酪氨酸补充剂通过调节肠道微生物组和代谢组改善小鼠移植物抗宿主病。
Tyrosine supplement ameliorates murine aGVHD by modulation of gut microbiome and metabolome.
机构信息
Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, Zhejiang, PR China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, PR China; Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, PR China; Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, PR China.
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Rd., Hangzhou 310016, Zhejiang, PR China.
出版信息
EBioMedicine. 2020 Nov;61:103048. doi: 10.1016/j.ebiom.2020.103048. Epub 2020 Oct 8.
BACKGROUND
Microbial communities and their metabolic components in the gut are of vital importance for immune homeostasis and have an influence on the susceptibility of the host to a number of immune-mediated diseases like acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the functional connections between microbiome and metabolome in aGVHD due to the complexity of the gastrointestinal environment.
METHOD
Initially, gut microbiota and fecal metabolic phenotype in aGVHD murine models were unleashed by performing 16S ribosomal DNA gene sequencing and ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics.
FINDINGS
The group with aGVHD experienced a significant drop in Lachnospiraceae_unclassified but an increase in the relative abundance of Clostridium XI, Clostridium XIVa and Enterococcus. Meanwhile, a lower content of tyrosine was observed in the gut of aGVHD mice. The correlation analysis revealed that tyrosine-related metabolites were inversely correlated with Clostridium XIVa, besides, Blautia and Enterococcus also displayed the negative tendency in aGVHD condition. Apart from exploring the importance and function of tyrosine, different tyrosine diets were offered to mice during transplantation. Additional tyrosine supplements can improve overall survival, ameliorate symptoms at the early stage of aGVHD and change the structure and composition of gut microbiota and fecal metabolic phenotype. In addition, aGVHD mice deprived from tyrosine displayed worse manifestations than the vehicle diet group.
INTERPRETATION
The results demonstrated the roles and mechanisms of gut microbiota, indispensable metabolites and tyrosine in the progression of aGVHD, which can be an underlying biomarker for aGVHD diagnosis and treatment.
FUNDING
This research was funded by the International Cooperation and Exchange Program (81520108002), the National Key R&D Program of China, Stem Cell and Translation Research (2018YFA0109300), National Natural Science Foundation of China (81670169, 81670148, 81870080 and 91949115) and Natural Science Foundation of Zhejiang Province (LQ19H080006).
背景
肠道中的微生物群落及其代谢成分对于免疫稳态至关重要，并影响宿主对许多免疫介导的疾病的易感性，如异基因造血干细胞移植（allo-HSCT）后急性移植物抗宿主病（aGVHD）。然而，由于胃肠道环境的复杂性，对于微生物组和代谢组在 aGVHD 中的功能联系知之甚少。
方法
最初，通过 16S 核糖体 DNA 基因测序和基于超高效液相色谱-质谱（UHPLC-MS）的代谢组学方法，揭示 aGVHD 小鼠模型中的肠道微生物群和粪便代谢表型。
发现
患有 aGVHD 的组中，lachnospiraceae_unclassified 的相对丰度显著下降，但 clostridium XI、clostridium XIVa 和 enterococcus 的相对丰度增加。同时，aGVHD 小鼠肠道中的酪氨酸含量较低。相关性分析显示，酪氨酸相关代谢物与 clostridium XIVa 呈负相关，此外，blautia 和 enterococcus 在 aGVHD 条件下也呈负相关趋势。除了探索酪氨酸的重要性和功能外，在移植期间还向小鼠提供了不同的酪氨酸饮食。额外的酪氨酸补充可以提高总生存率，改善 aGVHD 早期的症状，并改变肠道微生物群和粪便代谢表型的结构和组成。此外，缺乏酪氨酸的 aGVHD 小鼠表现出比载体饮食组更差的表现。
解释
结果表明了肠道微生物群、必需代谢物和酪氨酸在 aGVHD 进展中的作用和机制，可为 aGVHD 的诊断和治疗提供潜在的生物标志物。
资金
本研究由国际合作与交流计划（81520108002）、国家重点研发计划、干细胞与转化研究（2018YFA0109300）、国家自然科学基金（81670169、81670148、81870080 和 91949115）和浙江省自然科学基金（LQ19H080006）资助。
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