PT  - JOURNAL ARTICLE
AU  - Matthieu Rouland
AU  - Lucie Beaudoin
AU  - Ophélie Rouxel
AU  - Léo Bertrand
AU  - Lucie Cagninacci
AU  - Azadeh Saffarian
AU  - Thierry Pedron
AU  - Dalale Gueddouri
AU  - Sandra Guilmeau
AU  - Anne-Françoise Burnol
AU  - Latif Rachdi
AU  - Asmaa Tazi
AU  - Juliette Mouriès
AU  - Maria Rescigno
AU  - Nathalie Vergnolle
AU  - Philippe Sansonetti
AU  - Ute Christine Rogner
AU  - Agnès Lehuen
TI  - Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia
AID  - 10.1136/gutjnl-2020-323664
DP  - 2021 Feb 16
TA  - Gut
PG  - gutjnl-2020-323664
4099  - http://gut.bmj.com/content/early/2021/02/15/gutjnl-2020-323664.short
4100  - http://gut.bmj.com/content/early/2021/02/15/gutjnl-2020-323664.full
AB  - 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.