Further insights regarding a potential role for TLR signaling in the pathogenesis of intestinal inflammation may be learned from studying genetic polymorphisms in humans with diseases of intestinal inflammation and sepsis. The TLR4 Asp299Gly mutation is known to render TLR4 hyporesponsive to endotoxin (99) . This mutation has been associated with an increased incidence of inflammatory bowel disease (ulcerative colitis and Crohn's disease) (100, 101) . Furthermore, pancolitis, the most severe manifestation of ulcerative colitis, is more common in patients with the TLR1 Arg80Thr polymorphism and the TLR2 Arg753Gly polymorphism (102) . In patients with Crohn's disease, the TLR1 Ser602Ile polymorphism is associated with a reduced risk of developing ileal disease (102) . While no genetic polymorphisms have been associated with NEC, further study is necessary as the current observations were made on small cohorts of patients (103) .