Exploring the oral-gut linkage: Interrelationship between oral and systemic diseases

Abstract

The oral cavity harbors a diverse microbiota that plays a significant role in maintaining homeostasis. Disruption of this balance can lead to various oral diseases, including periodontitis. Accumulating evidence suggests a connection between periodontitis and extra-oral diseases such as cardiovascular disease, rheumatoid arthritis, obesity, and diabetes. During periodontitis, oral bacteria enter the bloodstream directly, impacting extra-oral organs. Furthermore, recent studies have uncovered another pathway, the direct oral-gut axis, where oral bacteria translocate to the gut through an enteral route, influencing gut microbiota and metabolism. Oral pathobionts associated with exacerbation of periodontal disease are implicated in gut pathology, including inflammatory bowel disease and colorectal cancer through ectopic gut colonization. Furthermore, oral bacteria can provoke host immune responses, leading to colitis and other inflammatory diseases. Conversely, mechanisms by which extra-oral conditions exacerbate oral diseases, such as periodontitis, are also beginning to be elucidated. This review discusses the bidirectional interrelationship between oral and systemic diseases based on the oral-gut linkage.

Figure 1.. The role of oral pathobiont bacteria on gut disease.

(A) Oral inflammation results in an expansion of oral pathobionts and thus increases translocation of such pathobionts to the gut. Gut-translocated oral pathobionts interact with the gut epithelium and activate inflammatory signals. Alternatively, oral pathobiont colonization leads to dysbiosis of the gut microbiota. As a result of these interactions, an inflammatory cascade is activated and ultimately proinflammatory cytokines are released. Additionally, interaction of oral pathobionts with gut immune cells, including macrophages (Mϕ), dendritic cells (DCs), and T cells, elicits pronounced inflammatory responses. Moreover, certain bacteria reach the liver via the bloodstream and contribute to the spread of intestinal inflammation. Oral inflammation also induces the development of oral pathobiont-reactive Th17 cells, which can transmigrate to the gut mucosa and contribute to inflammation. (B) P. gingivalis deploys gingipain, an enzymatic secretion, while F. nucleatum employs the outer membrane protein FadA and LPS to stimulate cell proliferation via interaction with gut epithelial cells. In the context of colorectal cancer tissue, Fap2, an additional specific surface protein of F. nucleatum, plays a pivotal role in the augmentation of bacterial enrichment and colonization. Fap2 also contributes to the suppression of anti-tumor activities mediated by NK cells.

Figure 2.. The effect of altered gut conditions on periodontitis.

(A) High-fat diet (HFD) intake leads to gut dysbiosis with altered microbial metabolic functions. Altered microbial metabolism induced by HFD increases serum uric acid levels, which exacerbate periodontal inflammation. (B) Ectopic gut colonization of P. gingivalis instigates the emergence of P. gingivalis-reactive Th17 cells in the gut mucosa. These Th17 cells that originate in the gut mucosa then migrate systemically to peripheral immune tissues. Following this migration, these cells relocate to the oral mucosa, where they contribute to the aggravation of oral inflammation.