Abstract
Combination regimens of Bifidobacterium infantis and Lactobacillus acidophilus have been demonstrated to prevent necrotizing enterocolitis (NEC) in clinical trials. However, the molecular mechanisms responsible for this protective effect are not well understood. Additionally, conditioned media from individual cultures of these two probiotics show strain specific modulation of inflammation using in vitro human intestinal NEC models. Here we report a transcription profiling analysis of gene expression in immature human fetal intestinal epithelial cells (H4 cells) pretreated with conditioned media from B. infantis (BCM) or L. acidophilus (LCM) prior to IL-1β stimulation. Compared with control media, the two probiotic-conditioned media (PCM) treatments altered the expression of hundreds of genes involved in the immune response, apoptosis and cell survival, cell adhesion, the cell cycle, development and angiogenesis. In IL-1β-stimulated cells, PCM treatment decreased the upregulation of genes in the NF-κB activation pathway and downregulated genes associated with extracellular matrix (ECM) remodeling. Compared with LCM, BCM showed more significant modulatory effects on ECM remodeling, reflected by a lower p value. IL-6 and IL-8 production was significantly reduced in IL-1β-stimulated cells pretreated with PCM (p<0.05), which was consistent with their altered gene expression. Western blot analysis showed that compared with IL-1β stimulation alone, PCM treatment attenuated the decrease of cytoplasmic IκBα and NF-κB p65 levels as well as the increase of nuclear NF-κB p65 levels in the stimulated cells (p<0.05). In conclusion, PCM treatment exerted anti-inflammatory effects in immature human fetal enterocytes primarily by modulating genes in the NF-κB signaling and ECM remodeling pathways. Additionally, some components of these signaling pathways, particularly the ECM remodeling pathway, were more profoundly affected by BCM than LCM.
Highlights
As the incidence of premature birth increases and occurs at earlier gestational ages, the illequipped gastrointestinal tract is increasingly required to participate in the process of bacterial colonization within the extrauterine environment
Using established intestinal models for human gut development, this laboratory has demonstrated an immature expression of innate immune response genes resulting in exaggerated inflammatory responses to initial bacterial colonization, likely contributing to the development of necrotizing enterocolitis (NEC) [1,8,9,10]
We further demonstrated that B. infantis-conditioned media prevented the decrease of body weight, attenuated enterocyte apoptotic cell death, mitigated reduced mucin production and maintained ileal integrity in Cronobacter sakazakii-induced intestinal inflammation of newborn mice [24]
Summary
As the incidence of premature birth increases and occurs at earlier gestational ages, the illequipped gastrointestinal tract is increasingly required to participate in the process of bacterial colonization within the extrauterine environment. The interaction between the immature intestinal tract and colonizing bacteria may lead to the most common gastrointestinal emergency of premature infants, necrotizing enterocolitis (NEC) [1]. This devastating condition is manifested by extensive intestinal inflammation of the distal intestine and affects almost 10% of all infants with a birth weight less than 1500 g [2,3]. Mortality associated with this life-threatening disease is as high as 40% to 50% in infants who require surgical intervention. A major strategy for preventing NEC is to find a means of reducing the immature inflammatory response and to accelerate the maturation of intestinal defenses [8]
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