异基因造血干细胞移植术后微生物多样性的变化与肠道移植物抗宿主病的关系
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摘要
目的:探讨异基因造血干细胞移植术后患者肠道微生物多样性的变化及其与肠道(gastrointestinal,GI)移植物抗宿主病(graft-versus-host disease,GVHD)的关系。方法:收集65例血液病患者移植前2周(移植前组),移植后1个月(移植后组)及GI GVHD发生时的粪便样品;同时收集26例供者及10例健康人(对照组)的粪便样品;提取粪便微生物中的16S rRNA并扩增其V4可变区,扩增产物在Illumina HiSeq 2500平台测序,对测序结果进行分析对比。结果:移植前组微生物多样性为5.70(3.74,10.60),对照组为7.30(4.89,11.41),2组比较差异无统计学意义;移植后组微生物多样性为3.88(2.39,6.49),低于对照组及移植前组。移植后微生物多样性在不发生GI GVHD的患者中为4.24(2.47,7.16),随后发生GI GVHD的患者中为2.90(1.48,5.64),2组比较差异无统计学意义;GI GVHD发生时的患者中微生物多样性为2.13(1.76,3.75),低于不发生GI GVHD的患者。结论:异基因造血干细胞移植术后肠道微生物多样性降低,并与GI GVHD相关。
Objective: To investigate the change of microbial diversity and its relation with gastrointestinal(GI) graft-versus-host disease(GVHD) following allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: Fecal samples were collected at the time point of 2 weeks before transplantation(pre-transplant group), 1 month after transplantation(post-tranplant group) and onset of GI GVHD in 65 hematonosis patients, which were also collected in 26 donors and 10 healthy subjects(control group). 16 S rRNA was extracted from fecal microbiotas whose V4 variable region was amplified. The amplification products were sequenced in Illumina HiSeq 2500 platform, and the sequencing results were analyzed and compared. Results: The microbial diversity was 5.70(3.74, 10.60)in pre-transplant group, 7.30(4.89, 11.41)in control group, and the differences between them were not statistically significant. The microbial diversity was 3.88(2.39, 6.49)in post-transplant group, lower than that in control group and pre-transplant group. After transplantation, the microbial diversity was 4.24(2.47, 7.16)in the patients without GI GVHD, while the microbial diverosity was 2.90(1.48, 5.64) in patients subsequently suffered from GI GVHD, but the differences between them were not statistically significant. The microbial diversity was 2.13(1.76, 3.75)onset of GI GVHD, which was lower than that without GI GVHD. Conclusion: Intestinal microbial diversity decreases after allo-HSCT, and is associated with with Gl GVHD.
Objective: To investigate the change of microbial diversity and its relation with gastrointestinal(GI) graft-versus-host disease(GVHD) following allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: Fecal samples were collected at the time point of 2 weeks before transplantation(pre-transplant group), 1 month after transplantation(post-tranplant group) and onset of GI GVHD in 65 hematonosis patients, which were also collected in 26 donors and 10 healthy subjects(control group). 16 S rRNA was extracted from fecal microbiotas whose V4 variable region was amplified. The amplification products were sequenced in Illumina HiSeq 2500 platform, and the sequencing results were analyzed and compared. Results: The microbial diversity was 5.70(3.74, 10.60)in pre-transplant group, 7.30(4.89, 11.41)in control group, and the differences between them were not statistically significant. The microbial diversity was 3.88(2.39, 6.49)in post-transplant group, lower than that in control group and pre-transplant group. After transplantation, the microbial diversity was 4.24(2.47, 7.16)in the patients without GI GVHD, while the microbial diverosity was 2.90(1.48, 5.64) in patients subsequently suffered from GI GVHD, but the differences between them were not statistically significant. The microbial diversity was 2.13(1.76, 3.75)onset of GI GVHD, which was lower than that without GI GVHD. Conclusion: Intestinal microbial diversity decreases after allo-HSCT, and is associated with with Gl GVHD.
引文
1 Kakihana K,Fujioka Y,Suda W,et al.Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut.Blood,2016;128(16):2083-2088.
2 Whangbo J,Ritz J,Bhatt A.Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant,2017;52(2):183-190.
3 Taur Y,Jenq RR,Perales MA,et al.The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.Blood,2014;124(7):1174-1182.
4 Jenq RR,Taur Y,Devlin SM,et al.Intestinal Blautia is associated with reduced death from graft-versus-host disease.Biol Blood Marrow Transplant,2015;21(8):1373-1383.
