Abstract
Dendritic cells (DCs) constitute the first point of contact between gut commensals and our immune system. Despite growing evidence of the immunomodulatory effects of probiotics, the interactions between the cells of the intestinal immune system and bacteria remain largely unknown. Indeed,, the aim of this work was to determine whether the probiotic Bifidobacterium breve CNCM I-4035 and its cell-free culture supernatant (CFS) have immunomodulatory effects in human intestinal-like dendritic cells (DCs) and how they respond to the pathogenic bacterium Salmonella enterica serovar Typhi, and also to elucidate the molecular mechanisms involved in these interactions. Human DCs were directly challenged with B. breve/CFS, S. typhi or a combination of these stimuli for 4 h. The expression pattern of genes involved in Toll-like receptor (TLR) signaling pathway and cytokine secretion was analyzed. CFS decreased pro-inflammatory cytokines and chemokines in human intestinal DCs challenged with S. typhi. In contrast, the B. breve CNCM I-4035 probiotic strain was a potent inducer of the pro-inflammatory cytokines and chemokines tested, i.e., TNF-α, IL-8 and RANTES, as well as anti-inflammatory cytokines including IL-10. CFS restored TGF-β levels in the presence of Salmonella. Live B.breve and its supernatant enhanced innate immune responses by the activation of TLR signaling pathway. These treatments upregulated TLR9 gene transcription. In addition, CFS was a more potent inducer of TLR9 expression than the probiotic bacteria in the presence of S. typhi. Expression levels of CASP8 and IRAK4 were also increased by CFS, and both treatments induced TOLLIP gene expression. Our results indicate that the probiotic strain B. breve CNCM I-4035 affects the intestinal immune response, whereas its supernatant exerts anti-inflammatory effects mediated by DCs. This supernatant may protect immune system from highly infectious agents such as Salmonella typhi and can down-regulate pro-inflammatory pathways.
Highlights
Probiotic bacteria including lactobacilli and bifidobacteria are part of a normal intestinal microbiota in humans and generally considered as potentially beneficial to various aspects of host metabolism [1]
The CFS decreased the release of pro-inflammatory cytokines (e.g., IL-6 and IL-12p40) and chemokines (e.g., RANTES/CCL5 and MIP1a/CCL3) in human intestinal dendritic cells (DCs) challenged with S. typhi (Figures 1 to 3)
A few studies have addressed the effects of bifidobacteria on human immunocompetent cells [27,28,29]; to the best of our knowledge, this is the first study to analyze the immune response to human intestinal-like DCs developed from CD34+ progenitor cells isolated from the umbilical cord blood
Summary
Probiotic bacteria including lactobacilli and bifidobacteria are part of a normal intestinal microbiota in humans and generally considered as potentially beneficial to various aspects of host metabolism [1]. The probiotic properties of commensal bacteria including lactobacilli and bıfidobacteria are likely to be determined at least in part by their effects on dendritic cells (DCs) [1], a complex, heterogeneous group of multifunctional antigen-presenting cells (APCs) that comprise a critical arm of the immune system [14,15]. These cells play a critical role in the orchestration of the adaptive immune response by inducing tolerance and adaptive immunity. The binding of microbe-associated molecules to these receptors can activate APCs and initiate a signaling transduction cascade that leads to the release of cytokines and initiation of the acquired immune response [18]
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