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

参考文献 44

[1]	Qin GN, Liu YY, Gao N, et al. Experience of ZHANG Boli in staged treating very early onset inflammatory bowel disease based on the theory of “similar diseases and syndromes of damp-turbidity-phlegm-rheum”[J]. J Tradit Chin Med, 2023, 64(22): 2282-2286. (in Chinese)
	(秦广宁, 刘耀远, 高宁, 等. 张伯礼基于“湿浊痰饮类病”学说分期论治极早发型炎症性肠病经验[J]. 中医杂志, 2023, 64(22): 2282-2286.)
[2]	Shao BL, Yang WJ, Cao Q. Landscape and predictions of inflammatory bowel disease in China: China will enter the compounding prevalence stage around 2030[J]. Front Public Health, 2022, 10: 1032679.
[3]	Li MR, Li YX, Lin XF, et al. Research progress on the interaction mechanism between parasites and gut microbiota[J]. China Anim Husb Vet Med, 2023, 50(3): 1129-1139. (in Chinese)
	(李梦蕊, 李永霞, 林晓凤, 等. 寄生虫与肠道菌群互作机制研究进展[J]. 中国畜牧兽医, 2023, 50(3): 1129-1139.) doi: 10.16431/j.cnki.1671-7236.2023.03.027
[4]	Buitrago G, Pickering D, Ruscher R, et al. A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis[J]. Transl Res, 2021, 232: 88-102.
[5]	Leonardi I, Gerstgrasser A, Schmidt TSB, et al. Preventive Trichuris suis ova (TSO) treatment protects immunocompetent rabbits from DSS colitis but may be detrimental under conditions of immunosuppression[J]. Sci Rep, 2017, 7(1): 16500.
[6]	Yang Y, Liu L, Liu XL, et al. Extracellular vesicles derived from Trichinella spiralis muscle larvae ameliorate TNBS-induced colitis in mice[J]. Front Immunol, 2020, 11: 1174.
[7]	Pang JD, Ding J, Zhang LX, et al. Effect of recombinant serine protease from adult stage of Trichinella spiralis on TNBS-induced experimental colitis in mice[J]. Int Immunopharmacol, 2020, 86: 106699.
[8]	Ma ZR, Li ZL, Zhang N, et al. Inhibition of GSDMD-mediated pyroptosis triggered by Trichinella spiralis intervention contributes to the alleviation of DSS-induced ulcerative colitis in mice[J]. Parasit Vectors, 2023, 16(1): 280.
[9]	Long SR, Liu RD, Kumar DV, et al. Immune protection of a helminth protein in the DSS-induced colitis model in mice[J]. Front Immunol, 2021, 12: 664998.
[10]	Hao CY, Wang W, Zhan B, et al. Trichinella spiralis paramyosin induces colonic regulatory T cells to mitigate inflammatory bowel disease[J]. Front Cell Dev Biol, 2021, 9: 695015.
[11]	Cook L, Reid KT, Häkkinen E, et al. Induction of stable human FOXP3⁺ Tregs by a parasite-derived TGF-β mimic[J]. Immunol Cell Biol, 2021, 99(8): 833-847.
[12]	Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(1): 56-66. doi: 10.1038/s41575-020-00360-x pmid: 33033392
[13]	Progatzky F, Shapiro M, Chng SH, et al. Regulation of intestinal immunity and tissue repair by enteric glia[J]. Nature, 2021, 599(7883): 125-130.
[14]	Maruszewska-Cheruiyot M, Szewczak L, Krawczak-Wójcik K, et al. The impact of intestinal inflammation on nematode’s excretory-secretory proteome[J]. Int J Mol Sci, 2023, 24(18): 14127.
[15]	Taghipour N, Mosaffa N, Aghdaei HA, et al. Immunomodulatory effect of Syphacia obvelata in treatment of experimental DSS-induced colitis in mouse model[J]. Sci Rep, 2019, 9(1): 19127.
[16]	Cobos C, Bansal PS, Wilson DT, et al. Peptides derived from hookworm anti-inflammatory proteins suppress inducible colitis in mice and inflammatory cytokine production by human cells[J]. Front Med, 2022, 9: 934852.
