Abstract
Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNFα, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis (LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1β in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1β, TNF-α and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.
Highlights
Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis that primarily afflicts preterm infants after the onset of enteral feeding
The primary predisposing factor for NEC is prematurity, which is associated with 1) immature mucosal barrier development, 2) altered barrier responses associated with increased susceptibility to inflammation and loss of epithelial integrity; and 3) abnormal intestinal microbiota patterns [20, 21]
In the field of early microbial interactions and infant disease prevention studies, evidence indicates that maternal probiotic supplementation during pregnancy and breastfeeding could be effective in reducing the risk of immune/inflammatory and metabolic diseases in both mother and infants [24]
Summary
Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis that primarily afflicts preterm infants after the onset of enteral feeding. It is the most frequent gastrointestinal emergency of preterm infants, representing a major cause of morbidity and death in neonates [1]. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development [2,3,4,5]. Recent studies have indicated that prematurity remains the most consistent risk factor for developing NEC. The increased susceptibility of preterm infants to developing NEC is attributed to immature mucosal barrier development, increased susceptibility to inflammation and loss of epithelial integrity and abnormal intestinal microbiota patterns [1, 7]
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