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
- intestinal microbiology
Data availability statement
Data are available on reasonable request at the corresponding author (firstname.lastname@example.org)
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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.
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