肠道微生物酶在ABO通用型红细胞制备中的研究进展

doi:10.3969/j.issn.1671-2587.2025.05.014

临床输血与检验 ›› 2025, Vol. 27 ›› Issue (5): 674-680.DOI: 10.3969/j.issn.1671-2587.2025.05.014

肠道微生物酶在ABO通用型红细胞制备中的研究进展

贺理, 王勇军

中南大学湘雅二医院输血科,湖南长沙 410011

收稿日期:2025-09-01 修回日期:2025-09-12 出版日期:2025-10-20 发布日期:2025-10-11
通讯作者: 王勇军,主要从事临床输血技术检测与临床用血管理研究,（E-mail）wangyongjun@csu.edu.cn。
作者简介:贺理,主要从事临床输血与免疫学诊断研究,（E-mail）heli@csu.edu.cn。

Research Progress on Gut Microbial Enzymes in the Preparation of ABO Universal Red Blood Cells

HE Li, WANG Yongjun

Department of Blood Transfusion, Xiangya Second Hospital of Central South University, Changsha, 410011

Received:2025-09-01 Revised:2025-09-12 Online:2025-10-20 Published:2025-10-11

摘要/Abstract

摘要： ABO通用型红细胞制备技术不仅能有效缓解因献血者ABO血型分布不均导致的血液供应紧张,还可显著降低由输血前检测带来的资源消耗以及人为操作失误所致的输血风险,是输血医学领域中具有重大临床价值的突破性技术。其中,酶法转化制备ABO通用型红细胞是目前唯一经过初步临床验证的安全有效途径。然而,筛选适用于制备ABO通用型红细胞的高效且特异的酶,仍是当前亟待解决的关键问题。本综述聚焦于肠道微生物酶在ABO通用型红细胞制备中的应用价值,将系统阐述以下内容：ABO血型抗原特点、酶法制备ABO通用型红细胞的原理与临床试验进展、降解A和B抗原的肠道微生物酶,以及该类酶在ABO通用型红细胞制备中的探索。

关键词: ABO血型, 通用型红细胞, 肠道菌群, 微生物酶, 酶转化O型红细胞

Abstract: The technology for preparing ABO universal red blood cells (RBCs) not only effectively alleviates blood supply shortages caused by the uneven distribution of ABO blood types among donors, but also significantly reduces resource consumption from pre-transfusion testing and transfusion risks due to human operational errors. It represents a breakthrough technology of significant clinical value in the field of transfusion medicine. Among these approaches, enzymatic conversion is currently the only method for preparing ABO-universal RBCs that has undergone preliminary clinical validation as safe and effective. However, screening for highly efficient and specific enzymes suitable for this purpose remains a critical challenge that requires urgent resolution. This review focuses on the application value of gut microbial enzymes in the preparation of ABO universal RBCs. It systematically elaborates on the following aspects: the characteristics of ABO blood group antigens, the principles and clinical trial progress of enzymatic preparation of ABO universal RBCs, gut microbial enzymes degrading A and B antigens, and the exploration of such enzymes in the production of ABO-universal RBCs.

Key words: ABO blood group, Universal red blood cells, Gut microbiota, Microbial enzymes, Enzyme-converted group O RBCs

中图分类号:

R457

贺理, 王勇军. 肠道微生物酶在ABO通用型红细胞制备中的研究进展[J]. 临床输血与检验, 2025, 27(5): 674-680.

HE Li, WANG Yongjun. Research Progress on Gut Microbial Enzymes in the Preparation of ABO Universal Red Blood Cells[J]. JOURNAL OF CLINICAL TRANSFUSION AND LABORATORY MEDICINE, 2025, 27(5): 674-680.

