Current models of necrotizing enterocolitis (NEC) propose that intraluminal 
microbes destroy intestinal mucosa and activate an inflammatory cascade that 
ends in necrosis. We suggest an alternate hypothesis wherein NEC is caused by 
injury to Paneth cells (PCs) in the intestinal crypts. PCs are specialized 
epithelia that protect intestinal stem cells from pathogens, stimulate stem cell 
differentiation, shape the intestinal microbiota, and assist in repairing the 
gut. Our novel model of NEC uses neonatal mice and ablates PCs followed by 
enteral infection. We contrast this model with other animal examples of NEC and 
the clinical disease. Selective destruction of PCs using dithizone likely 
releases tumor necrosis factor-α and other inflammatory mediators. We propose 
that this event produces inflammation in the submucosa, generates 
platelet-activating factor, and induces a coagulopathy. The role of PCs in NEC 
is consistent with the onset of disease in preterm infants after a period of 
PC-related maturation, the central role of PCs in crypt-related homeostasis, the 
anatomic location of pneumatosis intestinalis close to the crypts, and the 
proximity of PCs to occluded blood vessels that cause coagulation necrosis of 
the intestinal villi. We offer this hypothesis to promote new thoughts about how 
NEC occurs and its potential prevention.