Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis

Abstract

Gut microbiota play many important roles, such as the regulation of immunity and barrier function in the intestine, and are crucial for maintaining homeostasis in living organisms. The disruption in microbiota is called dysbiosis, which has been associated with various chronic inflammatory conditions, food allergies, colorectal cancer, etc. The gut microbiota is also affected by several other factors such as diet, antibiotics and other medications, or bacterial and viral infections. Moreover, there are some reports on the oral-gut-liver axis indicating that the disruption of oral microbiota affects the intestinal biota. Non-alcoholic fatty liver disease (NAFLD) is one of the systemic diseases caused due to the dysregulation of the oral-gut-liver axis. NAFLD is the most common liver disease reported in the developed countries. It includes liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Recently, accumulating evidence supports an association between NAFLD and dysbiosis of oral and gut microbiota. Periodontopathic bacteria, especially Porphyromonas gingivalis, have been correlated with the pathogenesis and development of NAFLD based on the clinical and basic research, and immunology. P. gingivalis was detected in the liver, and lipopolysaccharide from this bacteria has been shown to be involved in the progression of NAFLD, thereby indicating a direct role of P. gingivalis in NAFLD. Moreover, P. gingivalis induces dysbiosis of gut microbiota, which promotes the progression of NAFLD, through disrupting both metabolic and immunologic pathways. Here, we review the roles of microbial dysbiosis in NAFLD. Focusing on P. gingivalis, we evaluate and summarize the most recent advances in our understanding of the relationship between oral-gut microbiome symbiosis and the pathogenesis and progression of non-alcoholic fatty liver disease, as well as discuss novel strategies targeting both P. gingivalis and microbial dysbiosis.

Keywords: NAFLD; P. gingivalis; gut microbiota; microbial dysbiosis; oral microbiota.

Figure 1

Risk factors, pathogenesis, and systemic impacts of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease worldwide, usually presenting as fatty hepatocytes (simple steatosis). Non-alcoholic steatohepatitis (NASH) is a severe type of NAFLD. It is usually characterized by inflammation, cell damage, and apoptosis, and may include fibrosis. In turn, it can progress to cirrhosis or end-stage liver disease, i.e., hepatocellular carcinoma (HCC). In addition to heredity, one of the most widely accepted risk factors for NAFLD is excessive fat/glucose intake. Recent studies indicate that microbial dysbiosis takes an important role in the pathogenesis and the development of NAFLD. NAFLD leads not only to the development of hepatic diseases, but also connects with and contributes to systemic diseases, such as metabolic syndrome and extrahepatic disorders. NASH, non-alcoholic steatohepatitis; HCC, hepatocellular carcinoma; CDVs, cardiovascular diseases; CKD, chronic kidney disease, T2D, type 2 diabetes.

Figure 2

P. gingivalis impacts NAFLD via both the oral-liver and oral-gut axes. With respect to the oral-liver axis, P. gingivalis and its virulence factors can reach the liver directly via the blood circulation. Virulence factors such as fimbriae proteins, lipopolysaccharide (LPS) and gingipains elicit inflammatory immune reactions and activate intracellular signaling pathways by binding to the corresponding receptors. This results in inflammation, cell death, and dysfunctions, all of which are closely related to glucose and lipid metabolic disorders, insulin resistance, and fibrosis, which contribute to the pathogenesis of NAFLD. Biofilm and outer membrane vesicles (OMVs) play roles in the transfer of bacteria and virulence factors, such as gingipains, to the liver, the site of pathogenic action. P. gingivalis also affects NAFLD via the oral-gut-liver axis. It can enter the gastrointestinal tract via swallowing, where it can induce dysbiosis of the gut microbiota and enhance intestinal permeability. Thus, both the pathogenic bacteria, and related toxic products and mediators, can reach the liver via the portal vein, and play a role in NAFLD. LPS, lipopolysaccharide; TLR, Toll-like receptor; IL, interleukin; OMVs, outer membrane vesicles; CXCR, CXC-chemokine receptor; CR, complement receptor; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; NF-κB, nuclear factor kappa B; TGF-β, transforming growth factor β; PAR, proteinase-activated receptor; JNK, c-Jun-NH2-terminal kinase; IP, intestinal permeability; Gal, galectin; PI3K, phosphatidylinositol-3 kinase.

Figure 3

Therapeutic strategies in microbial dysbiosis-related NAFLD. Understanding the mechanism underlying microbial dysbiosis and its impacts on the pathogenesis of NAFLD through the gut-liver, oral-liver, and oral-gut-liver axes may contribute to the development of new options for treatment of the disease. Some very safe options, such as some probiotics, gut symbionts, and natural products, aimed at attenuating oral bacteria and correcting dysbiosis of the oral and gut microbiota, have received substantial attention. Additionally, treatments targeting the structures and virulence factors of P. gingivalis offer new treatment options specifically targeting bacteria. Abs, antibodies; FMT, fecal microbiota transplantation.