Abstract
Necrotizing enterocolitis (NEC) is a serious intestinal disease that occurs in newborn infants. It is associated with major morbidity and affects 5% of all infants admitted to neonatal intensive care units. Probiotics have variable efficacy in preventing necrotizing enterocolitis. Tight junctions (TJ) are protein complexes that maintain epithelial barrier integrity. We hypothesized that the probiotics Lactobacillus rhamnosus and Lactobacillus plantarum strengthen intestinal barrier function, promote TJ integrity, and protect against experimental NEC. Both an in vitro and an in vivo experimental model of NEC were studied. Cultured human intestinal Caco-2 cells were pretreated with L. rhamnosus and L. plantarum probiotics. TJ were then disrupted by EGTA calcium switch or LPS to mimic NEC in vitro. Trans-epithelial resistance (TER) and flux of fluorescein isothiocynate dextran was measured. TJ structure was evaluated by ZO-1 immunofluorescence. In vivo effects of ingested probiotics on intestinal injury and ZO-1 expression were assessed in a rat model of NEC infected with Cronobacter sakazakii (CS). Caco-2 cells treated with individual probiotics demonstrated higher TER and lower permeability compared to untreated cells (p<0.0001). ZO-1 immunofluorescence confirmed TJ stability in treated cells. Rat pups fed probiotics alone had more intestinal injury compared with controls (p=0.0106). Probiotics were protective against injury when given in combination with CS, with no difference in intestinal injury compared to controls (p=0.21). Increased permeability was observed in the probiotic and CS groups (p=0.03, p=0.05), but not in the probiotic plus CS group (p=0.79). Lactobacillus sp. strengthened intestinal barrier function and preserved TJ integrity in an in vitro experimental model of NEC. In vivo, probiotic bacteria were not beneficial when given alone, but were protective in the presence of CS in a rat model of NEC.
Highlights
Necrotizing enterocolitis (NEC) is an inflammatory intestinal disorder that affects premature infants
Trans-epithelial resistance (TER) was used as a measure of membrane barrier resistance and Tight junctions (TJ) disruption
TER was monitored throughout pretreatment with the probiotics, and again after the addition of the membrane-disrupting reagents [15]
Summary
Necrotizing enterocolitis (NEC) is an inflammatory intestinal disorder that affects premature infants. NEC is associated with an average mortality of 15–30%, but may be as high as 75–85% in its most severe forms [2,3]. Survivors may require surgical resection of necrotic bowel and incur associated morbidities, including short gut syndrome, growth delay, and neurodevelopment disorders [4]. The pathophysiology of NEC is not well understood and as a result, care is mostly supportive with no defined preventative therapy available. There currently are no recommended strategies that consistently prevent NEC [5,6]. The possibility of administering probiotic species to protect at-risk infants from developing NEC is a captivating concept that has received significant attention [7]
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