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. 2020 Nov:61:103048.
doi: 10.1016/j.ebiom.2020.103048. Epub 2020 Oct 8.

Tyrosine supplement ameliorates murine aGVHD by modulation of gut microbiome and metabolome

Xiaoqing Li  1 , Yu Lin  1 , Xue Li  1 , Xiaoxiao Xu  1 , Yanmin Zhao  1 , Lin Xu  1 , Yang Gao  2 , Yixue Li  1 , Yamin Tan  1 , Pengxu Qian  3 , He Huang  4
Affiliations

"V体育安卓版" Tyrosine supplement ameliorates murine aGVHD by modulation of gut microbiome and metabolome

V体育ios版 - Xiaoqing Li et al. EBioMedicine. 2020 Nov.

V体育官网入口 - Abstract

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. VSports手机版.

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. V体育安卓版.

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 V体育ios版. 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. VSports最新版本.

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). V体育平台登录.

Keywords: Correlation network; Gut microbiome; Metabolomics; Tyrosine; aGVHD. VSports注册入口.

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Conflict of interest statement

Declaration of Competing Interest The authors declare no conflicts of interest.

Figures

Fig. 1:
Fig. 1
Relative abundance of gut microbiota at phylum and genus levels. (a) BALB/c host mice receiving C57BL/6 TCD-BM (n=12) or TCD-BM+T cells (n=12) to establish aGVHD murine models. (b-e) Significant changes of (b) survival time (log-rank test, p<0.05), (c) weight changes (two-tailed Student's t-test, p<0.01), (d) clinical scores (two-tailed Student's t-test, p<0.01) and (e) pathology scores of each group on day 14. (f-g) 16S rDNA gene sequencing of fecal microbiota from TCD-BM (n=6) and TCD-BM+T cells groups (n=6) and the relative abundance of gut microbiota with the histogram of fold change (TCD-BM+T/TCD-BM) at the phylum level on days 14 (f) and 28 (g). (h-i) Relative abundance of top 20 genera with the histogram of fold change (TCD-BM+T/TCD-BM) on days 14 (h) and 28 (i). The number of mice in each group was indicated (n) within the bracket. The scores displayed mean ± SEM from three to four independent experiments. *p < 0.05, **p < 0.01.
Fig. 2:
Fig. 2
Changes in the metabolomics of TCD-BM and TCD-BM+T cells groups. (a, b) A comparison was made between detected metabolites with paired Student's t-test and then Bonferroni correction. The volcano plot shows the variation in the number of metabolites between TCD-BM (n=6) and TCD-BM+T cells (n=6) groups according to the –log (q value) and log2 (fold change) on days 14 (a) and 28 (b). (c) The most important 50 metabolites after Student's t-test and the hierarchical clustering of samples shown in the heatmap. (d) KEGG-annotated metabolic pathways between TCD-BM and TCD-BM+T cells groups. (e) On day 14, the heatmap summarizes the altered fecal metabolites related to tyrosine between TCD-BM and TCD-BM+T cells groups and only displays the decrease of tyrosine in the TCD-BM+T cells group (two-tailed Student's t-test, p<0.01). (f) On day 28, the TCD-BM+T cells group showed a significant decrease in tyrosine, L-dopa, L-aspartic acid, L-glutamic acid and S-adenosylhomocysteine (two-tailed Student's t-test, p<0.01). (g, h) Correlation network between altered metabolites (circular) and differentially abundant microbiota (square). A connection means that a microbe is correlated with a metabolite; red and blue lines indicate positive and negative correlations respectively; volume size refers to the strength of the correlation. Networks between TCD-BM and TCD-BM+T cells groups were shown on days 14 (g) and 28 (h). The number of mice in each group was indicated.
Fig. 3:
Fig. 3
Amelioration of aGVHD by tyrosine supplement. (a) 0% or 2% tyrosine diets were served to TCD-BM (n=18) and TCD-BM+T cells (n=18) groups from day -7 of irradiation until the end of experiments. Compared with TCD-BM+T cells + vehicle, 2% tyrosine diet can result in (b) the prolonging of survival time, (c) the loss of less weight (day 6 to 24, two-tailed Student's t-test, p<0.01; day 27 to 33, two-tailed Student's t-test, p<0.05) and (d) the decrease of clinical scores (day 12 to 30, two-tailed Student's t-test, p<0.01; day 9 to 33, two-tailed Student's t-test, p<0.05) in early aGVHD. The administration of 2% tyrosine can decrease the (e) pathological scores of the large intestine and skin on day 14. (f) 2% tyrosine diet protected intestines and skins from the attack of allogenic T-cells, as shown in HE images. The pathology scores reflected mean ± SEM from three to four independent experiments, with n = 6 in each group.
Fig. 4:
Fig. 4
Tyrosine supplement altered microbiome and metabolome. (a-d) The relative abundance of gut microbiota between TCD-BM+T cells + vehicle (n=6) and 2% tyrosine diet (n=6) groups and the histogram of fold change (TCD-BM+T cells + 2% tyrosine diet group/TCD-BM+T cells + vehicle group) at the phylum level on days 14 (a) and day 28 (b). Relative abundance of top 20 genera shown in the histogram of fold change (TCD-BM+T cells + 2% tyrosine diet group/TCD-BM+T cells + vehicle group) on days 14 (c) and 28 (d). (e-f) The heatmap summarizes the different fecal metabolites related to tyrosine between TCD-BM+T cells + vehicle (n=6) and 2% tyrosine diet (n=6) groups. The 2% tyrosine-diet group showed an increase in tyrosine saw (two-tailed Student's t-test, p<0.01) on day 14 (e), but no significant difference in tyrosine and other metabolites on day 28 (f). (g-h) The same correlation analysis was performed to build a network according to Fig. 2 g-h where nodes represent microbiota or metabolites between TCD-BM+T cells + vehicle and TCD-BM+T cells + 2% tyrosine diet groups on days 14 (g) and 28 (h).
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