肠道菌群与异基因干细胞移植后移植物抗宿主病的关系与展望

doi:10.12372/jcp.2023.23e0061

摘要/Abstract

摘要：

异基因造血干细胞移植(allo-HSCT)是一种治疗血液系统恶性肿瘤的策略，尽管近年来该领域取得了巨大进展，但仍存在较高的移植后死亡风险。除了潜在恶性肿瘤复发外，导致这种高死亡风险的主要因素是移植物抗宿主病(GVHD)。目前研究表明，肠道菌群在维持肠道和全身免疫功能方面发挥了重要作用，肠道菌群多样性、产生的代谢产物可直接或间接影响GVHD的发生发展，GVHD也可对肠道干细胞进行靶向损伤从而造成肠道菌群失调。文章概述了目前对肠道菌群与allo-HSCT后GVHD关系的研究，并对目前基于肠道菌群治疗GVHD的方法进行总结与展望。

关键词: 移植物抗宿主病, 肠道菌群, 造血干细胞移植, 治疗

Abstract:

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a strategy for the treatment of hematologic malignancies. Despite the tremendous progress in this field in recent years, there is still a high risk of post-transplant mortality. In addition to potential malignancy recurrence, the main factor contributing to this high mortality is graft-versus-host disease (GVHD). Current studies demonstrate that intestinal microbiota plays an important role in maintaining intestinal and systemic immune function, and that intestinal microbiota diversity and its metabolites can directly or indirectly influence the development of GVHD. GVHD can also damage intestinal stem cells subsequently causing intestinal flora dysbiosis. This article provides an overview of our current research on the relationship between intestinal microbiota and GVHD after allo-HSCT and summarizes current treatments for GVHD based on intestinal microbiota.

Key words: graft-versus-host disease, intestinal microbiota, hematopoietic stem cell transplantation, treatment

吴小艳, 张文知, 彭云. 肠道菌群与异基因干细胞移植后移植物抗宿主病的关系与展望[J]. 临床儿科杂志, 2023, 41(3): 161-166.

WU Xiaoyan, ZHANG Wenzhi, PENG Yun. Relationship between intestinal microbiota and graft-versus-host disease in allogeneic stem cell transplantation and its perspectives[J]. Journal of Clinical Pediatrics, 2023, 41(3): 161-166.

