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 3

IL-2LD–tuned gut microbiota protects from autoimmunity.

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IL-2LD–tuned gut microbiota protects from autoimmunity. The microbiota o...
The microbiota of IL-2LD–treated NOD mice was transferred to recipient NOD mice treated by antibiotics (ATB) for 14 days before fecal microbiota transplantation (FMT). NOD mice receiving FMT from untreated NOD mice were used as controls. 16S rRNA sequencing was used to profile gut microbiota at day 30 after treatment. (A) sPLS-DA was conducted to identify taxa separating NOD mice with FMT IL-2LD from NOD mice with control FMT. The contribution of each taxon identified by sPLS-DA was represented using a horizontal bar of length proportional to its sPLS-DA loading. 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. (B) Venn diagram showing the overlap between the lists of taxa affected by IL-2LD and IL-2LD FMT treatments relative to their control groups. (C and D) In an independent experiment, C57BL/6J mice were treated with IL-2LD. Five weeks later, fresh stools from these mice were collected and orally administered to 7-week-old female C57BL/6 mice previously treated daily for 14 days with ATB. DSS was administered in drinking water for 5 days after transplantation to trigger colitis. Mouse body weight change (C) and disease activity index (D) were evaluated until day 12. (E) In an independent experiment, 4-week-old female NOD mice were treated with IL-2LD or without IL-2LD. Five weeks later, fresh stools from these mice were collected and orally administered to 6-week-old female NOD mice previously treated daily for 14 days with ATB. Diabetes onset was screened for during the experiment. Student’s t test was used to compare measurements in treated and untreated mice at each time point. The Holm-Bonferroni adjustment was used for multiple-comparison correction. Statistical significances were reported as follows: *P < 0.05; ***P < 0.001. IL-2LD was administered or not to mice by means of IL-2–producing AAV. For each biological condition, the total number of mice used is provided in parentheses.