Probiotic-Derived Ecto-5'-Nucleotidase Produces Anti-Inflammatory Adenosine Metabolites in Treg-Deficient Scurfy Mice

Probiotic Limosilactobacillus reuteri DSM 17938 (DSM 17938) prolongs the survival of Treg-deficient scurfy (SF) mice and reduces multiorgan inflammation by a process requiring adenosine receptor 2A (A(2A)) on T cells. We hypothesized that L. reuteri-derived ecto-5'-nucleotidase (ecto-5'NT) activity acts to generate adenosine, which may be a central mediator for L. reuteri protection in SF mice. We evaluated DSM 17938-5'NT activity and the associated adenosine and inosine levels in plasma, gut, and liver of SF mice. We examined orally fed DSM 17938, DSM 17938 Delta 5NT (with a deleted 5'NT gene), and DSM 32846 (BG-R46) (a naturally selected strain derived from DSM 17938). Results showed that DSM 17938 and BG-R46 produced adenosine while exhausting AMP, whereas DSM 17938 increment 5NT did not generate adenosine in culture. Plasma 5'NT activity was increased by DSM 17938 or BG-R46, but not by DSM 17938 Delta 5NT in SF mice. BG-R46 increased both adenosine and inosine levels in the cecum of SF mice. DSM 17938 increased adenosine levels, whereas BG-R46 increased inosine levels in the liver. DSM 17938 Delta 5NT did not significantly change the levels of adenosine or inosine in the GI tract or the liver of SF mice. Although regulatory CD73(+)CD8(+) T cells were decreased in spleen and blood of SF mice, these regulatory T cells could be increased by orally feeding DSM 17938 or BG-R46, but not DSM 17938 Delta 5NT. In conclusion, probiotic-5'NT may be a central mediator of DSM 17938 protection against autoimmunity. Optimal 5'NT activity from various probiotic strains could be beneficial in treating Treg-associated immune disorders in humans.

Automated summary

Probiotic Limosilactobacillus reuteri DSM 17938 prolongs the survival of Treg-deficient scurfy mice and reduces multiorgan inflammation by activating adenosine receptor 2A on T cells. The ecto-5'-nucleotidase activity derived from L. reuteri generates adenosine, which may play a central role in the protection of SF mice.