睾吸虫半胱氨酸蛋白酶（CsCP）、华支睾吸虫粗提取物（CsCA）	DSS		激活TLRs，上调Th2/Treg相关细胞因子IL-10、IL-4和IL-13的表达，减少IL-12b、IL-23r、IL-7和IL-17A的表达，限制Th1/Th17细胞的转化		结肠炎症状改善	[22]
米亚太后殖吸虫 Metagonimus miyatai		囊蚴	DSS		组织中TNF-α、IL-1b和环氧化酶2（COX-2）的表达水平明显降低		临床症状明显减轻，体质量明显增加	[23]
肝片形吸虫 Fasciola hepatica		细胞外囊泡	DSS		促炎因子TNF-α、IL-6和IL-17A 显著下降，P38丝裂原活化蛋白激酶（MAPK）磷酸化和NF-κB表达下降		结肠组织中MPO活性降低，组织学可见中性粒细胞浸润减少	[24]
细粒棘球蚴 Echinococcus granulosus		原头节	DSS		结肠组织内的一氧化氮（NO）、TNF-α、诱导型一氧化氮合酶（iNOS）和NF-κB的表达降低		DAI减轻，组织学评分降低，表现出正常的结肠组织学结构	[27]
	囊液（抗原B）		DSS	M1型巨噬细胞F4/80⁺ CD11c⁺减少，M2型F4/80⁺和CD206⁺比例增加，结肠内iNOS表达降低，抵抗素样分子α（Fizz1）表达增加		临床症状减轻，小鼠肠道菌群改变		[28]
缩小膜壳绦虫 Hymenolepis diminuta	缩小膜壳绦虫抗原（HdAg）		DNBS	诱导IL-10 对巨噬细胞活化的抑制，动员 CD4⁺ CD25⁺ T 细胞的能力		症状严重程度降低		[30]
缩小膜壳绦虫 Hymenolepis diminuta	缩小膜壳绦虫提取物抗原（HdE）		DNBS	IL-4 和 IL-10增多，抗原触发免疫记忆		肠道炎症症状并不明显，可以保护先前寄生虫感染但并非首次感染的小鼠免受结肠炎的影响		[31]
蓝氏贾第鞭毛虫 Giardia lamblia	细胞外囊泡		DSS	降低TNF-α、IL-1β和IFN-γ的表达减轻结肠炎症状		模型小鼠体重恢复，临床症状减轻，炎症细胞浸润减少		[33]
十二指肠贾第鞭毛虫Giardia duodenalis	组织蛋白酶B		LPS	贾第虫与重组组织蛋白酶B刺激能引起p65磷酸化水平上升，有效抑制NF-κB通路		-		[34]
芽囊原虫 Blastocystis	ST4亚型		DSS	提高Foxp3⁺和IL-10的CD4⁺T细胞比例来抑制炎症的产生		促进肠道内益生菌的生长，抑制有害菌		[35]
芽囊原虫 Blastocystis	ST3亚型		DNBS	长期定植后TNF-α和IL-1β基因表达显着减少，而IFN-γ和IL-17re/17C的表达升高		组织学上观察炎症局限化；肠道内细菌种类趋于多样性		[36]
弓形虫 Toxoplasma	ToxoROP16_Ⅰ/Ⅲ		脂多糖（LPS）	M1向M2细胞转化，精氨酸酶-1（Arg-1）、IL-10、TGF-β1、磷酸化信号转导因子和转录激活因子3（p-STAT3）和p-STAT6的产生增加，NO和iNOS减少，减少Caco-2细胞凋亡的发生		-		[37]

表1

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