Of Rats and Infants and Necrotizing Enterocolitis

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 27 · Number 3 · Spring 1984 OF RATS AND INFANTS AND NECROTIZING ENTEROCOLITIS HOWARD MOLTZ* Necrotizing enterocolitis (NEC) is a disease of the human infant, estimated to cause death in fully one-third of those afflicted [I]. Symptomatologically , NEC is characterized by gaseous abdominal distension, gastric retention and emesis, intestinal bleeding, and, in the terminal stages, perforation of the ileum and colon resulting in overwhelming sepsis. The mean age at the time of onset is 5-10 days, although the symptoms often appear as early as 24 hours and as late as 2 months postpartum [2-4]. Although NEC was first described more than a century ago, it has come to be recognized as a clinical problem only during the last 20 years [5, 6]. The incidence of the disease, at least in the United States, is difficult to assess: data concerning frequency of occurrence range from 1% to as high as 7.5% in newborn and premature nurseries and intensive care units [7-9]. Necrotizing enterocolitis appears in outbreaks or periodic clusters that are entirely unpredictable. This epidemic occurrence suggests an infectious etiology. And, indeed, certain Enterobacteriaceae, such as Escherichia coli and Klebsiellapneumoniae, have been implicated in the pathogenesis of the disease [10-16]. However, the mechanism of their pathogenicity in relation to NEC has not been established [17-19]. Perhaps, as McNeish, Fleming, Turner, and Evans [20] suggested, E. coli and Klebsiella species, when given the opportunity to adhere to the mucosal sur- *Committee on Biopsychology, University of Chicago, 5848 University Avenue, Chicago, Illinois 60637.© 1984 by The University of Chicago. AU rights reserved. 0031-5982/84/2703-0392$01.00 Perspectives in Biology and Medicine, 27, 3 · Spring 1984 \ 327 face of the intestine, proliferate and then become invasive and enterotoxigenic . There are several risk factors predisposing the human neonate to necrotizing enterocolitis. The most obvious is prematurity—infants with birth weights below 2,000 grams account for 80% ofthe cases [I]. And as might be expected, the lower the birth weight, the higher the mortality [1,3,6,7,21, 22]. Stress, in the form ofhypoxia or cold, also predisposes the infant to NEC [23-25]. Under stress, blood is shunted away from the mesenteric vascular bed to maximize oxygen delivery to the heart and brain [26, 27]. This redistribution of blood produces splanchnic ischemia , making the mucosa of the gut susceptible to bacterial adherence and subsequent bacterial invasion [20, 28-30]. A third risk factor often implicated in the etiology of NEC is oral feeding [5, 31, 32]. Food in the gastrointestinal tract, to the extent that it slows intestinal motility, promotes the overgrowth of enteropathogenic organisms. Moreover, fat, a major component of the infant diet, is poorly absorbed from the infant gut and provides a substrate for bacterial proliferation [12]. Acute enteritis is often seen in neonatal animals. Piglets, for example, frequendy suffer from a disease called "colibacillosis," the symptoms of which parallel those of NEC [33]. Moreover, an NEC-like syndrome has been induced experimentally in the neonatal laboratory rat. The disease in each species carries such signs as gastric distension, delayed gastric emptying, and hemorrhagic and necrotic sites in the bowel [34-36]. In both the piglet and rat, stress has been identified as a predisposing condition, and E. colt has been implicated in the pathogenesis of the observed enteritis [33, 37]. Indeed, the isolation of E. coli in essentially pure culture from the small intestine of a piglet that was alive shortly before necropsy is now taken as definitive evidence ofcolibacillosis [38]. That NEC or an NEC-like syndrome can be induced in the neonatal laboratory rat, and that it probably occurs spontaneously in the wild, has led us to formulate a hypothesis about a phenomenon my students and I have been investigating for over a decade. The phenomenon concerns the release of a pheromone by the lactating rat that strongly attracts preweanling young. This pheromone is carried in the feces of the female [39] and is first emitted 14 days after the start oflactation. It ceases to be emitted at approximately 27 days [40]. In parallel with the female's emission of the pheromone is...