Cell Walls of <em>Saccharomyces cerevisiae</em> Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

<div><h3>Background</h3><p><em>Salmonella</em> 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. <em>Salmonella</em> has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of <em>Saccharomyces cerevisiae</em> have shown to bind mannose-specific lectin of Gram-negative bacteria including <em>Salmonella</em>, 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.</p> <h3>Methods and Principal Findings</h3><p>Using a <em>Salmonella</em> 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 <em>IL-3</em>, but not <em>TNF-α</em>, <em>IL-1</em> or <em>IL-6</em>, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced <em>IL-3</em> expression in control hosts. Consequent to LPS challenge, <em>IL-3</em> 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 (<em>PEPCK</em>) and liver glycolysis (<em>ENO2</em>), and intriguingly liver fatty acid synthesis through <em>ATP citrate synthase</em> (<em>CS</em>) down-regulation and <em>ATP citrate lyase</em> (<em>ACLY</em>) and <em>malic enzyme</em> (<em>ME</em>) up-regulations. However, MOS host's lower energy demands were sufficiently met through TCA citrate-derived energy, as indicated by <em>CS</em> up-regulation.</p> <h3>Conclusions</h3><p>MOS terminated inflammation earlier than VIRG and reduced glucose mobilization, thus representing a novel biological strategy to alleviate <em>Salmonella</em>-induced systemic inflammation in human and animal hosts.</p>