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

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