Nlrp3-R258W Mutation Protects Mice from Animal Models of Colitis and Colorectal Cancer

Inflammatory bowel disease (IBD) has long been a prominent threat to human health. Moreover, uncontrolled progression of IBD can lead to increased risk for colorectal cancer. As an important gene in the innate immune system, NLRP3 has been linked with IBD and colorectal cancer, however the research results are controversial, which prompted us to study the role of NLRP3 in these diseases further. Using mice carrying the Nlrp3^-R258W mutation which acquires an autoactivation of the NLRP3 inflammasome, we discovered that this mutation provided the mice with significant protection from DSS induced colitis. It was found that the Nlrp3^-R258W mice exhibited dramatically less weight loss and mortality compared with wildtype controls. Our data also showed that the Nlrp3^-R258W mice generated less proinflammatory cytokines/chemokines such as IL-6 and COX2, but produced more protective cytokine such as IL-18. More surprisingly, cohousing of Nlrp3^-R258W mice with wildtype mice reduced their resistance to DSS colitis, which indicated that microbiota played a key role during the regulation of IBD by the Nlrp3^-R258W mutation. In addition, from AOM/DSS induced colorectal cancer model, we found a similar protective effect in the Nlrp3^-R258W mice, which was also dependent on the microbiota from the mutation mice as evidenced by cohousing experiments. In summary, we have demonstrated that the Nlrp3^-R258W mutation led to a shift in the microbiota of the mice, which turned out to be a key causative factor to mediate the resistance to colitis and colorectal cancer.