Use of tnf-alpha blocking agent for preventing, suppressing and/or delaying the onset of type 1 diabetes

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. The inventors 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 auto-immune inflammation and hyperglycemia. The inventors used several mouse models of autoimmune T1D as well as mice rendered hyperglycemic without inflammation to study gut mucosa and microbiota dysbiosis. They analyzed cytokine expression by immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. They also assessed the role of anti-TNFα on gut mucosa inflammation and T1D onset. The inventors show in models of autoimmune T1D a conserved loss of 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 hyperglycemia with no inflammation failed to do so. Moreover, antiinflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence. The results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycemia. Anti-inflammatory treatment with TNF-blocking agent preserves gut homeostasis and protective commensal flora reducing T1D incidence. More particularly, the results reveal SFB as a potential biomarker of T1D progression in at-risk individuals and suggest that an anti-inflammatory treatment with TNF blocking agents might be of interest to reduce intestinal alteration associated with T1D onset.

Gut . 2021 Feb 16;gutjnl-2020-323664. doi: 10.1136/gutjnl-2020-323664. Online ahead of print.

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