The "Gum-Gut" Axis in Inflammatory Bowel Diseases: A Hypothesis-Driven Review of Associations and Advances

Abstract

In modern medicine, the oral cavity has often been viewed as a passive conduit to the upper airways and gastrointestinal tract; however, its connection to the rest of the body has been increasingly explored over the last 40 years. For several diseases, the periodontium and gingiva are at the center of this oral-systemic link. Over 50 systemic conditions have been specifically associated with gingival and periodontal inflammation, including inflammatory bowel diseases (IBD), which have recently been elevated from simple "associations" to elegant, mechanistic investigations. IBD and periodontitis have been reported to impact each other's progression via a bidirectional relationship whereby chronic oral or intestinal inflammation can impact the other; however, the precise mechanisms for how this occurs remain unclear. Classically, the etiology of gingival inflammation (gingivitis) is oral microbial dysbiosis in the subgingival crevice that can lead to destructive periodontal disease (periodontitis); however, the current understanding of gingival involvement in IBD is that it may represent a separate disease entity from classical gingivitis, arising from mechanisms related to systemic inflammatory activation of niche-resident immune cells. Synthesizing available evidence, we hypothesize that once established, IBD can be driven by microbiomial and inflammatory changes originating specifically from the gingival niche through saliva, thereby worsening IBD outcomes and thus perpetuating a vicious cycle. In this review, we introduce the concept of the "gum-gut axis" as a framework for examining this reciprocal relationship between the periodontium and the gastrointestinal tract. To support and explore this gum-gut axis, we 1) provide a narrative review of historical studies reporting gingival and periodontal manifestations in IBD, 2) describe the current understanding and advances for the gum-gut axis, and 3) underscore the importance of collaborative treatment and research plans between oral and GI practitioners to benefit this patient population.

Keywords: Crohn’s disease; gingivitis; gum–gut; inflammatory bowel disease; microbiome; oral–gut; periodontitis; ulcerative colitis.

Figure 1

A Bidirectional Influence of oral and systemic health. (A) Emerging associations between systemic disease on oral health include diseases of the skin, lungs, gastrointestinal tract as well as endocrine and hematopoietic systems. (B) The number of systemic diseases impacted by oral inflammatory diseases of the periodontium (gingivitis and periodontitis) continues to increase as more studies are conducted. Many of the same systems that influence oral health are influenced by periodontal health.

Figure 2

Evidence for IBD-induced gingivitis as a separate disease entity. (Left) “Classically” defined gingivitis involves well-defined increases to pro-inflammatory cytokines secondary to defined shifts in the microbiome. The inflammation clinically documented in IBD often discordant with biofilm deposits on the tooth surface, suggesting a role for the systemic inflammation of IBD to cause oral inflammation in parallel with or independent of biofilm deposits. This inflammation may itself shift the oral microbiome which then may cause further gingival inflammation. A sampling of the gingival crevicular fluid (GCF) and saliva (biofluids), gingival tissues (full-thickness biopsies), and subgingival microbes (microbiome) allows for a detailed understanding of the inflammatory and microbiomial shifts shared and unique to these possibly unique diseases.

Figure 3

The History of the gum–gut axis in IBD. Over many centuries, the chronic inflammatory diseases of the gut and periodontium were noted but not classified into defined disease entities until the late 1800s and early 1900s. First with case reports, then association studies, and finally clinical trials using biosampling primarily of the oral cavity, the evidence for the bidirectional relationship became better understood. More studies are required, including longitudinal cohorts, to understand the temporal associations and to further test causality.

Figure 4

Linking the gum–gut axis from birth to adulthood. Due to the uniqueness of each site, neonatal and adult oral and gut microbiomes do not resemble one another. However, a common feature is that both sites and their distinct niches are established with a nascent microbiome that diversifies during development. The oral microbiome stabilize at a later development timeframe when compared to the gut microbiome due to the shedding of primary teeth until about 12 years old and the subsequent eruption of permanent teeth. This provides a narrower window of gut microbiome vulnerability compared to the oral cavity. Both oral and gut microbiome diversification and stabilization are reportedly driven by environmental influences. The influence of the oral cavity to the lower gastrointestinal tract can occur via saliva and also via vasculature (local inflammation seeding to distant sites) whereas the primary mode of gut to oral influence is via the mechanisms of local-to-systemic inflammation such as the delivery of effector cytokines or activation of oral tissue-resident immune cells.

Figure 5

Future directions to better elucidate the gum–gut axis. Due to the uniquely active and remittent inflammatory states of periodontal disease and inflammatory bowel disease, there is an exciting future for collaborative efforts between GI and oral health care providers to answer these questions. This will require biosampling both oral and intestinal sites to correlate dysbiosis and inflammatory changes across niches and across time, better modeling using ex vivo models, and better phenotyping of both diseases. In the future, predictive modeling and precision medical approaches are possible to treat both oral and GI diseases.