参考文献

[1] SENDER R,FUCHS S,MILO R.Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans[J]. Cell,2016,164(3):337-340.
[2] D'ARGENIO V,SALVATORE F. The role of the gut microbiome in the healthy adult status[J]. Clin Chim Acta, 2015,451(Pt A):97-102.
[3] HADERER M,NEUBERT P,RINNER E,et al.Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases[J]. Gut,2022,71(3):580-592.
[4] BRUCE-KELLER A J,SALBAUM J M,BERTHOUD H R. Harnessing gut microbes for mental health: getting from here to there[J]. Biol Psychiatry,2018,83(3):214-223.
[5] BERLEMONT R,MARTINY A C.Glycoside hydrolases across environmental microbial communities[J]. PLoS Comput Biol,2016,12(12):e1005300.
[6] HOSKINS L C,BOULDING E T.Degradation of blood group antigens in human colon ecosystems. I. In vitro production of ABH blood group-degrading enzymes by enteric bacteria[J]. J Clin Invest,1976,57(1):63-73.
[7] HOSOI E.Biological and clinical aspects of ABO blood group system[J]. J Med Invest,2008,55(3/4):174-182.
[8] CHESTER M A,OLSSON M L.The ABO blood group gene: a locus of considerable genetic diversity[J]. Transfus Med Rev,2001,15(3):177-200.
[9] DANIELS G.ABO, H,Lewis Systems[M]//Human Blood Groups,3rd edition.2013: 11-95.
[10] HAKOMORI S.Antigen structure and genetic basis of histo-blood groups A,B and O: their changes associated with human cancer[J]. Biochim Biophys Acta,1999, 1473(1):247-266.
[11] LLOYD K O.The chemistry and immunochemistry of blood group A,B,H,and Lewis antigens: past,present and future[J]. Glycoconj J,2000,17(7/8/9):531-541.
[12] GOLDSTEIN J,SIVIGLIA G,HURST R,et al.Group B erythrocytes enzymatically converted to group O survive normally in A,B,and O individuals[J]. Science,1982, 215(4529):168-170.
[13] LENNY L L,HURST R,GOLDSTEIN J,et al.Single-unit transfusions of RBC enzymatically converted from group B to group O to a and O normal volunteers[J]. Blood, 1991,77(6):1383-1388.
[14] LENNY L L,HURST R,GOLDSTEIN J,et al.Transfusions to group O subjects of 2 units of red cells enzymatically converted from group B to group O[J]. Transfusion,1994,34(3):209-214.
[15] LENNY L L,HURST R,ZHU A,et al.Multiple-unit and second transfusions of red cells enzymatically converted from group B to group O: report on the end of phase 1 trials[J]. Transfusion,1995,35(11):899-902.
[16] KRUSKALL M S,AUBUCHON J P,ANTHONY K Y, et al.Transfusion to blood group A and O patients of group B RBCs that have been enzymatically converted to group O[J]. Transfusion,2000,40(11):1290-1298.
[17] DOMINGUEZ-BELLO M G,GODOY-VITORINO F, KNIGHT R,et al. Role of the microbiome in human development[J]. Gut,2019,68(6):1108-1114.
[18] MCNEIL N I.The contribution of the large intestine to energy supplies in man[J]. Am J Clin Nutr,1984, 39(2):338-342.
[19] GUETTERMAN H M,HUEY S L,KNIGHT R,et al.Vitamin B-12 and the gastrointestinal microbiome: a systematic review[J]. Adv Nutr,2022,13(2):530-558.
[20] GUSTAFSSON J K,ERMUND A,JOHANSSON M E V,et al. An ex vivo method for studying mucus formation,properties,and thickness in human colonic biopsies and mouse small and large intestinal explants[J]. Am J Physiol Gastrointest Liver Physiol,2012,302(4):G430-G438.
[21] LUIS A S,HANSSON G C.Intestinal mucus and their glycans: A habitat for thriving microbiota[J]. Cell Host Microbe,2023,31(7):1087-1100.
