Tyrosine supplement ameliorates murine aGVHD by modulation of gut microbiome and metabolome
Xiaoqing Li,
Yu Lin,
Xue Li,
Xiaoxiao Xu,
Yanmin Zhao,
Lin Xu,
Yang Gao,
Yixue Li,
Yamin Tan,
Pengxu Qian,
He Huang
Affiliations
Xiaoqing Li
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
Yu Lin
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
Xue Li
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
Xiaoxiao Xu
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
Yanmin Zhao
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
Lin Xu
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
Yang Gao
Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3 Qingchun East Rd., Hangzhou 310016, Zhejiang, PR China
Yixue Li
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
Yamin Tan
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
Pengxu Qian
Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, PR China; Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, PR China; Center of Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou 310012, PR China; Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, PR China; Corresponding authors at: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, PR China.
He Huang
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; Corresponding authors at: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, PR China.
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).
