Modeling Inter-Kingdom Regulation of Inflammatory Signaling in Human Intestinal Epithelial Cells

The human gastrointestinal (GI) tract is colonized by a highly diverse and complex microbial community (i.e., microbiota). The microbiota plays an important role in several aspects of host physiology including the development of the immune system, specifically mediating inflammatory responses. While a majority of these effects are mediated through small molecules produced by the microbial community, the mechanisms involved in mediating their effects in host cells are poorly understood. We have developed a mathematical model describing the effect of the microbiota metabolite indole on host inflammatory signaling in HCT-8 human intestinal epithelial cells. In this model, indole modulates the activation of transcription factor nuclear factor κ B (NF-κB) and produces the chemokine interleukin-8 (IL-8) through the activation of the aryl hydrocarbon receptor (AhR). Phosphorylated NF-κB exhibits dose and time-dependent responses to indole concentrations, most notably for all TNF-α concentrations at 1 mM of indole treatment. All indole concentrations show a significant down regulation of IL-8 production for 0.1 ng/mL TNF-α stimulation. The model shows agreeable simulation results with the experimental data for IL-8 secretion and normalized NF-κB values. Our results suggest that microbial metabolites such as indole can modulate inflammatory signaling in intestinal epithelial cells through receptor-mediated processes.