Julia Stolk1, Doug Chung2
1Leiden University, 2Certara
Introduction: While loss of epithelial barrier function (EBF) is known to play an important role in inflammatory bowel diseases (IBD), the mechanisms of pathogenesis remain poorly understood [1], [2]. Currently, treatments focus on the uncontrolled inflammation and overproduction of pro-inflammatory cytokines (cytpro), rather than the repair of the barrier function [3]. This, however, is crucial as mucosal healing requires a resolution of both the chronic inflammation and the repair of the epithelial barrier. Therefore, we aimed to build a quantitative systems pharmacology (QSP) model to investigate the crucial role of damaged EBF in the pathogenesis of IBD to enable the development of new targets for treatment. Objectives: Firstly, we aimed to make a system of ordinary differentiation equations (ODEs) that describes the response of the EBF to epithelial damage and bacterial infiltration. Then, we aimed to calibrate the model to fit in vitro experimental data. Finally, we aimed to make a data model of in vivo mouse data and to calibrate the model to investigate the dynamics of the recovery epithelial barrier function in the IBD. Methods: Equations were implemented to describe the dynamics and interactions of epithelial cells, cytpro, pathogenic bacteria, mucus function and EBF. The system of ODEs was tested by a sanity test for a healthy scenario – where no epithelial damage occurred, and for bacterial infiltration. In vitro and in vivo experimental data were interpreted by formalizing data models to relate cytpro levels, transepithelial electrical resistance, and dextran permeability to the QSP model outputs. The model was then calibrated to fit that data. The model was further tested by a local sensitivity analysis to determine the impact of each individual parameters on the system of ODEs. Results: The QSP model was capable of simulating a healthy gut epithelium with no initial pro-inflammatory epithelial cells, no pro-inflammatory cytokines, and no pathogenic bacteria, as well as simulating damage and inflammation resulting from bacterial infiltration into the lamina propria. The model described the in vitro EBF decrease of 30% and 80% in response to 14,800 picomolar exogenous TNF-a and Escherichia coli strain E2348/69, respectively. Also, the model quantitatively explained data from dextran sulfate sodium-induced moderate and severe colitis mouse studies measuring EBF, epithelial permeability, and cytpro concentrations. Running the in vivo model for fourteen days revealed that the model is not only able to describe the interactions of bacterial infiltration, cytpro levels and the EBF, but also the interactions of those interactions. Finally, the differences in parameter values between the in vivo moderate colitis and in vivo severe colitis suggest that mice that are healthy at one point, have a phenotype which makes them more sensitive to inflammation and makes their immune response less capable in fighting of bacteria, which makes them experience more severe disease when they are exposed to certain bacteria. Conclusion: The QSP model describes the key interactions and kinetics of EBF in response to bacterial infiltration and epithelial damage for a healthy gut – where the barrier can recover, and for an IBD scenario – where chronic inflammation occurs. This model can be further integrated into existing mechanistic models of gut inflammation in IBD, enabling the investigation of new classes of therapeutics targeting epithelial-microbe interactions such as live biotherapeutic products.
[1] S. Alatab et al., “The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017,” Lancet Gastroenterol Hepatol, vol. 5, no. 1, pp. 17–30, 2020, doi: https://doi.org/10.1016/S2468-1253(19)30333-4. [2] M. Friedrich et al., “HDAC inhibitors promote intestinal epithelial regeneration via autocrine TGFβ1 signalling in inflammation,” Mucosal Immunol, vol. 12, no. 3, pp. 656–667, May 2019, doi: 10.1038/s41385-019-0135-7. [3] L. Thoo, M. Noti, and P. Krebs, “Keep calm: the intestinal barrier at the interface of peace and war,” Nov. 01, 2019, Springer Nature. doi: 10.1038/s41419-019-2086-z.
Reference: PAGE 33 (2025) Abstr 11688 [www.page-meeting.org/?abstract=11688]
Poster: Drug/Disease Modelling - Other Topics