The oral-gut immune axis: a bidirectional hypothesis of the oral cavity as an immune programming hub for systemic and gut mucosal immunity

The oral cavity has long been viewed simply as the site of food intake. Research in recent years has shown that the oral mucosa is a site of chronic low-grade inflammation that continuously produces inflammatory mediators. Given its specific structure, microbial products and immune mediators in the oral cavity can enter the bloodstream, while swallowed saliva continuously delivers oral microorganisms and their products to the gut. Oral dysbiosis, particularly in periodontitis, has been associated with systemic immune reprogramming, including trained immunity of monocytes, neutrophil priming, and expansion of gut-homing T helper 17 (Th17) cells. These modifications may contribute to intestinal barrier dysfunction, alterations in gut microbiota composition, and an increased risk of inflammatory bowel disease, colorectal cancer, and metabolic dysfunction-associated steatotic liver disease. However, current evidence is largely associative: the presence of oral bacteria in intestinal tissue does not establish that they initiate intestinal disease, and an inflamed gut may itself favor the colonization of oral-derived taxa. Bidirectional influences between oral and gut inflammation therefore cannot be excluded, and reverse causation remains plausible. Genetic studies have identified polymorphisms in genes of innate immunity, such as nucleotide-binding oligomerization domain-containing protein 2 (NOD2), interleukin-23 receptor (IL23R), and the interleukin-1 gene cluster (IL1 cluster), in both periodontitis and gastrointestinal diseases. However, because these loci are highly pleiotropic and have been associated with multiple inflammatory disorders affecting different organs, shared susceptibility genes alone cannot distinguish a genuine oral-to-gut axis from independent diseases sharing common immune-related genetic architecture. We propose the Oral-Gut Immune Axis (OGIA) here as a testable hypothesis, not as an established paradigm. OGIA is a predominantly, but not exclusively, oral-to-gut directional model that positions the oral cavity as a potential immune programming hub. Under specific genetic and microbial conditions, periodontal inflammation may act as an upstream contributor to gastrointestinal pathology. This framework generates testable predictions and identifies oral-targeted interventions as candidate preventive strategies, while acknowledging that current evidence remains insufficient to establish causality. Accordingly, the OGIA framework does not claim that microbial translocation is a demonstrated cause of human gastrointestinal disease. It treats translocation as one candidate mechanism among several, to be discriminated from systemic immune signaling in future studies.