Abstract
Background Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown.Methods and Principal FindingsUsing a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy demands were sufficiently met through TCA citrate-derived energy, as indicated by CS up-regulation.ConclusionsMOS terminated inflammation earlier than VIRG and reduced glucose mobilization, thus representing a novel biological strategy to alleviate Salmonella-induced systemic inflammation in human and animal hosts.
Highlights
Salmonella is a leading human food-borne pathogen, worldwide [1]
To make a clear distinction between the effects of Mannose-rich oligosaccharides (MOS) and VIRG among hosts within the physiological and inflammatory (LPS-challenged) conditions, we relied on microarray results that detailed the coordinately regulated biological mechanisms underlying innate immunity and nutrient metabolism
All data files from this experiment have been deposited into the MIAME compliant Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih. gov/projects/geo
Summary
Salmonella is a leading human food-borne pathogen, worldwide [1]. The pathogen invades the intestinal epithelium by using its specialized Type III secretory systems (T3SS) to cause acute systemic or extra-intestinal inflammation [2]. Has Salmonella become more difficult to control in poultry production, but antibiotic treatment of Salmonella-induced gastrointestinal and systemic infections has become less successful among hospitalized patients, causing higher death rates [1], [4]. Evidence exist that mannose-rich oligosaccharides (MOS), purified from cells walls of Saccharomyces cerevisiae, competitively binds mannose-specific lectin, namely FimH, of Gram-negative bacteria expressing the Type 1 fimbriae, including Salmonella, thereby reducing their adherence to mannose-containing glycoprotein receptors on intestinal epithelial cells in humans and chickens [5], [6]. Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. Molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown
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