Does Obesity or Hyperglycemia Alter Metabolic Endotoxemia?

Abstract

Obesity increases the risk of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Changes in the composition of intestinal bacteria are associated with obesity, T2D, and NAFLD. An important goal is to move beyond characterizing microbial taxonomy and identify bacterial derived components that can impact host immunity and metabolism. Postbiotics are bacterial components or metabolites derived from living or dead bacteria. Lipopolysaccharide (LPS) is a postbiotic that engages host immunity and influences inflammation through activation of toll-like receptor 4 (TLR4). Activation of TLR4 by LPS induces production of pro-inflammatory cytokines, but certain types of LPS can antagonize TLR4. Metabolic endotoxemia describes a chronic, low-level increase of LPS in blood during metabolic disease. We recently discovered that the type of LPS determines beneficial or detrimental impact on metabolism. The type of LPS is dictated by different species (or strains) of bacteria. Features of metabolic disease that alter the type of metabolic endotoxemia are not known. Changes in bacterial composition or gut barrier function are positioned to alter the balance of LPS in the gut lumen and in circulation. We set out to understand whether obesity or hyperglycemia can alter the TLR4 activation properties in the gut and circulation during metabolic endotoxemia using mouse models of obesity and hyperglycemia, and human samples. We found that hyperglycemia leads to increased fecal TLR4 activation. Further, obesity or hyperglycemia was sufficient to increase TLR4 activation in both the portal and systemic circulation of mice during a fed-state. Finally, obesity in humans increases systemic TLR4 activation. This work is important in furthering our understanding of how metabolic disease characteristics can alter inflammation. Future work will investigate how specific dietary components alter TLR4 activity in the gut lumen and circulation and determine how obesity and hyperglycemia alter the activation of other pattern recognition receptors.