Submitted: 06/01/12

Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Immaturity of the innate immune system of the gut is cen-tral to the pathogenesis of NEC. Recent studies suggest a key role for Paneth cells in this disease. Addressing basic ques-tions on the development and function of immature Paneth cells may shed light on the puzzling pathophysiology of NEC. Current animal models of NEC are lim-ited in their capacity to answer these questions. Paneth cells are highly specialized secre-tory cells located at the base of the crypts of Lieberkühn in the small intestine that play a central role in intestinal innate immunity. Paneth cell granules contain high concentrations of antimicrobial pep-tides and various immune mediators that are released into the intestinal lumen to shape the intestinal microbiota and protect the intestinal epithelium and its stem cells against pathogens.1 In the human fetus, Paneth cells first appear in the first trimes-ter, mature by the current age of viability (22–24 weeks gestation), and increase in numbers by term gestation. The role of Paneth cells in utero is unknown given that there are few, if any, bacteria in the fetal gut. Microbial colonization of the intestine of the premature infant begins at birth, and the dynamics differ signifi-cantly from that of the term infant due to antibiotic exposure, environmental factors including those due to prolonged hospital-ization, and immaturity of virtually every aspect of neonatal intestinal immunity (including Paneth cell function). The distribution of Paneth cells along the healthy intestine reflects the differing physiology of the small intestine and the Paneth cells and necrotizing enterocoliti