Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors

Baokun He, Thomas K Hoang, Ting Wang, Michael Ferris, Christopher M Taylor, Xiangjun Tian, Meng Luo, Dat Q Tran, Jain Zhou, Nina Tatevian, Fayong Luo, Jose G Molina, Michael R Blackburn, Thomas H Gomez, Stefan Roos, J Marc Rhoads, Yuying Liu, Baokun He, Thomas K Hoang, Ting Wang, Michael Ferris, Christopher M Taylor, Xiangjun Tian, Meng Luo, Dat Q Tran, Jain Zhou, Nina Tatevian, Fayong Luo, Jose G Molina, Michael R Blackburn, Thomas H Gomez, Stefan Roos, J Marc Rhoads, Yuying Liu

Abstract

Regulatory T (T reg) cell deficiency causes lethal, CD4+ T cell-driven autoimmune diseases. Stem cell transplantation is used to treat these diseases, but this procedure is limited by the availability of a suitable donor. The intestinal microbiota drives host immune homeostasis by regulating the differentiation and expansion of T reg, Th1, and Th2 cells. It is currently unclear if T reg cell deficiency-mediated autoimmune disorders can be treated by targeting the enteric microbiota. Here, we demonstrate that Foxp3+ T reg cell deficiency results in gut microbial dysbiosis and autoimmunity over the lifespan of scurfy (SF) mouse. Remodeling microbiota with Lactobacillus reuteri prolonged survival and reduced multiorgan inflammation in SF mice. L. reuteri changed the metabolomic profile disrupted by T reg cell deficiency, and a major effect was to restore levels of the purine metabolite inosine. Feeding inosine itself prolonged life and inhibited multiorgan inflammation by reducing Th1/Th2 cells and their associated cytokines. Mechanistically, the inhibition of inosine on the differentiation of Th1 and Th2 cells in vitro depended on adenosine A2A receptors, which were also required for the efficacy of inosine and of L. reuteri in vivo. These results reveal that the microbiota-inosine-A2A receptor axis might represent a potential avenue for combatting autoimmune diseases mediated by T reg cell dysfunction.

© 2017 He et al.