[22] ROSSEZ Y,MAES E,LEFEBVRE DARROMAN T,et al.Almost all human gastric mucin O-glycans harbor blood group A,B or H antigens and are potential binding sites for Helicobacter pylori[J]. Glycobiology,2012, 22(9):1193-1206.
[23] HEGGELUND J E,VARROT A,IMBERTY A,et al.Histo-blood group antigens as mediators of infections[J]. Curr Opin Struct Biol,2017,44:190-200.
[24] YANG H,WU J Y,HUANG X C,et al.ABO genotype alters the gut microbiota by regulating GalNAc levels in pigs[J]. Nature,2022,606(7913):358-367.
[25] HOSKINS L C,AGUSTINES M,MCKEE W B,et al.Mucin degradation in human colon ecosystems. Isolation and properties of fecal strains that degrade ABH blood group antigens and oligosaccharides from mucin glycoproteins[J]. J Clin Invest,1985,75(3):944-953.
[26] EL KAOUTARI A,ARMOUGOM F,GORDON J I, et al.The abundance and variety of carbohydrate-active enzymes in the human gut microbiota[J]. Nat Rev Microbiol, 2013,11(7):497-504.
[27] IKEGAYA M,MIYAZAKI T,PARK E Y.Biochemical characterization of Bombyx mori α-N-acetylgalactosaminidase belonging to the glycoside hydrolase family 31[J]. Insect Mol Biol,2021,30(4):367-378.
[28] MIYAZAKI T,PARK E Y.Crystal structure of the Enterococcus faecalis α-N-acetylgalactosaminidase,a member of the glycoside hydrolase family 31[J]. FEBS Lett,2020,594(14):2282-2293.
[29] CALCUTT M J,HSIEH H Y,CHAPMAN L F,et al.Identification,molecular cloning and expression of an alpha-N-acetylgalactosaminidase gene from Clostridium perfringens[J]. FEMS Microbiol Lett,2002,214(1):77-80.
[30] HSIEH H Y,CALCUTT M J,CHAPMAN L F,et al.Purification and characterization of a recombinant alpha-N-acetylgalactosaminidase from Clostridium perfringens[J]. Protein Expr Purif,2003,32(2):309-316.
[31] RAHFELD P,SIM L,MOON H,et al.An enzymatic pathway in the human gut microbiome that converts A to universal O type blood[J]. Nat Microbiol,2019,4(9):1475-1485.
[32] JENSEN M,STENFELT L,RICCI HAGMAN J,et al.Akkermansia muciniphila exoglycosidases target extended blood group antigens to generate ABO-universal blood[J]. Nat Microbiol,2024,9(5):1176-1188.
[33] FUJITA K,OURA F,NAGAMINE N,et al.Identification and molecular cloning of a novel glycoside hydrolase family of core 1 type O-glycan-specific endo-alpha-N-acetylgalactosaminidase from Bifidobacterium longum[J]. J Biol Chem,2005,280(45):37415-37422.
[34] KATAYAMA T,FUJITA K,YAMAMOTO K.Novel bifidobacterial glycosidases acting on sugar chains of mucin glycoproteins[J]. J Biosci Bioeng,2005,99(5):457-465.
[35] KULINICH A,WANG Q,DUAN X C,et al.Biochemical characterization of the endo-α-N-acetylgalactosaminidase pool of the human gut symbiont Tyzzerella Nexilis[J]. Carbohydr Res,2020,490:107962.
[36] KOUTSIOULIS D,LANDRY D,GUTHRIE E P.Novel endo-alpha-N-acetylgalactosaminidases with broader substrate specificity[J]. Glycobiology,2008,18(10):799-805.
[37] RAHFELD P,WARDMAN J F,MEHR K,et al.Prospecting for microbial α-N-acetylgalactosaminidases yields a new class of GH31 O-glycanase[J]. J Biol Chem,2019,294(44):16400-16415.
[38] KIYOHARA M,NAKATOMI T,KURIHARA S,et al.α-N-acetylgalactosaminidase from infant-associated bifidobacteria belonging to novel glycoside hydrolase family 129 is implicated in alternative mucin degradation pathway[J]. J Biol Chem,2012,287(1):693-700.
