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

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 FINDINGS: Using 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. CONCLUSIONS: MOS 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

The Protracted Evolution of a Plate Boundary: Eastern Cuba Block and Old Bahamas Channel

International audienceThe Eastern Cuban block has experienced a complex tectonic history characterized by plate interactions, resulting in a diverse array of geological features observable in the offshore sedimentary record. We investigate the tectonic evolution of offshore Eastern Cuba, specifically in the Old Bahamas Channel and its surrounding areas, by integrating multi‐channel seismic (MCS) reflection and published geological data. Our analysis employs stratigraphic frameworks and MCS data to assess deformation and key geological events in the region. We highlight the complex tectonic history of the Eastern Cuban block, marked by significant geodynamic events, such as rifting, the subduction of the oceanic Proto‐Caribbean plate, and syn‐orogenic and post‐orogenic phases. The seismic units observed in the majority of the study area reveal the early evolution of the Northern Proto‐Caribbean margin, subsequently impacted by the Cuban orogeny and the reactivation of the Cuban Transform Fault zone corresponding to a former plate boundary. We propose estimated ages for the seismic sequences, correlating them with available well data from neighboring regions. This study offers valuable insights into the tectonic history and geological evolution of offshore Eastern Cuba, contributing to a more comprehensive understanding of the region's geodynamic development

Schematic illustration of MOS effects on glucose metabolism between control and LPS-challenged hosts.

<p>(i) LPS triggered no major intestinal metabolic activities; (ii) in absence of glucose mobilization, liver glucose uptake and transport were repressed by <i>DIO2</i> down-regulation and <i>KCNA3</i> up-regulation, respectively; (iii) glycolysis and glycogen synthesis were coordinately reduced by <i>ENO2</i> and <i>UGP2</i> down-regulation, respectively; (iv) <i>CS</i> up-regulation increased TCA-derived energy from high liver pyruvate; (v) <i>PRKAG2</i> up-regulation inhibited fatty acid and cholesterol biosynthesis.</p

Schematic illustration of LPS effects on glucose metabolism between MOS- and VIRG-fed hosts.

<p>(i) LPS caused no major intestinal metabolic activities in MOS-fed hosts; (ii) in absence of liver glucose mobilization, <i>KCNA3</i> was up-regulated, whereas <i>ENO2</i> and <i>UGP2</i> down-regulation reduced glycolysis and glycogen synthesis, respectively; (iii) <i>CS</i> up-regulation increased TCA cycle-derived energy from high liver pyruvate; (iv) <i>ACLY</i>, <i>ME</i> and <i>FAS</i> down-regulations inhibited liver fatty acid biosynthesis; whereas PRKAG2 up-regulation inhibited fatty acid and cholesterol biosynthesis.</p

Genes identified as differentially expressed due to LPS within antibiotic-fed hosts¹.

1<p>Hosts fed antibiotic (VIRG): LPS-challenged v/s non-challenged controls; The complete raw data have been deposited in the Gene Expression Omnibus (GEO) database, <a href="http://www.ncbi.nlm.nih.gov/projects/geo" target="_blank">www.ncbi.nlm.nih.gov/projects/geo</a> (accession no. GSE28959).</p>2<p>+: up-regulated genes by LPS; −: down-regulated genes by LPS.</p

Schematic illustration of VIRG effects on glucose metabolism between control and LPS-challenged hosts.

<p>(i) LPS increased intestinal gluconeogenesis by up-regulating <i>PEPCK</i>; (ii) mobilized glucose increased liver glycolytic activities through <i>ENO2</i> up-regulation; (iii) <i>CS</i> down-regulation reduced utilization of glycolytic substrates by the TCA cycle for energy; (iv) <i>ACLY</i>, <i>ME</i> and <i>FAS</i> up-regulations increased liver fatty acid biosynthesis from high liver citrate.</p

Concentrations of liver metabolites.

<p>Among VIRG-fed hosts, LPS reduced liver citrate, but increased pyruvate levels (<i>A</i>). However, higher citrate and lower pyruvate levels were observed in liver of LPS-challenged hosts fed MOS than VIRG (<i>B</i>). Data are presented as mean ± SEM (<i>n</i> = 6). *, <i>P</i><0.05, **, <i>P</i><0.01 by Scheffe's <i>t</i> test.</p

Genes identified as differentially expressed due to LPS within MOS-fed hosts¹.

1<p>Hosts fed MOS: LPS-challenged v/s non-challenged controls; The complete raw data have been deposited in the Gene Expression Omnibus (GEO) database, <a href="http://www.ncbi.nlm.nih.gov/projects/geo" target="_blank">www.ncbi.nlm.nih.gov/projects/geo</a> (accession no. GSE28959).</p>2<p>+: up-regulated genes by LPS; −: down-regulated genes by LPS.</p

Genes identified as differentially expressed due to main LPS effects¹.

1<p>Pooled LPS-challenged hosts: MOS+VIRG (antibiotic) groups; The complete raw data have been deposited in the Gene Expression Omnibus (GEO) database, <a href="http://www.ncbi.nlm.nih.gov/projects/geo" target="_blank">www.ncbi.nlm.nih.gov/projects/geo</a> (accession no. GSE28959).</p>2<p>+: up-regulated genes by LPS; −: down-regulated genes by LPS.</p