Inflammatory bowel disease (IBD) remain major clinical challenges and are currently incurable. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, and TNFR1 polymorphisms have been described in IBD patients. Interleukin 10 (IL-10) receptor deficiency has been linked to early-onset human IBD and mice lacking expression of IL-10 develop spontaneous colitis from loss of immune tolerance to normal gut microbiota. We have shown that combining IL-10 deficiency with loss of TNFR1 results in severe colitis by 8 weeks.