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    Alterations in the microbiota and gut in type 1 diabetes are associated with inflammation rather than hyperglycaemia

    Team Agnès Lehuen

    Alterations in the microbiota and gut in type 1 diabetes are associated with inflammation rather than hyperglycaemia

     

    Although type 1 diabetes is a pathology that mainly affects the pancreas, it also affects the gut. In an article published in the journal Gut, Agnès Lehuen's team (Immunology of Diabetes, Institut Cochin) shows that the intestinal alterations associated with diabetes are linked to inflammation of the mucosa and not to hyperglycemia. Countering this inflammation not only improves intestinal integrity but also reduces the incidence of diabetes in mice susceptible to the disease.

     

    Type 1 diabetes is an autoimmune disease characterized by the progressive destruction of the pancreatic beta cells that produce insulin. In addition, patients with type 1 diabetes also exhibit significant bowel alterations, with low-grade local inflammation, weakened mucosal integrity, and disruption of the immune system and of gut microbiota. 

    The authors sought to better understand the mechanisms responsible for these alterations. They showed a loss of production by mucosal immune cells of cytokines (IL-17 and IL-22) that are involved in strengthening the intestinal barrier. The production of these cytokines is stimulated by specific bacteria in the microbiota, such as the segmented filamentous bacteria (SFB) which gradually disappears from the intestinal microbiota of animals which will develop diabetes. Thus, these animals exhibit a loss of mucus production, an increased permeability of the digestive mucosa, and an increased passage of compounds and bacteria from the microbiota in the bloodstream to the liver.

     

    But why these anomalies? Since type 1 diabetes is both an autoimmune disease and a metabolic disease, two mechanisms might cause these alterations: intestinal inflammation on the one hand, and hyperglycemia on the other.

    Using murine models of hyperglycemia without inflammation and murine models of inflammatory diabetes by transfer of diabetogenic immune cells, the authors discovered that only inflammatory models made it possible to identically recapitulate alterations in the intestinal mucosa and microbiota, including the loss of SFB. Thus, autoimmune cells attacking the pancreas can also migrate into the intestine and can cause local deleterious inflammation mediated by TNF-alpha.

     

    Mouse models of type 1 diabetes show inflammatory alterations of the gut mucosa and microbiota with loss of cytokines (IL-17A, IL-22 and IL-23A) that stimulate the integrity of the digestive barrier. Anti-inflammatory treatment helps blocking these changes and reduces the incidence of diabetes. SFB: Segmented filamentous bacteria, TNF: Tumor necrosis factor.

    © BMJ

     

     

     

    Finally, by giving anti-TNF-alpha antibody treatment to animals that had received diabetogenic immune cells, the authors observed an increase in intestinal mucosa integrity, a lower alteration of the microbiota, a decrease in inflammation and above all, a decrease in incidence of diabetes.

     

    These results thus underline the importance of alterations in the intestine in the pathophysiology of type 1 diabetes as well as the therapeutic potential associated with their treatment.

     

    Reference

    Rouland M*, Beaudoin L*, Rouxel O*, Bertrand L*, Cagninacci L, Saffarian A, Pedron T, Gueddouri D, Guilmeau S, Burnol A-F, Rachdi L, Tazi A, Mouriès A, Rescigno M, Vergnolle N, Sansonetti P, Rogner UC, Lehuen A. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia. Gut (2021) doi: 10.1136/gutjnl-2020-323664 (*co-authors)

     

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