A Preliminary Quantitative Systems Pharmacology (QSP) Model of Immune Interactions along the ‘Gut-Lung Axis’

Abstract

The microbiome has been associated with maintaining normal human homeostasis and physiological functions. Numerous studies indicate that the gut microbiome and its related metabolites influence pulmonary immune homeostasis and lung physiology, and conversely, local respiratory tract processes are involved in the distal modulation of gut mucosal immune system. Additionally, the gut dysbiosis is associated with outcomes of radiation therapy for lung cancer and complications associated with radiotherapy such as radiation-induced pneumonitis and radiation fibrosis. The causation behind these associations is poorly understood and still speculative, although emerging experimental evidence indicates that the crosstalk of the gut microbiome and the lungs is primarily mediated through metabolism-related genotoxicity, defective immunosurveillance, and systemic inflammation. This bidirectional communication channel between the gut and the lung immune system is referred to as the gut-lung axis. Understanding this phenomenon in humans has been a challenge due to practical and ethical concerns associated with human experimentation. Computational models have recently been used to tackle this challenge, providing researchers with new tools to study immuno-oncology related problems. We aim to develop a Quantitative Systems Pharmacology (QSP) model that incorporates detailed mechanisms for important immune interactions along the gutlung axis. The model comprises three compartments (gut, lungs, and blood) and the relevant cellular pathways, including replication, migration, and apoptosis of various immune cell types and production, transportation, and degradation of cytokines and inflammatory biomarkers. The model allows testing new hypotheses to understand the gut microbiome’s influence on radiotherapy and radiation pneumonitis. Using parameter perturbation to simulate the response of inflammatory biomarkers, the model captured the biological heterogeneity associated with the onset and dynamics of radiation pneumonitis. With additional experimental validation, the model can enable researchers to examine the complex microbiome-associated immune responses and how the dysregulation of these processes may contribute to the pathobiology of the disease.