IL-18 maintains the homeostasis of mucosal immune system via inflammasome-independent but microbiota-dependent manner.

Inflammasomes and their product interleukin 18 (IL-18) play important roles in gut microbiota monitoring and homeostasis, and their loss of function could lead to microbiota dysbiosis and accelerate disease progression. However, the impacts of the resulting microbiota dysbiosis on the mucosal immune system are largely unknown. Here, we show that dysbiotic microbiota from Il18-/- mice induced immune cell loss in the small intestine (SI) in an inflammasome-independent manner. Cohousing experiments revealed that the immunotoxic phenotype of these microbiota was transferable to wild type (WT) mice and induced immune cell death through the receptor-interacting protein kinase 3 (RIP3)-mixed lineage kinase domain like pseudokinase (MLKL) pathway. Analysis of microbiota composition identified two types of bacteria at the genus level, Ureaplasma and Parasutterella, that accumulated in Il18-/- mice and negatively mediated changes in immune cells in the SI. Furthermore, dysbiosis in Il18-/- mice also contributed to increased susceptibility to Listeria infection. Collectively, our results demonstrate that IL-18 is essential to microbiota homeostasis and that dysbiotic microbiota could significantly shape the landscape of the immune system.