[17]	Xu X, Wen X, Chi Y, et al. Activation-induced T helper cell death contributes to Th1/Th2 polarization following murine Schistosoma japonicum infection[J]. J Biomed Biotechnol, 2010, 2010: 202397.
[18]	Zhou HL, Zeng XJ, Sun DC, et al. Monosexual cercariae of Schistosoma japonicum infection protects against DSS-induced colitis by shifting the Th1/Th2 balance and modulating the gut microbiota[J]. Front Microbiol, 2020, 11: 606605.
[19]	Zhu TY, Xue QK, Liu YY, et al. Analysis of intestinal microflora and metabolites from mice with DSS-induced IBD treated with Schistosoma soluble egg antigen[J]. Front Cell Dev Biol, 2021, 9: 777218.
[20]	Li L, Chen X, Wu Y, et al. Schistosoma japonicum soluble egg antigens ameliorate experimental colitis in murine model[J]. Acta Univ Med Anhui, 2018, 53(10): 1556-1561. (in Chinese)
	(李路, 陈熙, 武艺, 等. 日本血吸虫虫卵可溶性抗原抑制TNBS小鼠结肠炎的实验研究[J]. 安徽医科大学学报, 2018, 53(10): 1556-1561.)
[21]	Zhang LC, Wu XY, Yang RB, et al. Recombinant protein Schistosoma japonicum-derived molecule attenuates dextran sulfate sodium-induced colitis by inhibiting miRNA-217-5p to alleviate apoptosis[J]. World J Gastroenterol, 2021, 27(46): 7982-7994.
[22]	Xie XY, Wu ZS, Wu YH, et al. Cysteine protease of Clonorchis sinensis alleviates DSS-induced colitis in mice[J]. PLoS Negl Trop Dis, 2022, 16(9): e0010774.
[23]	Lee MR, Jeong YI, Kim HJ, et al. Metagonimus miyatai ameliorates dextran sodium sulfate-induced colitis in mice[J]. Parasitol Int, 2020, 74: 101924.
[24]	Roig J, Saiz ML, Galiano A, et al. Extracellular vesicles from the helminth Fasciola hepatica prevent DSS-induced acute ulcerative colitis in a T-lymphocyte independent mode[J]. Front Microbiol, 2018, 9: 1036.
[25]	Li XR, Yan HB, Li L, et al. Advances in genomics research on tapeworms[J]. Chin J Zoonoses, 2021, 37(2): 152-158. (in Chinese)
	(李秀荣, 闫鸿斌, 李立, 等. 绦虫基因组学研究进展[J]. 中国人兽共患病学报, 2021, 37(2): 152-158.)
[26]	Xilizati KLX, Wang CS, Wang JL, et al. Bioinformatics analysis of the sensitization mechanisms and molecular targets of Echinococcus granulosus[J]. Chin J Parasitol Parasit Dis, 2022, 40(3): 319-323. (in Chinese)
	(西力扎提•库来西, 王春生, 王佳玲, 等. 细粒棘球蚴致敏反应机制和分子靶标的生物信息学分析[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(3): 319-323.) doi: 10.12140/j.issn.1000-7423.2022.03.006
[27]	Khelifi L, Soufli I, Labsi M, et al. Immune-protective effect of echinococcosis on colitis experimental model is dependent of down regulation of TNF-α and NO production[J]. Acta Trop, 2017, 166: 7-15. doi: S0001-706X(16)30517-4 pmid: 27983971
[28]	Bao JL, Qi WJ, Sun C, et al. Echinococcus granulosus sensu stricto and antigen B may decrease inflammatory bowel disease through regulation of M1/2 polarization[J]. Parasit Vectors, 2022, 15(1): 391.
[29]	Weinstock JV, Elliott DE. Helminth infections decrease host susceptibility to immune-mediated diseases[J]. J Immunol, 2014, 193(7): 3239-3247. doi: 10.4049/jimmunol.1400927 pmid: 25240019
[30]	Reyes JL, Lopes F, Leung G, et al. Macrophages treated with antigen from the tapeworm Hymenolepis diminuta condition CD25⁺ T cells to suppress colitis[J]. FASEB J, 2019, 33(4): 5676-5689. doi: 10.1096/fj.201802160R pmid: 30668930
[31]	Arai T, Lopes F, Shute A, et al. Young mice expel the tapeworm Hymenolepis diminuta and are protected from colitis by triggering a memory response with worm antigen[J]. Am J Physiol Gastrointest Liver Physiol, 2018, 314(4): G461-G470.
