Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions

Abstract

Diet-induced metabolic endotoxemia is an important factor in the development of many chronic diseases in animals and man. The gut epithelium is an efficient barrier that prevents the absorption of liposaccharide (LPS). Structural changes to the intestinal epithelium in response to dietary alterations allow LPS to enter the bloodstream, resulting in an increase in the plasma levels of LPS (termed metabolic endotoxemia). LPS activates Toll-like receptor-4 (TLR4) leading to the production of numerous pro-inflammatory cytokines and, hence, low-grade systemic inflammation. Thus, metabolic endotoxemia can lead to several chronic inflammatory conditions. Obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) can also cause an increase in gut permeability and potential pharmacological and dietary interventions could be used to reduce the chronic low-grade inflammation associated with endotoxemia.

Keywords: Toll-like receptor; antimicrobial peptides; gut permeability; high-fat diet; lipopolysaccharide; metabolic endotoxemia.

Figure 1

The Structure of LPS. LPS is made up of three parts: Lipid A, core, and the O-polysaccharide chain. Covalently attached to lipid A is the core part of the molecule, divided into the inner and outer core. The inner core is next to the lipid A section, which contains sugars such as L-glycerol-D-manno heptose (Hep) and 3-deoxy-D-manno-octulosonic acid (Kdo). The outer core contains common sugars such as hexosamines and hexoses (Hex). Attached to the outer core are repeating subunits of oligosaccharides, referred to as the O-chain (3). Adapted from Erridge et al. (3).

Figure 2

TLR4 signaling via MyD88-dependent and independent pathway to activate NFkB related target genes: Upon stimulation of myeloid differentiation primary response protein 88 (MyD88) dependent pathway involves the activation of MyD88 which recruits IL-1 receptor-associated kinase-4 (IRAK-4). IRAK-4 phosphorylates IRAK-1 and allows tumor necrosis factor receptor associated factor 6 (TRAF6) to associate with IRAK1. IRAK1/TRAF6 then activates TAK₁, TAB₁, and TAB₂. The TRAF6, TAK₁, TAB₁, and TAB₂ forms a larger complex with ubiquitin-conjugating enzyme E32 variant 1 isoform A (Ubc13) and Uev1A which activates TAK₁. Polyubiquitin chain is then removed by A20 and conserved cylindromatosis (CYLD). Activated TAK₁ phosphorylates the IKK complex (IKKα. IKKβ and IKKγ) ultimately resulting in the translocation of nuclear factor-κB (NF-κB) into the nucleus, resulting in the transcription of proinflammatory cytokines. MyD88 independent pathway involves TIR-domain-containing adapter-inducing interferon-β (TRIF) leading to the activation of TNF receptor associated factor 3 (TRAF3) and the translocation of interferon regulatory factor 3 (IRF3) to the nucleus leading to IFNB gene transcription. Image made using BioRender.

Figure 3

Components of the intestinal epithelial cells of the small intestine. The intestinal epithelium is composed of a signal layer of intestinal epithelial cells (IECs) covered by a mucus layer continuously secreted by goblet cells to act as a first physical barrier against pathogenic bacteria. The outer mucus layer is colonized by bacteria whereas the inner mucus is a bacteria-free loose layer. Paneth cell secrete antimicrobial peptides (AMPs) into the inner mucus and enteroendocrine cells produce hormones where secretory IgA (sIgA) are also present to protect against commensal bacteria and contribute to the formation of a biochemical barrier. Stem cells are located at the base of the crypt that give rise to four cells in the intestinal epithelial: enterocytes, enteroendocrine cells, goblet cells, and Paneth cells that migrate upwards and move to the distal end of a villus where they are shed. Enteroendocrine cells produce hormones, goblet cells produce mucus, and Paneth cells produce AMPs. Other cells include truft cells, macrophages, dendritic cells T-cells, B-cells, and M-cells in the Peyer’s patches of the intestine involved in transporting antigens from the lumen to cells of the immune system. Image made using BioRender.

Figure 4

Intestinal epithelial cell junctional proteins. Tight junctions are at the apical end of junctional complexes composed of three transmembrane proteins: occludin claudins and junctional adhesion molecules (JAMs) that bind intracellular membrane proteins, zonula occludens (ZOs) which connects the transmembrane tight junction to the actin skeleton. Below the tight junctions are adherens junctions composed of transmembrane proteins, E-cadherin and nectin linked to the cytoskeleton by scaffolding proteins, catenin and afadin linked to actin filaments. Desmosomes are made up of the transmembrane liner glycoproteins, desmoglein and democollin which are cadherin proteins linked to intermediate keratin filaments. Gap junctions form a tunnel for small molecules to pass between adjacent epithelial cells. Image made using BioRender.

Figure 5

Comparison between a healthy and “leaky gut.” A “leaky gut” affects the lining of the intestine and tight junctions are damaged in response to stress for example, a high-fat diet, this allows the passage of LPS and other pathogens into the bloodstream, causing the activation of the immune system and inflammation. Image made using BioRender.