The effect of the "Oral-Gut" axis on periodontitis in inflammatory bowel disease: A review of microbe and immune mechanism associations

Abstract

Periodontitis and inflammatory bowel diseases (IBD) are inflammatory diseases of the gastrointestinal tract that share common features of microbial-induced ecological dysregulation and host immune inflammatory response. The close relationship between periodontitis and IBD is characterized by a higher prevalence of IBD in patients with periodontitis and a higher prevalence and severity of periodontitis in patients with IBD, indicating that periodontitis and IBD are different from the traditional independent diseases and form an "Oral-Gut" axis between the two, which affect each other and thus form a vicious circle. However, the specific mechanisms leading to the association between the two are not fully understood. In this article, we describe the interconnection between periodontitis and IBD in terms of microbial pathogenesis and immune dysregulation, including the ectopic colonization of the gut by pathogenic bacteria associated with periodontitis that promotes inflammation in the gut by activating the host immune response, and the alteration of the oral microbiota due to IBD that affects the periodontal inflammatory response. Among the microbial factors, pathogenic bacteria such as Klebsiella, Porphyromonas gingivalis and Fusobacterium nucleatum may act as the microbial bridge between periodontitis and IBD, while among the immune mechanisms, Th17 cell responses and the secreted pro-inflammatory factors IL-1β, IL-6 and TNF-α play a key role in the development of both diseases. This suggests that in future studies, we can look for targets in the "Oral-Gut" axis to control and intervene in periodontal inflammation by regulating periodontal or intestinal flora through immunological methods.

Keywords: IBD; immunity; microbiology; oral-gut axis; periodontitis.

Figure 1

A general review of studies on the oral-gut axis.

Figure 2

Microbial correlation between periodontitis and IBD (The bacteria underlined in the diagram are the ones mentioned in our paper). In periodontitis, the oral flora is altered and P. gingivalis evades host immune defense to destroy periodontal tissue by releasing virulence factors such as proteases and lipopolysaccharides; alterations in the composition of the intestinal microbiota leading to changes in bacterial metabolites such as BSH may play an important role in the pathogenesis of IBD; through the oral-gut axis, periodontal pathogenic bacteria such as Klebsiella, P. gingivalis, and F nucleatum can ectopically colonize the intestine and disrupt the intestinal barrier thus leading to intestinal ecological dysregulation and chronic inflammation. (A) P. gingivalis produces virulence factors such as LPS. Source (Takeuchi et al., 2019). (B) P. gingivalis produces virulence factors such as proteases. Source (Zhang et al., 2021d). (C) F nucleatum destroys the intestinal mucosa. Source (Liu et al., 2021b). (D) The role of FXR in IBD. Source (Ding et al., 2015).

Figure 3

Immune mechanism correlation between periodontitis and IBD. In the pathogenesis of periodontitis, neutrophils are continuously recruited, migrate and infiltrate at the site of inflammation and secrete pro-inflammatory factors such as TNF-α and IL-8, macrophages tend to differentiate towards M1 and secrete IFN-γ. P. gingivalis induces IL-1β production through the TLR pathway, upregulates RANKL and M-CSF expression, and activates the NF-ĸB signaling pathway, thereby inducing bone resorption. The pathogenesis of IBD is similar to periodontitis, with neutrophils and macrophages inducing an inflammatory response through the release of virulence factors, pro-inflammatory mediators, and enhanced Th1 and Th17 cell responses; MMP-9 increases MLCK expression and induces an increase in intestinal TJ permeability through activation of NF-κB p65. Due to the oral-intestinal axis, periodontitis and IBD can be interrelated through immune mechanisms, with periodontal pathogenic bacteria ectopically colonizing the intestine, increasing intestinal Th17 and Th1 cell responses and promoting intestinal inflammation; while Th17/Treg imbalance not only disrupts the oral microbiota and exacerbates bone resorption, but also leads to intestinal ecological dysregulation. (A) Antibactericidal mechanisms of C5a-TLR2 cross-talk induced by P. gingivalis. Source (Jia et al., 2019a). (B) M-CSF and RANKL induce bone resorption. Source (Karlis et al., 2020). (C) The role of bile acid and FXR in Th17/Treg balance. Source (Yan et al., 2020). (D) MMP-9 causes increased intestinal permeability. Source (Al-Sadi et al., 2021).