Low-dose IL-2 shapes a tolerogenic gut microbiota that improves autoimmunity and gut inflammation
Nicolas Tchitchek, Otriv Nguekap Tchoumba, Gabriel Pires, Sarah Dandou, Julien Campagne, Guillaume Churlaud, Gwladys Fourcade, Thomas W. Hoffmann, Francesco Strozzi, Camille Gaal, Christophe Bonny, Emmanuelle Le Chatelier, Stanislav Dusko Erlich, Harry Sokol, David Klatzmann
Nicolas Tchitchek, Otriv Nguekap Tchoumba, Gabriel Pires, Sarah Dandou, Julien Campagne, Guillaume Churlaud, Gwladys Fourcade, Thomas W. Hoffmann, Francesco Strozzi, Camille Gaal, Christophe Bonny, Emmanuelle Le Chatelier, Stanislav Dusko Erlich, Harry Sokol, David Klatzmann
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Research Article Therapeutics

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

Abstract

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-2LD) stimulates Tregs and is a promising treatment for autoimmune and inflammatory diseases. We aimed to evaluate the impact of IL-2LD 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-2LD. We performed fecal microbiota transplantation (FMT) from IL-2LD–treated to naive recipient mice and evaluated its effects in models of gut inflammation and diabetes. IL-2LD 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-2LD and for microbial pathways involved in the biosynthesis of amino acids, short-chain fatty acids, and L-arginine. Our results demonstrate that IL-2LD induced changes in gut microbiota that are involved in the immunoregulatory effects of IL-2LD 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.

Authors

Nicolas Tchitchek, Otriv Nguekap Tchoumba, Gabriel Pires, Sarah Dandou, Julien Campagne, Guillaume Churlaud, Gwladys Fourcade, Thomas W. Hoffmann, Francesco Strozzi, Camille Gaal, Christophe Bonny, Emmanuelle Le Chatelier, Stanislav Dusko Erlich, Harry Sokol, David Klatzmann

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Figure 4

Metagenomics reveals microbial species affected by IL-2LD.

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Metagenomics reveals microbial species affected by IL-2LD. To gain more ...
To gain more insight into the impact of IL-2LD on microbial composition, gut microbiome profiling of NOD and C57BL/6J mice before and 30 days after IL-2LD treatment was performed using metagenomics. (A) Distogram representation showing the distance between microbiome profiles. Similarities were calculated using the Simka algorithm, which compares profiles using a k-mer approach without needing a reference metagenome, and using the Jaccard distance coefficient on abundance levels. (B) Venn diagram showing the overlap between the lists of taxa significantly affected by IL-2LD in NOD and C57BL/6J mice. The names of the overlapping species are indicated, and their upregulation and downregulation relative to controls are respectively indicated by red or green arrows. (C and D) Principal component analysis representations of the gut microbiome profiles of NOD and C57BL/6J mice before and after treatment with IL-2LD generated using the abundance levels of taxa significantly affected by IL-2LD. IL-2LD was administered to mice by means of an IL-2–producing AAV vector.