Oral Infections, Metabolic Inflammation, Genetics, and Cardiometabolic Diseases

Although several epidemiologic studies reported plausible and potentially causal associations between oral infections and cardiometabolic diseases (CMDs), controversy still lingers. This might be due to unrecognized confounding from metabolic inflammation and genetics, both of which alter the immune responses of the host. Low-grade inflammation termed metainflammation is the hallmark of obesity, insulin resistance, type 2 diabetes, and CMDs. According to the common soil theory, the continuum of obesity to CMDs is the same pathology at different time points, and early metainflammations, such as hyperglycemia and obesity, display many adverse cardiometabolic characteristics. Consequently, adipose tissue is now considered a dynamic endocrine organ that expresses many proinflammatory cytokines such as TNF- α, IL-6, plasminogen activator inhibitor 1, and IL-1 β. In metainflammation, IL-1 β and reactive oxygen species are generated, and IL-1 β is a pivotal molecule in the pathogenesis of CMDs. Note that the same cytokines expressed in metainflammation are also reported in oral infections. In metabolic inflammation and oral infections, the innate immune system is activated through pattern recognition receptors—which include transmembrane receptors such as toll-like receptors (TLRs), cytosolic receptors such as nucleotide-binding oligomerization domain–like receptors, and multiprotein complexes called inflammasome. In general, TLR-2s are presumed to recognize lipoteichoic acid of Gram-positive microbes—and TLR-4s, lipopolysaccharide of Gram-negative microbes—while nucleotide-binding oligomerization domain–like receptors detect both Gram-positive and Gram-negative peptidoglycans on the bacterial cell walls. However, a high-fat diet activates TLR-2s, and obesity activates TLR-4s and induces spontaneous increases in serum lipopolysaccharide levels (metabolic endotoxemia). Moreover, genetics controls lipid-related transcriptome and the differentiation of monocyte and macrophages. Additionally, genetics influences CMDs, and this creates a confounding relationship among oral infections, metainflammation, and genetics. Therefore, future studies must elucidate whether oral infections can increase the risk of CMDs independent of the aforementioned confounding factors.