参考文献 54

[1]	Zhang F, Zuo T, Yeoh YK, et al. Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease[J]. Nat Commun, 2021, 12(1): 65. doi: 10.1038/s41467-020-20240-x pmid: 33397897
[2]	Malard F, Gasc C, Plantamura E, et al. High gastrointestinal microbial diversity and clinical outcome in graft-versus-host disease patients[J]. Bone Marrow Transplant, 2018, 53(12): 1493-1497. doi: 10.1038/s41409-018-0254-x
[3]	Ferrara JLM, Chaudhry MS. GVHD: biology matters[J]. Blood Adv, 2018, 2(22): 3411-3417. doi: 10.1182/bloodadvances.2018020214 pmid: 30482771
[4]	Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation[J]. Blood, 2000, 95(9): 2754-2759. pmid: 10779417
[5]	de Vos WM, Tilg H, Van Hul M, et al. Gut microbiome and health: mechanistic insights[J]. Gut, 2022, 71(5): 1020-1032. doi: 10.1136/gutjnl-2021-326789 pmid: 35105664
[6]	Fujiwara H. Crosstalk between intestinal microbiota derived metabolites and tissues in allogeneic hematopoietic cell transplantation[J]. Front Immunol, 2021, 12: 703298. doi: 10.3389/fimmu.2021.703298
[7]	Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease[J]. Nature, 2016, 535(7610): 75-84. doi: 10.1038/nature18848
[8]	Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation[J]. Blood, 2014, 124(7): 1174-1182. doi: 10.1182/blood-2014-02-554725 pmid: 24939656
[9]	Fredricks DN. The gut microbiota and graft-versus-host disease[J]. J Clin Invest, 2019, 129(5): 1808-1817. doi: 10.1172/JCI125797 pmid: 31042160
[10]	Shono Y, van den Brink MRM. Gut microbiota injury in allogeneic haematopoietic stem cell transplantation[J]. Nat Rev Cancer, 2018, 18(5): 283-295. doi: 10.1038/nrc.2018.10 pmid: 29449660
[11]	Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation[J]. N Engl J Med, 2020, 382(9): 822-834. doi: 10.1056/NEJMoa1900623
[12]	Wolfe AE, Markey KA. The contribution of the intestinal microbiome to immune recovery after HCT[J]. Front Immunol, 2022, 13: 988121. doi: 10.3389/fimmu.2022.988121
[13]	Golob JL, Pergam SA, Srinivasan S, et al. Stool microbiota at neutrophil recovery is predictive for severe acute graft vs host disease after hematopoietic cell transplantation[J]. Clin Infect Dis, 2017, 65(12): 1984-1991. doi: 10.1093/cid/cix699 pmid: 29020185
[14]	Sadowska-klasa A, Piekarska A, Prejzne RW, et al. Colonization with multidrug-resistant bacteria increases the risk of complications and a fatal outcome after allogeneic hematopoietic cell transplantation[J]. Ann Hematol, 2017, 97(3): 509-517. doi: 10.1007/s00277-017-3205-5
[15]	Bowerman KL, Varelias A, Lachner N, et al. Continuous pre- and post-transplant exposure to a disease-associated gut microbiome promotes hyper-acute graft-versus-host disease in wild-type mice[J]. Gut Microbes, 2020, 11(4): 754-770. doi: 10.1080/19490976.2019.1705729 pmid: 31928131
[16]	Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease[J]. Biol Blood Marrow Transplant, 2014, 20(5): 640-645. doi: 10.1016/j.bbmt.2014.01.030
[17]	Lindner S, Peled JU. Update in clinical and mouse microbiota research in allogeneic haematopoietic cell transplantation[J]. Curr Opin Hematol, 2020, 27(6): 360-367. doi: 10.1097/MOH.0000000000000616 pmid: 33003084
[18]	Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice[J]. Sci Transl Med, 2016, 8(339): 339ra71.
[19]	Brubaker SW, Bonham KS, Zanoni I, et al. Innate immune pattern recognition: a cell biological perspective[J]. Annu Rev Immunol, 2015, 33: 257-290. doi: 10.1146/annurev-immunol-032414-112240 pmid: 25581309
[20]	Penack O, Peczynski C, van der Werf S, et al. Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation - a prospective, non-interventional study of the EBMT Transplant Complication Working Party[J]. Haematologica, 2019, 105(7): 1977-1983. doi: 10.3324/haematol.2019.228668
[21]	Koehn BH, Saha A, McDonald-hyman C, et al. Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD[J]. Blood, 2019, 134(19): 1670-1682. doi: 10.1182/blood.2019001950 pmid: 31533918
[22]	Li J, Zhang X, Chen Y, et al. A promising insight: the potential influence and therapeutic value of the gut microbiota in GI GVHD[J]. Oxid Med Cell Longev, 2022: 2124627.
[23]	Markey KA, MacDonald KP, Hill GR. The biology of graft-versus-host disease: experimental systems instructing clinical practice[J]. Blood, 2014, 124(3): 354-362. doi: 10.1182/blood-2014-02-514745 pmid: 24914137
[24]	Hong YQ, Wan B, Li XF. Macrophage regulation of graft-vs-host disease[J]. World J Clin Cases, 2020, 8(10): 1793-1805. doi: 10.12998/wjcc.v8.i10.1793
[25]	Nieves EC, Toubai T, Peltier DC, et al. STAT3 expression in host myeloid cells controls graft-versus-host disease severity[J]. Biol Blood Marrow Transplant, 2017, 23(10): 1622-1630. doi: 10.1016/j.bbmt.2017.06.018
[26]	Hill GR, Koyama M. Cytokines and costimulation in acute graft-versus-host disease[J]. Blood, 2020, 136(4): 418-428. doi: 10.1182/blood.2019000952 pmid: 32526028
[27]	Schwab L, Goroncy L, Palaniyandi S, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage[J]. Nat Med, 2014, 20(6): 648-654. doi: 10.1038/nm.3517 pmid: 24836575
[28]	Ara T, Hashimoto D. Novel insights into the mechanism of GVHD-induced tissue damage[J]. Front Immunol, 2021, 12: 713631. doi: 10.3389/fimmu.2021.713631
