The dynamic oral-gastric microbial axis connects oral and gastric health: current evidence and disputes

Abstract

Emerging evidence indicates that oral microbes are closely related to gastric microbes and gastric lesions, including gastric atrophy, intestinal metaplasia and gastric cancer (GC). Helicobacter pylori is a key pathogen involved in GC. However, the increasing prevalence of H. pylori-negative GC and gastric dysbiosis in GC patients emphasize the potential role of other microbial factors. In this review, we discussed the current evidence about the relationship between the oral-gastric microbial axis and oral and gastric health. Epidemiologic evidence indicates that poor oral hygiene is related to greater GC risk. Multiple oral-associated microbes are enriched in the stomach of GC patients. Once colonizing the stomach, oral-associated microbes Streptococcus anginosus and Prevotella melaninogenica, are involved in gastric inflammation or carcinogenesis. Microbial metabolites such as lactate, nitrite, and acetaldehyde promote malignant transformation. The stomach, as a checkpoint of microbial transmission in the digestive tract, is of great importance since the link between oral microbes and intestinal diseases has been emphasized. Still, new technologies and standardized metrics are necessary to identify potential pathogenetic microbes for GC and the core microbiota, interactions, richness, colonization, location and effect (CIRCLE). In the future, oral microbes could be candidates for noninvasive indicators to predict gastric diseases.

Fig. 1. Oral microbes are involved in dysbiosis and microbial interactions during carcinogenesis.

As gastric lesions develop from inflammation to cancer, the abundance of the dominant colonizer H. pylori decreases, while that of oral-associated microbes increases. Oral-associated microbes co-occur with each other and have complex interactions with other microbes. The direct effects and indirect effects are shown by solid and dashed arrows, respectively. Created with BioRender.com.

Fig. 2. The mechanisms of microbe-host interplay affecting gastric carcinogenesis.

Persistent H. pylori infection induces gastric gland atrophy and subsequently suppresses endocrine activity. The Bacteroidales family S24-7 activates ILC-2 to produce IL-5, contributing to diminished H. pylori. S. anginosus stimulates the recruitment of neutrophils and monocytes to mediate epithelial dysplasia. Oral-associated microbes produce carcinogens such as lactate, LPS, nitrite, and acetaldehyde. L-Lactate assists H. pylori in resisting complement C4b. P. melaninogenica LPS synergistic with TCDA promotes gastric epithelial cell proliferation by activating the IL-6/JAK1/STAT3 pathway. Acetaldehyde causes DNA damage and mutation in epithelial cells. Suppressed bacterial arginine degradation provides arginine availability for tumor cell growth. The direct effects and indirect effects are shown by solid and dashed arrows, respectively. Created with BioRender.com.

Fig. 3. Microbes of the oral cavity and stomach communicate through the upper gastrointestinal tract.

The representative oral microbiota in healthy individuals contains the major gastric microbiota in healthy individuals, although most oral microbes are blocked by the mucus barrier secreted by the healthy gastric mucosa. However, under certain circumstances, such as persistent H. pylori infection, the weakened gastric mucus barrier allows oral-associated microbes to invade. Ectopically colonized microbes promote gastric carcinogenesis through direct contact or products. Oral and gastric dysbiosis have potential effects on the brain, probably triggering feedback on lifestyle and self-maintenance. The direct effects and indirect effects are shown by solid and dashed arrows, respectively. Created with BioRender.com.

Fig. 4. Visual depiction of the potential oral–gastric microbial axis.

Six aspects to explore the unknown universe of oral–gastric microbes. New technology and standardized metrics are called on to identify potential pathogenetic microbes and their core microbiota, location, interaction, effect, richness and colonization (CIRCLE). Prospective solutions to these issues are listed on the left. ISH, in situ hybridization; SRT, spatially resolved transcriptomics; SAHMI, single-cell analysis of host–microbiome interactions; WGS, whole-genome sequencing; WES, whole-exome sequencing; RNA-seq, whole-transcriptome sequencing.