Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

Abstract

Lipopolysaccharide is a virulence factor of gram-negative bacteria with a crucial importance to the bacterial surface integrity. From the host's perspective, lipopolysaccharide plays a role in both local and systemic inflammation, activates both innate and adaptive immunity, and can trigger inflammation either directly (as a microbe-associated molecular pattern) or indirectly (by inducing the generation of nonmicrobial, danger-associated molecular patterns). Translocation of lipopolysaccharide into the circulation causes endotoxemia, which is typically measured as the biological activity of lipopolysaccharide to induce coagulation of an aqueous extract of blood cells of the assay. Apparently healthy subjects have a low circulating lipopolysaccharide activity, since it is neutralized and cleared rapidly. However, chronic endotoxemia is involved in the pathogenesis of many inflammation-driven conditions, especially cardiometabolic disorders. These include atherosclerotic cardiovascular diseases, obesity, liver diseases, diabetes, and metabolic syndrome, where endotoxemia has been recognized as a risk factor. The main source of endotoxemia is thought to be the gut microbiota. However, the oral dysbiosis in periodontitis, which is typically enriched with gram-negative bacterial species, may also contribute to endotoxemia. As endotoxemia is associated with an increased risk of cardiometabolic disorders, lipopolysaccharide could be considered as a molecular link between periodontal microbiota and cardiometabolic diseases.

Keywords: microbiota; mouth; oral infections; oral inflammation; plaque; saliva.

FIGURE 1

Membrane composition of gram‐positive and gram‐negative bacteria. A, Difference between membrane layers of gram‐positive and gram‐negative bacteria and the presence of lipopolysaccharide (LPS) on the outer membrane of the gram‐negative species. B, General chemical structure of lipopolysaccharide molecule composed of four chemically distinct moieties. Courtesy of Dr Alexander Strachan, University of Plymouth, UK

FIGURE 2

Lipopolysaccharide (LPS)‐toll‐like receptor 4 (TLR4) signaling. Lipopolysaccharide is recognized by the complex of toll‐like receptor 4, cluster of differentiation 14 (CD14), and myeloid differentiation 2 (MD‐2). Toll‐like receptor 4 activation leads to the recruitment of additional effector proteins, including myeloid differentiation primary response protein 88 (MYD88), toll/interleukin‐1 receptor domain‐containing adapter protein (TIRAP), toll/interleukin‐1 domain‐containing adaptor protein inducing interferon‐beta‐related adaptor molecule (TRAM), and toll/interleukin‐1 domain‐containing adaptor protein inducing interferon‐beta (TRIF). These further trigger a cascade enabling nuclear factor‐κB (NF‐κB) and interferon regulatory factor 3 (IRF3) to diffuse into the nucleus and to activate the transcription of cytokines, especially tumor necrosis factor alpha, interleukin‐1beta, interleukin‐6, and interleukin‐8, and interferons, aiming at eliminating pathogens. In the circulation, lipopolysaccharide is transported by lipopolysaccharide binding protein (LBP), phospholipid transfer protein (PLTP), and by lipoproteins. Under standard physiologic conditions, lipopolysaccharide preferentially associates with high‐density lipoprotein (HDL), which contributes to its clearance via the liver and bile

FIGURE 3

Lipopolysaccharide (LPS) of periodontal bacteria activates the innate and adaptive immune cascades and leads to the destruction of soft and hard tissues of the periodontium, leading to clinical signs of periodontitis. IL, interleukin; MMP, matrix metalloproteinase; MPO, myeloperoxidase; NK, natural killer; TGF, transforming growth factor; TNF, tumor necrosis factor; RANKL, receptor activator of nuclear factor‐κB ligand; ROS, reactive oxygen species

FIGURE 4

Translocation of lipopolysaccharide from the oral cavity to the circulation leads to endotoxemia, which may affect several organs and contribute to the development of various cardiometabolic disorders. ALD, alcoholic liver disease; NAFLD, nonalcoholic fatty liver disease

FIGURE 5

The association of missing teeth with serum lipopolysaccharide activity, C‐reactive protein (CRP), and antibody levels to periodontal bacteria. Serum lipopolysaccharide activity was determined by Limulus amebocyte lysate from a population‐based sample of FINRISK‐97 including 6671 participants. A trained nurse counted the number of teeth during the clinical examinations. Number of participants in the groups divided according to the number of missing teeth are 0‐1 missing teeth, 1440; 2‐4 teeth, 1270; 5‐8 teeth, 883; 9‐31 teeth, 1979; edentulous, 1099. Mean and 95% confidence interval of logarithmically (ln) transformed lipopolysaccharide activity, C‐reactive protein, and immunoglobulin G (IgG)‐class antibodies to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis (combined), are shown. P‐values for unweighted linear terms from an ANOVA test and adjusted P‐value from a linear regression model adjusted for age, gender, and smoking are presented. EU/ml, endotoxin units; EU, enzyme‐linked immunosorbent assay units