In summary, our results demonstrate that the activation of AIM2 in the small intestine leads to IL-18 release, which regulates the expression of ZO-1, claudin-2 and RegIIIγ expression, thus improving the intestinal barrier function, which controls gut microbiota translocation to PLNs and the generation of a proinflammatory response against insulin-producing β cells, thus delaying STZ-induced T1D progression in our murine model. Here, TJP1 is linked to type 1 diabetes mellitus.