[29]	Peled JU, Hanash AM, Jenq RR. Role of the intestinal mucosa in acute gastrointestinal GVHD[J]. Hematology, 2016, 2016(1): 119-127. doi: 10.1182/asheducation-2016.1.119
[30]	Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease[J]. Immunity, 2012, 37(2): 339-350. doi: 10.1016/j.immuni.2012.05.028 pmid: 22921121
[31]	Drucker DJ, Habener JF, Holst JJ. Discovery, charac-terization, and clinical development of the glucagon-like peptides[J]. J Clin Invest, 2017, 127(12): 4217-4227. doi: 10.1172/JCI97233 pmid: 29202475
[32]	Connor EE, Evock-Clover CM, Walker MP, et al. COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: Comparative physiology of glucagon-like peptide-2: implications and applications for production and health of ruminants[J]. J Anim Sci, 2015, 93(2): 492-501. doi: 10.2527/jas.2014-8577 pmid: 26020740
[33]	Nguyen CL, Docampo MD, van den Brink MR, et al. The role of the intestinal microbiota in allogeneic HCT: clinical associations and preclinical mechanisms[J]. Curr Opin Genet Dev, 2021, 66: 25-35. doi: 10.1016/j.gde.2020.11.007 pmid: 33388483
[34]	Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism[J]. Gut Microbes, 2016, 7(3): 189-200. doi: 10.1080/19490976.2015.1134082 pmid: 26963409
[35]	Mathewson ND, Jenq R, Mathew AV, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease[J]. Nat Immunol, 2016, 17(5): 505-513. doi: 10.1038/ni.3400 pmid: 26998764
[36]	Ingham AC, Kielsen K, Mordhorst H, et al. Microbiota long-term dynamics and prediction of acute graft-versus-host disease in pediatric allogeneic stem cell transplantation[J]. Microbiome, 2021, 9(1): 148. doi: 10.1186/s40168-021-01100-2 pmid: 34183060
[37]	Kusakabe S, Fukushima K, Maeda T, et al. Pre- and post-serial metagenomic analysis of gut microbiota as a prognostic factor in patients undergoing haematopoietic stem cell transplantation[J]. Br J Haematol, 2020, 188(3): 438-449. doi: 10.1111/bjh.16205
[38]	Stein-thoeringer CK, Nichols KB, Lazrak A, et al. Lactose drives Enterococcus expansion to promote graft-versus-host disease[J]. Science, 2019, 366(6469): 1143-1149. doi: 10.1126/science.aax3760 pmid: 31780560
[39]	Markey KA, Schluter J, Gomes ALC, et al. The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD[J]. Blood, 2020, 136(1): 130-136. doi: 10.1182/blood.2019003369 pmid: 32430495
[40]	Bruno-barcena JM, Azcarate-peril MA. Galacto-oligosaccharides and colorectal cancer: feeding our intestinal probiome[J]. J Funct Foods, 2015, 12: 92-108. pmid: 25584074
[41]	Schwabkey ZI, Jenq RR. Microbiome anomalies in allogeneic hematopoietic cell transplantation[J]. Annu Rev Med, 2020, 71: 137-148. doi: 10.1146/annurev-med-052918-122440 pmid: 31986084
[42]	Ladas EJ, Bhatia M, Chen L, et al. The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation[J]. Bone Marrow Transplant, 2016, 51(2): 262-266. doi: 10.1038/bmt.2015.275
[43]	Gerbitz A, Schultz M, Wilke A, et al. Probiotic effects on experimental graft-versus-host disease: let them eat yogurt[J]. Blood, 2004, 103(11): 4365-4367. doi: 10.1182/blood-2003-11-3769 pmid: 14962899
[44]	Gorshein E, Wei C, Ambrosy S, et al. Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation[J]. Clin Transplant, 2017, 31(5).
[45]	Holscher HD, Faust KL, Czerkies LA, et al. Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial[J]. JPEN J Parenter Enteral Nutr, 2012, 36(1 Suppl): 95S-105S. doi: 10.1177/0148607111430087
[46]	Iyama S, Sato T, Tatsumi H, et al. Efficacy of enteral supplementation enriched with glutamine, fiber, and oligosaccharide on mucosal injury following hematopoietic stem cell transplantation[J]. Case Rep Oncol, 2014, 7(3): 692-699. doi: 10.1159/000368714 pmid: 25493082
[47]	Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections[J]. Am J Gastroenterol, 2013, 108(4): 478-498. doi: 10.1038/ajg.2013.4
[48]	Shouval R, Geva M, Nagler A, et al. Fecal microbiota transplantation for treatment of acute graft-versus-host disease[J]. Clin Hematol Int, 2019, 1(1): 28-35. doi: 10.2991/chi.d.190316.002
[49]	Kakihana K, Fujioka Y, Suda W, et al. Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut[J]. Blood, 2016, 128(16): 2083-2088. doi: 10.1182/blood-2016-05-717652 pmid: 27461930
[50]	van Lier YF, Davids M, Haverkate NJE, et al. Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients[J]. Sci Transl Med, 2020, 12(556): eaaz8926. doi: 10.1126/scitranslmed.aaz8926
[51]	Lee JH, Wood TK, Lee J. Roles of indole as an interspecies and interkingdom signaling molecule[J]. Trends Microbiol, 2015, 23(11): 707-718. doi: 10.1016/j.tim.2015.08.001
[52]	Swimm A, Giver CR, Defilipp Z, et al. Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease[J]. Blood, 2018, 132(23): 2506-2519. doi: 10.1182/blood-2018-03-838193 pmid: 30257880
[53]	Riwes M, Reddy P. Short chain fatty acids: postbiotics/metabolites and graft versus host disease colitis[J]. Semin Hematol, 2020, 57(1): 1-6. doi: S0037-1963(20)30004-4 pmid: 32690138
[54]	Zhao Y, Huang J, Li T, et al. Berberine ameliorates aGVHD by gut microbiota remodelling, TLR4 signalling suppression and colonic barrier repairment for NLRP3 inflammasome inhibition[J]. J Cell Mol Med, 2022, 26(4): 1060-1070. doi: 10.1111/jcmm.17158 pmid: 34984827