5 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-versushost disease.Biol Blood Marrow Transplant,2014;20(5):640-645.
6 Jenq RR,Ubeda C,Taur Y,et al.Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation.J Exp Med,2012;209(5):903-911.
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9贾晋松,黄晓军,刘代红,等.异基因造血干细胞移植过程中患者艰难梭菌感染与肠道微生态失调关系的临床研究.中国实验血液学杂志,2008;16(1):135-139.
10 Salazar N,Valdes-Varela L,Gonzalez S,et al.Nutrition and the gut microbiome in the elderly.Gut Microbes,2017;8(2):82-97.
11 Dethlefsen L,Huse S,Sogin ML,et al.The pervasive effects of an antibiotic on the human gut microbiota,as revealed by deep 16SrRNA sequencing.PLoS Biol,2008;6(11):e280.
12 Sanchez B,Gueimonde M,Pena AS,et al.Intestinal microbiota as modulators of the immune system.J Immunol Res,2015;2015:159094.
13 Shono K,Docampo MD,Peled JU,et al.Intestinal microbiotarelated effects on graft-versus-host disease.Int J Hematol.2015;101(5):428-437.
14吕梦楠,韩明哲.肠道微生物与移植物抗宿主病研究进展.中华血液学杂志,2017;38(12):1085-1088.
15 Staffas A,Burgos da Silva M,van den Brink MR.The intestinal microbiota in allogeneic hematopoietic cell transplant and graftversus-host disease.Blood,2017;129(8):927-933.
16李宁.肠道菌群紊乱与粪菌移植.肠外与肠内营养,2014;21(4):193-197.
17 Spindelboeck W,Schulz E,Uhl B,et al.Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute,refractory gastrointestinal graft-versushost-disease.Haenmtologica,2017;102(5):e210-e213.
18 Shahinas D,Silverman M,Sittler T,et al.Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing.MBio,2012;3(5):e00338-12.
2 Whangbo J,Ritz J,Bhatt A.Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant,2017;52(2):183-190.
3 Taur Y,Jenq RR,Perales MA,et al.The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.Blood,2014;124(7):1174-1182.
4 Jenq RR,Taur Y,Devlin SM,et al.Intestinal Blautia is associated with reduced death from graft-versus-host disease.Biol Blood Marrow Transplant,2015;21(8):1373-1383.
5 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-versushost disease.Biol Blood Marrow Transplant,2014;20(5):640-645.
6 Jenq RR,Ubeda C,Taur Y,et al.Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation.J Exp Med,2012;209(5):903-911.
7 Taur Y,Xavier JB,Lipuma L,et al.Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation.Clin Infect Dis,2012;55(7):905-914.
8 Turnbaugh PJ,Hamady M,Yatsunenko T,et al.A core gut microbiome in obese and lean twins.Nature,2009;457(7228):480-484.
9贾晋松,黄晓军,刘代红,等.异基因造血干细胞移植过程中患者艰难梭菌感染与肠道微生态失调关系的临床研究.中国实验血液学杂志,2008;16(1):135-139.
10 Salazar N,Valdes-Varela L,Gonzalez S,et al.Nutrition and the gut microbiome in the elderly.Gut Microbes,2017;8(2):82-97.
11 Dethlefsen L,Huse S,Sogin ML,et al.The pervasive effects of an antibiotic on the human gut microbiota,as revealed by deep 16SrRNA sequencing.PLoS Biol,2008;6(11):e280.
12 Sanchez B,Gueimonde M,Pena AS,et al.Intestinal microbiota as modulators of the immune system.J Immunol Res,2015;2015:159094.
13 Shono K,Docampo MD,Peled JU,et al.Intestinal microbiotarelated effects on graft-versus-host disease.Int J Hematol.2015;101(5):428-437.
14吕梦楠,韩明哲.肠道微生物与移植物抗宿主病研究进展.中华血液学杂志,2017;38(12):1085-1088.
15 Staffas A,Burgos da Silva M,van den Brink MR.The intestinal microbiota in allogeneic hematopoietic cell transplant and graftversus-host disease.Blood,2017;129(8):927-933.
16李宁.肠道菌群紊乱与粪菌移植.肠外与肠内营养,2014;21(4):193-197.
17 Spindelboeck W,Schulz E,Uhl B,et al.Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute,refractory gastrointestinal graft-versushost-disease.Haenmtologica,2017;102(5):e210-e213.
18 Shahinas D,Silverman M,Sittler T,et al.Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing.MBio,2012;3(5):e00338-12.