Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis

Abstract

The liver carries out a wide range of functions ranging from the control of metabolites, nutrient storage, and detoxification to immunosurveillance. While inflammation is essential for the tissue remodeling and maintenance of homeostasis and normal liver physiology, constant exposure to dietary and microbial products creates a niche for potentially prolonged immune activation and unresolved inflammation in susceptible host. Failure to restrain inflammation can lead to development of chronic liver diseases characterized by fibrosis, cirrhosis and eventually liver failure. The liver maintains close interactions with numerous organs which can influence its metabolism and physiology. It is also known that oral cavity microenvironment can influence the physiological conditions of other organs and emerging evidence implicates that this could be true for the liver as well. Presence of chronic inflammation and dysbiotic microbiota is a common feature leading to clinical pathology both in periodontitis and chronic liver diseases (CLDs). In fact, known CLDs appear to have some relationship with periodontitis, which impacts the onset or progression of these conditions in a bidirectional crosstalk. In this review, we explore the emerging association between oral-gut-liver axis focusing on periodontitis and common CLDs including nonalcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and hepatocellular cancer. We highlight the immune pathways and oral microbiome interactions which can link oral cavity and liver health and offer perspectives for future research.

Keywords: chronic viral hepatitis; cirrhosis; fatty liver disease; hepatocellular cancer; liver; periodontal; periodontitis.

FIGURE 1

Clinicopathological stages of chronic liver diseases. The liver in its homeostatic state performs its normal physiological functions, which can be altered by viral infections with HBV or HCV and by the accumulation of fat (NAFL) due to systemic dysfunctions associated with different conditions such as diabetes and obesity. Non‐resolution of viral infection leads to chronic hepatitis, and the continuous accumulation of fat in the liver increases the chances of developing NASH via lipotoxicity events. These conditions are characterized by an underlying chronic inflammation that can lead to irreversible liver damage through an increase in the fibrotic response (cirrhosis) which can be accompanied by liver cell malignancy (HCC). This figure was created using BioRender

FIGURE 2

Proposed effects of P gingivalis on hepatic cells. Once the bacteria reache the liver, its invasion into hepatocytes is triggered by the P gingivalis induced‐impaired function of the lysosome‐autophagosome complex (LC3^‐/LAMP2⁺). P gingivalis outer‐membrane vesicles can be released into the cytoplasm and reduce the conversion of phospho‐GSK3 (inactive form) into GSK3 (active form), subsequently inhibiting the glycogenesis mediated by the Insulin/IRS‐1 receptor signaling pathway. In parallel, P gingivalis‐derived LPS triggers TLR‐4 signaling cascade that increases transcription of pro‐inflammatory genes, such as TNF‐ α and IL‐1β. The released inactive pro‐IL‐1β can be converted into active IL‐1β, given that P gingivalis‐derived LPS also up‐regulates the inflammasome complex formed by NLRP3 and Caspase‐1. A boost in the concentration of pro‐inflammatory cytokines in the hepatic milieu removes HSCs from their quiescent state. Further, HSCs can also be activated by the release of galectin‐3 (Gal‐3) and TGF‐β1 by hepatocytes and Mac2⁺ Kupffer cells upon LPS exposure. Subsequently, the TGF‐β1/TGFβR2 downstream cascade in activated HSCs up‐regulates the transcription of α‐SMA which is responsible for HSC differentiation into myofibroblasts. This figure was created using BioRender

FIGURE 3

Proposed role of oral microbiome in oral‐gut‐liver axis. Individuals with periodontitis present microbial dysbiosis in different compartments of the oral cavity, especially in periodontal pockets, which is also accompanied by dysbiosis in the intestinal microbiota. In cases of chronic liver diseases, particularly cirrhosis, swallowed bacteria of the oral niche can reach the intestine since an underlying reduction of gastric acid secretion can occur in these conditions. An overgrowth of oral bacteria in the intestine triggers an inflammatory response that increases the permeability of the intestinal mucosa. Then, MAMPs, particularly LPS, can cross the damaged gut epithelial barrier and reach the liver via portal circulation where they trigger or exacerbate pre‐existing chronic liver inflammation. This figure was created using BioRender

FIGURE 4

Proposed role of host response in oral‐gut‐liver axis. An altered systemic immune profile in periodontitis can exacerbate chronic liver inflammation and/or virus survival in hepatic cells. Circulating CD56^loCD16⁺ Natural Killer (NK) cells are anergic in the peripheral blood of individuals with periodontitis, which can favor HBV and HCV survival. Neutrophils (Nφs) and monocytes (Mϕs) are hyper‐responsive and synthesize large concentrations of pro‐ inflammatory cytokines upon circulating LPS stimulus, hence potentiating this effect in distant organs, especially in cases underlied by systemic dysfunctions, such as NAFLD/NASH. These cells also exhibit a reduced phagocytic capacity, which can compromise the immune surveillance being carried out by the liver. Additionally, Nφs and Mϕs constituvely produce more reactive oxygen species (ROS) which can overlap the elevated concentration of these metabolites in HCC and overall CLDs. Higher concentrations of IL‐6 and IL‐1β released by peripheral CD14⁺ Mϕs prompt CD4⁺ T cells to produce IL‐17, a known pro‐fibrogenic mediator, which can trigger a pro‐cirrhotic milieu. This can be potentialized by the increased number of circulating CD4⁺ T. However, these cells have diminished ability to synthesize IFN‐y and accordingly reduced peripheral populations of CD4⁺IFN‐γ⁺ cells are found in periodontitis; this phenotypic change further compromises anti‐virus defense. The systemic increase in the number of CD4⁺CCR7⁺ and CD8+CCR7⁺ T cells may also contribute to an exacerbation of the inflammatory response in CLDs. This figure was created using BioRender