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 6

IL-2LD affects the gut microbiome in patients with autoimmune disorders.

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IL-2LD affects the gut microbiome in patients with autoimmune disorders....
To evaluate the potential of IL-2LD to modify the gut microbiome in humans, 6 patients with various autoimmune diseases were treated with IL-2LD. Samples were collected at baseline and between 3 and 9 months after the first injection. Microbiome profiling was performed using metagenomics. (A) Heatmap representation of the relative abundances for the 5 bacterial species found to be differentially abundant in the gut microbiome of patients treated with IL-2LD relative to the baseline condition. (B) Heatmap representation of relative abundances for the 63 microbial pathways found to be differentially abundant in the gut microbiome of patients. (C) Pie chart showing the number of taxa associated with the microbial pathways differentially abundant in patients relative to baseline. Gut microbial pathways are colored according to their classes. The number of contributing species is indicated in parentheses for each pathway. Pathways with fewer than 36 associated taxa are colored in gray.