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 2

IL-2LD affects gut microbiota composition in mice.

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IL-2LD affects gut microbiota composition in mice. NOD and BALB/c mice w...
NOD and BALB/c mice were treated or not with IL-2LD by means of IL-2–producing or luciferase-producing AAV vectors. Profiling of their gut microbiota, collected 30 days after treatment, was performed using 16S rRNA sequencing. (A and B) Comparisons were made between NOD mice and BALB/c mice treated or not with IL-2LD. (C) An additional comparison was made between NOD mice and BALB/c mice without IL-2LD to comprehend the gut microbial specificities associated with these mouse backgrounds. For each comparison, sPLS-DA was conducted to identify the gut microbial taxa best able to discriminate the conditions. The contribution of each taxon identified by sPLS-DA was represented using a horizontal bar of length proportional to its sPLS-DA loading. Horizontal bars were gradient-colored based on the log2 of the taxa abundance fold-changes relative to the reference group. For each analysis, a heatmap of relative abundances combined with unsupervised hierarchical clustering was used to evaluate the capacity of the list of taxa to discriminate the conditions. The family (f__) or order (o__) associated with the taxa identified by sPLS-DA is indicated in parentheses.