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  • Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia

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Gut microbiota
Original research
Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia
  1. Matthieu Rouland1,2,
  2. Lucie Beaudoin1,2,
  3. Ophélie Rouxel1,2,
  4. Léo Bertrand1,2,
  5. Lucie Cagninacci1,2,
  6. Azadeh Saffarian3,
  7. Thierry Pedron3,
  8. Dalale Gueddouri1,
  9. Sandra Guilmeau1,
  10. Anne-Françoise Burnol1,
  11. Latif Rachdi1,
  12. Asmaa Tazi1,
  13. Juliette Mouriès4,5,
  14. Maria Rescigno4,5,
  15. Nathalie Vergnolle6,
  16. Philippe Sansonetti3,
  17. Ute Christine Rogner1,2,
  18. Agnès Lehuen1,2
  1. 1 Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
  2. 2 Laboratoire d'Excellence Inflamex, Université de Paris, Paris, France
  3. 3 Institut Pasteur, INSERM U1202, Paris, France
  4. 4 Department of Biomedical Sciences - IRCCS, Via Rita Levi Montalcini, 20090 Pieve Emanuele, Humanitas University, Milan, Italy
  5. 5 IRCCS, Via Manzoni 56, 20089 Rozzano, Humanitas Clinical and Research Center, Milan, Italy
  6. 6 Université de Toulouse, Institut de Recherche en Santé Digestive, INSERM U1220, INRAE, ENVT, Toulouse, France
  1. Correspondence to Professor Agnès Lehuen, Institut Cochin, Université de Paris, CNRS UMR 8104 and INSERM U1016, 123 Boulevard de Port-Royal, Paris 75014, France; agnes.lehuen{at}inserm.fr

Abstract

Objective Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia.

Design We used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset.

Results We show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence.

Conclusion Our results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

  • diabetes mellitus
  • mucosal immunity
  • inflammation
  • intestinal microbiology

Data availability statement

Data are available on reasonable request at the corresponding author (agnes.lehuen@inserm.fr)

https://doi.org/10.1136/gutjnl-2020-323664

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    Data availability statement

    Data are available on reasonable request at the corresponding author (agnes.lehuen@inserm.fr)

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    Footnotes

    • MR, LB, OR and LB are joint first authors.

    • Contributors MR, LBea, OR and LBer performed most of the experiments and data analysis; LC performed experiments and data analysis; AS and TP produced 16S sequencing as well as bioinformatics analyses; DG and LR participated in the S961 experiments; JM and AT contributed to CFU analyses; NV provided Infliximab; SG, A-FB, MR, NV and PS provided intellectual input. MR, LBea, LBer, UCR and AL wrote the paper. AL supervised the whole project.

    • Funding This work was supported by Agence Nationale de la Recherche (ANR-11-IDEX-0005-02 Laboratory of Excellence INFLAMEX and ANR-17-CE14-0002-01 Diab1MAIT), Fondation pour la Recherche Médicale (DEQ20140329520 and EQU201903007779), the INSERM crosscutting program on microbiota and the European Foundation for the Study of Diabetes–Juvenile Diabetes Research Foundation–MR, OR and LBer were supported by the French Ministry of Research.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.