Low-dose interleukin-2 shapes a tolerogenic gut microbiota that improves autoimmunity and gut inflammation.

Gut microbiota (GM) dysbiosis is associated with inflammatory bowel diseases and also with cardiometabolic, neurologic, and autoimmune diseases. GM composition has a direct effect on the immune system, and vice versa, and particularly on regulatory T cell (Treg) homeostasis. Low-dose interleukin-2 (IL-2LD) stimulates Tregs and is a promising treatment for autoimmune and inflammatory diseases. We aimed to evaluate the impacts of IL-2LD on GM, and correlatively on the immune system. We used 16S ribosomal RNA profiling and metagenomics to characterise GM of mice and humans treated or not with IL-2LD. We performed fecal microbiota transplantation (FMT) from IL-2LD-treated to naive recipient mice and evaluated its effects in models of type-1 diabetes and gut inflammation. IL-2LD markedly affects GM composition in mice and humans. Transfer of an IL-2-tuned microbiota by FMT prevented type 1 diabetes in NOD mice and protected C57BL/6J mice from dextran sulfate sodium-induced colitis. Metagenomic analyses highlighted a role for several species impacted by IL-2LD and for gut microbial pathways involved in the biosynthesis of amino acids, short-chain fatty acids, and L-arginine. Our results demonstrate that IL-2LD induces changes in GM that are involved in the therapeutic effects of IL-2LD and suggest cross-talk between Tregs and GM. These results provide novel perspectives for understanding the mode of action of Treg-directed therapies.