[32]	Liu B, Wang Q, He YJ, et al. Research progress on immune regulation of medical protozoa-related proteins[J]. Chin J Parasitol Parasit Dis, 2021, 39(1): 112-119. (in Chinese)
	(刘冰, 王奇, 贺拥军, 等. 医学原虫相关蛋白的免疫调节作用研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(1): 112-119.) doi: 10.12140/j.issn.1000-7423.2021.01.017
[33]	Kim HJ, Lee YJ, Back SO, et al. Treatment with extracellular vesicles from Giardia lamblia alleviates dextran sulfate sodium-induced colitis in C57BL/6 mice[J]. Korean J Parasitol, 2022, 60(5): 309-315.
[34]	Xing XP. The research on alleviation of LPS-induced intestinal inflammation by treatment with Giardia duodenalis in intestinal epithelial cells[D]. Harbin:Northeast Agricultural University, 2021: Ⅰ- Ⅱ. (in Chinese)
	(邢熙萍. 十二指肠贾第虫对LPS诱导肠上皮细胞炎症缓解作用的研究[D]. 哈尔滨: 东北农业大学, 2021: Ⅰ- Ⅱ.)
[35]	Deng L, Wojciech L, Png CW, et al. Colonization with two different Blastocystis subtypes in DSS-induced colitis mice is associated with strikingly different microbiome and pathological features[J]. Theranostics, 2023, 13(3): 1165-1179. doi: 10.7150/thno.81583 pmid: 36793854
[36]	Billy V, Lhotská Z, Jirků M, et al. Blastocystis colonization alters the gut microbiome and, in some cases, promotes faster recovery from induced colitis[J]. Front Microbiol, 2021, 12: 641483.
[37]	Xu YW, Xing RX, Zhang WH, et al. Toxoplasma ROP16_Ⅰ/Ⅲameliorated inflammatory bowel diseases via inducing M2 phenotype of macrophages[J]. World J Gastroenterol, 2019, 25(45): 6634-6652.
[38]	Chen YY, Wang XT, Dai Y, et al. Progress on the intervention of inflammatory conditions by helminthes and their derived molecules[J]. Chin J Parasitol Parasit Dis, 2021, 39(3): 380-385. (in Chinese)
	(陈玉莹, 王晓婷, 戴洋, 等. 蠕虫及其来源分子干预炎症性疾病的研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(3): 380-385.) doi: 10.12140/j.issn.1000-7423.2021.03.014
[39]	Summers RW, Elliott DE, Qadir K, et al. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease[J]. Am J Gastroenterol, 2003, 98(9): 2034-2041. pmid: 14499784
[40]	Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy in Crohn’s disease[J]. Gut, 2005, 54(1): 87-90. doi: 10.1136/gut.2004.041749 pmid: 15591509
[41]	Summers RW, Elliott DE, Urban JF Jr, et al. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial[J]. Gastroenterology, 2005, 128(4): 825-832. doi: 10.1053/j.gastro.2005.01.005 pmid: 15825065
[42]	Schölmerich J, Fellermann K, Seibold FW, et al. A randomised, double-blind, placebo-controlled trial of Trichuris suis ova in active Crohn’s disease[J]. J Crohns Colitis, 2017, 11(4): 390-399. doi: 10.1093/ecco-jcc/jjw184 pmid: 27707789
[43]	Capron M, Béghin L, Leclercq C, et al. Safety of P28GST, a protein derived from a schistosome helminth parasite, in patients with Crohn’s disease: a pilot study (ACROHNEM)[J]. J Clin Med, 2019, 9(1): 41.
[44]	Strachan DP. Hay fever, hygiene, and household size[J]. BMJ, 1989, 299(6710): 1259-1260. doi: 10.1136/bmj.299.6710.1259 pmid: 2513902