BACKGROUND: Chronic visceral hypersensitivity is associated with an overstressed pain response to noxious stimuli (hyperalgesia). Microbiota are active modulators of host biology and are implicated in the etiology of visceral hypersensitivity. OBJECTIVES: we studied the association between the circulating mRNA transcriptome, the intensity of induced visceral pain (IVP), and variation in the oral microbiome among participants with and without baseline visceral hypersensitivity. METHODS: Transcriptomic profiles and microbial abundance were correlated with IVP intensity. Host mRNA and microbes associated with IVP were explored, linking variation in the microbiome to host RNA biology. RESULTS: 259 OTUs were found to be associated with IVP through correlation to differential expression of 471 genes in molecular pathways related to inflammation and neural mechanisms, including Rho and PI3K/AKT pathways. The bacterial families Lachnospiraceae, Prevotellaceae, and Veillonellaceae showed the highest degree of association. Oral microbial profiles with reduced diversity were characteristic of participants with visceral hypersensitivity. CONCLUSIONS: Our results suggest that the oral microbiome may be involved in systemic immune and inflammatory effects and play a role in nervous system and stem cell pathways. The interactions between visceral hypersensitivity, differentially expressed molecular pathways, and microbiota described here provide a framework for further work exploring the relationship between host and microbiome.