[39] CHAKLADAR S,CHENG L,CHOI M,et al.Mechanistic evaluation of MelA α-galactosidase from Citrobacter freundii: a family 4 glycosyl hydrolase in which oxidation is rate-limiting[J]. Biochemistry,2011,50(20):4298-4308.
[40] NAGAO Y,NAKADA T,IMOTO M,et al.Purification and analysis of the structure of alpha-galactosidase from Escherichia coli[J]. Biochem Biophys Res Commun,1988,151(1): 236-241.
[41] ZHANG X L,VRIJENHOEK J E P,BONTEN M J M, et al. A genetic element present on megaplasmids allows Enterococcus faecium to use raffinose as carbon source[J]. Environ Microbiol,2011,13(2):518-528.
[42] IKEGAYA M,PARK E Y,MIYAZAKI T.Structure-function analysis of bacterial GH31 α-galactosidases specific for α-(1→4)-galactobiose[J]. FEBS J,2023,290(20):4984-4998.
[43] REDDY S K,BÅGENHOLM V,PUDLO N A,et al. A β-mannan utilization locus in Bacteroides ovatus involves a GH36 α-galactosidase active on galactomannans[J]. FEBS Lett,2016,590(14):2106-2118.
[44] HELBERT W,POULET L,DROUILLARD S,et al.Discovery of novel carbohydrate-active enzymes through the rational exploration of the protein sequences space[J]. Proc Natl Acad Sci USA,2019,116(13):6063-6068.
[45] LEDER S,HARTMEIER W,MARX S P.Alpha-galactosidase of Bifidobacterium adolescentis DSM 20083[J]. Curr Microbiol,1999,38(2):101-106.
[46] ZHAO H,LU L L,XIAO M,et al.Cloning and characterization of a novel alpha-galactosidase from Bifidobacterium breve 203 capable of synthesizing Gal-alpha-1,4 linkage[J]. FEMS Microbiol Lett,2008,285(2):278-283.
[47] SHIN Y J,WOO S H,JEONG H M,et al.Characterization of novel α-galactosidase in glycohydrolase family 97 from Bacteroides thetaiotaomicron and its immobilization for industrial application[J]. Int J Biol Macromol,2020,152:727-734.
[48] LIU Q P,SULZENBACHER G,YUAN H P,et al.Bacterial glycosidases for the production of universal red blood cells[J]. Nat Biotechnol,2007,25(4):454-464.
[49] LIU Q P,YUAN H P,BENNETT E P,et al.Identification of a GH110 subfamily of alpha 1,3-galactosidases: novel enzymes for removal of the alpha 3Gal xenotransplantation antigen[J]. J Biol Chem,2008,283(13):8545-8554.
[50] WAKINAKA T,KIYOHARA M,KURIHARA S, et al.Bifidobacterial α-galactosidase with unique carbohydrate-binding module specifically acts on blood group B antigen[J]. Glycobiology,2013,23(2):232-240.
[51] MÖLLER C,TERHOLSEN H,SCHMÖKER O,et al. Identification and protein engineering of galactosidases for the conversion of blood type B to blood type O[J]. Chembiochem,2025,26(7):e202500072.
[52] GOLDSTEIN J.Conversion of ABO blood groups[J]. Transfus Med Rev,1989,3(3):206-212.
[53] MACMILLAN S,HOSGOOD S A,WALKER-PANSE L, et al.Enzymatic conversion of human blood group A kidneys to universal blood group O[J]. Nat Commun, 2024,15(1):2795.
[54] GARRATTY G.Modulating the red cell membrane to produce universal/stealth donor red cells suitable for transfusion[J]. Vox Sang,2008,94(2):87-95.
[55] ZENG J,MA M,JIANG X J,et al.Enzymatic conversion of blood group B kidney prevents hyperacute antibody-mediated injuries in ABO-incompatible transplantation[J]. Nat Commun,2025,16(1):1506.
[56] Abstract of 29th regional congress of the ISBT[J]. Vox Sang,2019,114(S1):5-240.
[57] OLSSON M L,CLAUSEN H.Modifying the red cell surface: towards an ABO-universal blood supply[J]. Br J Haematol,2008,140(1):3-12.

