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 commu-nity (i.e., microbiota). The microbiota plays an important role in the development of the immune system, specifically mediating inflammatory responses, however the exact mechanisms are poorly understood. We have developed a mathematical model describing the effect of indole on host inflammatory signaling in HCT-8 human intestinal epithelial cells. In this model, indole modulates transcription factor nuclear factor kappa B (NF-kappa B) and produces the chemokine interleukin-8 (IL-8) through the activation of the aryl hydrocar-bon receptor (AhR). Phosphorylated NF-kappa B exhibits dose and time-dependent responses to indole concen-trations and IL-8 production shows a significant down-regulation for 0.1 ng/mL TNF-alpha stimulation. The model shows agreeable simulation results with the experimental data for IL-8 secretion and normalized NF-kappa B values. Our results suggest that microbial metabolites such as indole can modulate inflammatory signaling in HTC-8 cells through receptor-mediated processes. (C) 2020 Elsevier Ltd. All rights reserved.