Abstract
Balance among the complex interactions of the gut microbial community is important for intestinal health. Probiotic bacteria can improve bacterial balance and have been used to treat gastrointestinal diseases. Neonatal necrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disorder primarily affecting premature infants. NEC is associated with extensive inflammatory NF-κB signaling activation as well as intestinal barrier disruption. Clinical studies have shown that probiotic administration may protect against NEC, however there are safety concerns associated with the ingestion of large bacterial loads in preterm infants. Bacteria-free conditioned media (CM) from certain probiotic organisms have been shown to retain bioactivity including anti-inflammatory and cytoprotective properties without the risks of live organisms. We hypothesized that the CM from Lactobacillus acidophilus (La), Bifidobacterium infantis (Bi), and Lactobacillus plantarum (Lp), used separately or together would protect against NEC. A rodent model with intestinal injury similar to NEC was used to study the effect of CM from Lp, La/Bi, and La/Bi/Lp on the pathophysiology of NEC. All the CM suppressed NF-κB activation via preserved IκBα expression and this protected IκBα was associated with decreased liver activity of the proteasome, which is the degrading machinery for IκBα. These CM effects also caused decreases in intestinal production of the pro-inflammatory cytokine TNF-α, a downstream target of the NF-κB pathway. Combined La/Bi and La/Bi/Lp CM in addition protected intestinal barrier function by maintaining tight junction protein ZO-1 levels and localization at the tight junction. Double combined La/Bi CM significantly reduced intestinal injury incidence from 43% to 28% and triple combined La/Bi/Lp CM further reduced intestinal injury incidence to 20%. Thus, this study demonstrates different protective mechanisms and synergistic bioactivity of the CM from different organisms in ameliorating NEC-like intestinal injury in an animal model.
Highlights
Necrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disorder that affects approximately 10% of premature infants born,1500 gm
Pups were subjected to major risk factors for human NEC, resulting in changes in the immature rat pups similar to those found in humans as follows: the abdomen was distended, blood was detected in the stool, and the ileum and proximal colon were the most affected parts of the intestine [37]
Combined conditioned media (CM) from all three organisms further reduced NEC-like intestinal injury incidence from 43% to 20% (n = 41, p = 0.0064)
Summary
Necrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disorder that affects approximately 10% of premature infants born ,1500 gm. It has been hypothesized that the immature intestinal barrier of the preterm gut results in increased translocation of intestinal microbiota across the epithelium. In response to bacterial stimulation, increased NF-kB signaling of the immature enterocyte leads to exaggerated production of inflammatory cytokines, resulting in further barrier disruption and intestinal necrosis which causes the signs and symptoms of disease [7,8,9,10]. The mechanisms by which probiotics protect against intestinal diseases include optimization of microbial balance, competitive exclusion of pathogens, promotion of mucus secretion and bacteriocin production, enhancement of barrier integrity, and maturation of intestinal immunity [14]
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