肠道微生物酶在ABO通用型红细胞制备中的研究进展

Research Progress on Gut Microbial Enzymes in the Preparation of ABO Universal Red Blood Cells

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

关于本刊

作者中心

在线期刊

访问统计

联系我们

[1]	王欣蕊, 杨洪燕, 秦冉冉, 高雨菡, 侯瑞琴. 红细胞ABO血型抗原减弱或缺失机制的研究进展[J]. 临床输血与检验, 2025, 27(5): 689-694.
[2]	许海艳, 张一宁, 梁燕, 邢艳, 许亚莉, 崔颖. 7 567例恶性肿瘤住院患者ABO血型、Rh表型及不规则抗体的分布与回顾性分析^*[J]. 临床输血与检验, 2025, 27(4): 462-469.
[3]	张咏, 耿良权, 强萍, 范倩, 刘会兰. ABO血型主要及双向不合对757例非血缘脐血移植结局的影响分析^*[J]. 临床输血与检验, 2025, 27(4): 518-525.
[4]	梁爽, 马雅琳, 吴凡, 刘通, 孙丽艳, 汤戎, 曾劲峰. ABO基因c.213-217delC单碱基缺失导致O表型的分析^*[J]. 临床输血与检验, 2025, 27(4): 526-529.
[5]	李峣, 史鸣昊, 沈忠军, 王欣, 赵丽艳. ABO基因启动子甲基化在肿瘤患者ABO血型抗原表达减弱中的作用和机制的研究进展^*[J]. 临床输血与检验, 2025, 27(2): 283-288.
[6]	李国才, 桂嵘, 黄雪原, 屈琳, 周雄辉, 刘凤霞. 湖南省ABO血型分布及其与恶性肿瘤的相关性分析^*[J]. 临床输血与检验, 2025, 27(1): 70-75.
[7]	李艳, 周丽玲, 马肇泽, 祝凯捷, 王辰龙. 25例B亚型/AB亚型的ABO基因序列分析^*[J]. 临床输血与检验, 2024, 26(6): 787-791.
[8]	庄金木, 周世乔. ABO血型不相合血小板输注的临床效果与安全性研究[J]. 临床输血与检验, 2024, 26(4): 516-520.
[9]	杨昊, 董树岭, 杨乾坤, 韩月, 王书亚, 靳慧芳, 郑露, 唐悦. 双重滤过血浆置换和血浆置换对ABO血型不容肾移植受者术前血型抗体去除效果单中心对比研究^*[J]. 临床输血与检验, 2024, 26(3): 325-331.
[10]	阳雪新, 魏亚明. ABO非同型血小板输注的现状及建议^*[J]. 临床输血与检验, 2024, 26(1): 17-22.
[11]	阳雪新, 袁咏梅, 吴兆勇, 苑召虎, 刘珍, 童欣欣, 陈小卫, 魏亚明. ABO次侧不相合血小板输注的有效性和安全性初步研究^*[J]. 临床输血与检验, 2024, 26(1): 42-48.
[12]	杨牧云, 邓红英, 张杰, 戴万案. 恩施土家族苗族地区患者ABO正反定型不符原因及分子生物学分析[J]. 临床输血与检验, 2023, 25(6): 773-777.
[13]	徐晶, 杜忻, 陈佳, 余真强, 徐晓琴. 1例B/O嵌合血型献血者的测序结果分析及临床输血策略[J]. 临床输血与检验, 2023, 25(6): 845-847.
[14]	尤来委, 程勇, 郭建荣. ABO血型对癌症患者静脉血栓栓塞症影响的研究进展^*[J]. 临床输血与检验, 2023, 25(6): 857-861.
[15]	异基因造血干细胞移植临床输血专家共识起草专家组. 异基因造血干细胞移植临床输血专家共识[J]. 临床输血与检验, 2023, 25(5): 586-593.