Figures

Figure 1.
Figure 1.
Dynamics of autoimmunity development and microbiota dysbiosis over 22 d of life in T reg cell-deficient scurfy (SF) mice. (A) Percentage of IFN-γ– or IL-4–producing-CD4+ T cells in spleen of WT and SF mice at the indicated age (two-way ANOVA; n = 6–12 per group). (B) Plasma IFN-γ and IL-4 levels at the indicated age (two-way ANOVA; n = 6–12 per group). (C) Gut microbial Shannon diversity analysis (two-way ANOVA; n = 6–12 per group). (D) Gut microbial analysis of weighted unifrac-based three-dimensional PCoA plots of WT and SF mice at the indicated age (n = 6–12 per group). (E and F) Relative abundance of predominant bacteria (>1% in any sample) at the genus level (E) and relative abundance of total bacteria at the genus level (F; two-way ANOVA; n = 6–12 per group). **, P < 0.01; ***, P < 0.001. SF versus WT. Error bars represent mean ± SEM.
Figure 2.
Figure 2.
L. reuteri early treatment modulates the intestinal microbiota in SF mice. (A) Gut microbial Shannon diversity analysis, comparing groups of WT, SF, and SF treated with L. reuteri (SFL; one-way ANOVA; n = 10–12 per group). (B) Weighted UniFrac-based three-dimensional PCoA analysis of gut microbiota of WT, SF, and SFL mice (n = 10–12 per group). (C) Nonparametric multiple dimensional scaling analysis of gut microbiota of WT, SF, and SFL mice (n = 10–12 per group). (D–F) Relative abundance of predominant bacteria (>1% in any sample) at the phylum level [D], and at the genus level (E), and relative abundance of total bacteria at genus level (F) in feces (one-way ANOVA; n = 10–12 per group). (G) Relative abundance of Lactobacillus at the species level in feces (one-way ANOVA; n = 10–12 per group). **, P < 0.01; ***, P < 0.001. SF versus WT. #, P < 0.05; ##, P < 0.01; and ###, P < 0.001. SFL versus SF. Error bars represent mean ± SEM.
Figure 3.
Figure 3.
L. reuteri early treatment increases survival and suppresses autoimmunity in SF mice. (A) Scheme for L. reuteri early treatment on WT or SF mice for sample analysis and survival observation. (B) Survival curves of SF and SFL mice (Kaplan-Meier survival curves and log-rank test; n = 10–17 per group). (C) Representative H&E staining of liver and lung from WT, WTL, SF, and SFL mice. Bars, 200 µm (n = 6–12 per group). (D) Quantitation of inflammatory infiltrates in liver and lung of WT, WTL, SF, and SFL (one-way ANOVA; n = 6–12 per group). (E and F) The frequency of IFN-γ or IL-4–producing-CD4+ T cells in spleen (E) and MLNs (F) of mice (one-way ANOVA; n = 6–12 per group). (G) Plasma levels of IFN-γ and IL-4 in WT, WTL, SF, and SFL mice (one-way ANOVA; n = 6–12 per group). *, P < 0.05; ***, P < 0.001. SF versus WT. #, P < 0.05; ##, P < 0.01; ###, P < 0.001. SFL versus SF. Error bars represent mean ± SEM.
Figure 4.
Figure 4.
Plasma metabolomic profiles are modulated by L. reuteri early treatment of SF mice. (A) PCA clustering from plasma metabolites of WT, SF, and SFL (n = 5–6 per group). (B) Heat map of 525 metabolites in plasma of WT, SF, and SFL mice. Each lane represents a different mouse. The scale bar indicates fold change of SF versus WT or SFL versus SF (n = 5–6 per group). (C) Numbers of plasma metabolites affected, either up-regulated (↑) or down-regulated (↓; P < 0.05), by SF versus WT or SFL versus SF mice (n = 5–6 per group). (D) Heat map showing the levels of 29 plasma metabolites that were significantly altered by L. reuteri treatment in SF mice. Colors indicate fold changes with P < 0.05 (SF vs. WT or SFL vs. SF). (E) Relative quantification of metabolites related to inosine pathway in plasma (one-way ANOVA; n = 5–6 per group). *, P < 0.05; **, P < 0.01. SF versus WT. #, P < 0.05. SFL versus SF. Error bars represent mean ± SEM.
Figure 5.
Figure 5.
Inosine suppresses Th1/Th2 cell differentiation via adenosine A2A receptor in vitro. (A) mRNA expression of IFN-γ in Th1 cells with 2 mM of inosine treatment for 24 or 72 h (one-way ANOVA; n = 4 independent experiments). (B) mRNA expression of IL-4 in Th2 cells with 2 mM of inosine treatment for 24 or 72 h (one-way ANOVA; n = 4 independent experiments). (C and D) Effect of inosine on Th1 (C) or Th2 (D) cell differentiation from WT, A1−/−, A2A−/−, A2B−/−, and A3−/− mice (n = 3 independent experiments). (E and F) cAMP level in Th1 cells (E) or cAMP level in Th2 cells (F) of WT or A2A−/− mice after inosine and A2A receptor-selective agonist CGS31680 treatment (one-way ANOVA; n = 4 independent experiments). ***, P < 0.001. Error bars represent mean ± SEM.
Figure 6.
Figure 6.
Inosine inhibits autoimmunity in SF mice via adenosine A2A receptors. (A) Scheme of WT or SF mice treated with inosine (WTI or SFI) or inosine in combination with an A2A receptor-selective antagonist SCH58261 (WTIS or SFIS) or SF mice treated with only SCH58261 (SFS) for sample analysis and survival observation. (B) Survival curves to compare inosine-fed SF (SFI) with SF without inosine feeding (Kaplan-Meier survival curves and log-rank test; n = 8–17 per group). (C) Representative H&E staining of liver and lung from WT, WTI, WTIS, SF, SFI, SFS, and SFIS; bar, 200 µm (n = 6–12 per group). (D) Quantification of inflammatory infiltrates in liver and lung of WT, WTI, WTIS, SF, SFI, SFS, and SFIS (one-way ANOVA; n = 6–12 per group). (E) The frequency of IFN-γ or IL-4–producing CD4+ T cells in spleen of mice (one-way ANOVA; n = 6–12 per group). (F) Plasma levels of IFN-γ and IL-4 in WT, WTI, WTIS, SF, SFI, SFS, and SFIS mice (one-way ANOVA; n = 6–12 per group). ***, P < 0.001. SF versus WT. †††, P < 0.001. SFI versus SF. ‡‡‡, P < 0.001. SFIS versus SFI. Error bars represent mean ± SEM.
Figure 7.
Figure 7.
Inhibition of autoimmunity by L. reuteri is mediated by adenosine A2A receptors. (A) Scheme of SF mice treated with L. reuteri (SFL) in the combination with an A2A receptor-selective antagonist SCH58261 (SFLS) or SCH58261 alone (SFS) for sample analysis. (B) Representative H&E staining of liver and lung from SF, SFL, SFS, and SFLS mice; bar, 200 µm (n = 6–12 per group). (C) Quantification of inflammatory infiltrates in liver and lung of SF, SFL, SFS, and SFLS mice (one-way ANOVA; n = 6–12 per group). (D) The frequency of IFN-γ or IL-4–producing CD4+ T cells in spleen of mice (one-way ANOVA; n = 6–12 per group). (E) Plasma levels of IFN-γ and IL-4 in SF, SFL, SFS, and SFLS mice (one-way ANOVA; n = 6–12 per group). ##, P < 0.01; ###, P < 0.001. SFL versus SF. ‡, P < 0.05; ‡‡, P < 0.01. SFLS versus SFL. Error bars represent mean ± SEM.
Figure 8.
Figure 8.
Mechanisms of Lactobacillus reuteri protection against T reg cell deficiency–mediated autoimmunity. T reg cell deficiency shapes gut microbiota and induces autoimmunity resulting in multiorgan inflammation and early death (left). L. reuteri remodels gut microbiota, alters the metabolites, and protects against T reg cell deficiency–induced autoimmunity by suppressing Th1/Th2 cells via inosine–adenosine A2A interaction (right).

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