Senior Director Certara Applied BioSimulation, Sheffield, United Kingdom, California, United States
Disclosure(s):
Douglas W. Chung, M.S.: No financial relationships to disclose
Objectives: While loss of epithelial barrier function (EBF) plays a significant role in inflammatory bowel diseases (IBD), the mechanisms of pathogenesis remain unknown [1]. Currently, treatments focus on the uncontrolled inflammation rather than the repair of the barrier function and, therefore, mucosal healing. We aimed to develop a mechanistic model that describes the response of the EBF to epithelial damage and bacterial infiltration by calibrating to in vitro experimental data [2,3]. Further, we interpreted in vivo mouse markers [4-7] to EBF measures to calibrate an in vivo model capable of investigating the dynamics of the recovery of the EBF in an IBD context.
Methods: A system of ordinary differentiation equations (ODEs) was implemented to describe the dynamics and interactions of healthy and inflammatory epithelial cells, pro-inflammatory cytokines, pathogenic bacteria, mucus function, and EBF. We evaluated the model for healthy intact EBF and damaged EBF with bacterial infiltration. In vitro and in vivo experimental data were interpreted by defining data models to relate cytokine levels, transepithelial electrical resistance, and dextran permeability to calibrate the model. A local sensitivity analysis (LSA) was performed to identify the most impactful model parameter on the recovery of the EBF in IBD.
Results: The model simulates a healthy gut epithelium with no initial pro-inflammatory epithelial cells, cytokines, or pathogenic bacteria and a damaged, inflamed epithelium with subsequent bacterial infiltration into the lamina propria. The model quantitatively describes the in vitro cell culture response to varying pathogenic bacterial strains and serial concentrations of exogenous TNF-α. Also, the model quantitatively describes observations in moderate to severe colitis mouse models, including EBF, epithelial permeability, and cytokine levels. The model describes the interactions between bacterial infiltration, cytokine levels, and the EBF in vivo over fourteen days. The LSA revealed differences between the moderate colitis and severe colitis mouse models, suggesting a predisposition toward inflammation and a compromised immune response to bacterial infiltration.
Conclusion: The QSP model describes the key interactions and kinetics of EBF in response to bacterial infiltration, epithelial damage, and pro-inflammatory cytokines for a healthy gut with full EBF recovery- and for an IBD scenario - with chronic inflammation. This model can be integrated into an existing quantitative systems pharmacology (QSP) platform of IBD [8], enabling the investigation of new classes of therapeutics targeting epithelial-microbe interactions or targets for regenerating the intestinal epithelium.
Citations: [1] Salim, S. Y., & Söderholm, J. D. (2011). Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflammatory Bowel Diseases, 17(1), 362–381. https://doi.org/10.1002/IBD.21403 [2] Sasaki, M., Sitaraman, S. V., Babbin, B. A., Gerner-Smidt, P., Ribot, E. M., Garrett, N., Alpern, J. A., Akyildiz, A., Theiss, A. L., Nusrat, A., & Klapproth, J. M. A. (2007). Invasive Escherichia coli are a feature of Crohn’s disease. Laboratory Investigation, 87(10), 1042–1054. https://doi.org/10.1038/labinvest.3700661 [3] Wang, F., Schwarz, B. T., Graham, W. V., Wang, Y., Su, L., Clayburgh, D. R., Abraham, C., & Turner, J. R. (2006). IFN-γ-Induced TNFR2 Expression Is Required for TNF-Dependent Intestinal Epithelial Barrier Dysfunction. Gastroenterology, 131(4), 1153–1163. https://doi.org/10.1053/j.gastro.2006.08.022 [4] Tang, Y., Clayburgh, D. R., Mittal, N., Goretsky, T., Dirisina, R., Zhang, Z., Kron, M., Ivancic, D., Katzman, R. B., Grimm, G., Lee, G., Fryer, J., Nusrat, A., Turner, J. R., & Barrett, T. A. (2010). Epithelial NF-κB Enhances Transmucosal Fluid Movement by Altering Tight Junction Protein Composition after T Cell Activation. The American Journal of Pathology, 176(1), 158–167. https://doi.org/10.2353/AJPATH.2010.090548 [5] Wu, H., Chen, Q. Y., Wang, W. Z., Chu, S., Liu, X. X., Liu, Y. J., Tan, C., Zhu, F., Deng, S. J., Dong, Y. L., Yu, T., Gao, F., He, H. X., Leng, X. Y., & Fan, H. (2021). Compound sophorae decoction enhances intestinal barrier function of dextran sodium sulfate induced colitis via regulating notch signaling pathway in mice. Biomedicine & Pharmacotherapy, 133, 110937. https://doi.org/10.1016/J.BIOPHA.2020.110937 [6] Alves, J. L., Lemos, L., Rodrigues, N. M., Pereira, V. B., Barros, P. A. V., Canesso, M. C. C., Guimarães, M. A. F., Cara, D. C., Miyoshi, A., Azevedo, V. A., Maioli, T. U., Gomes-Santos, A. C., & Faria, A. M. C. (2023). Immunomodulatory effects of different strains of Lactococcus lactis in DSS-induced colitis. Brazilian Journal of Microbiology: [Publication of the Brazilian Society for Microbiology], 54(2), 1203–1215. https://doi.org/10.1007/S42770-023-00928-0 [7] Sheng, K., He, S., Sun, M., Zhang, G., Kong, X., Wang, J., & Wang, Y. (2020). Synbiotic supplementation containing Bifidobacterium infantis and xylooligosaccharides alleviates dextran sulfate sodium-induced ulcerative colitis. Food & Function, 11(5), 3964–3974. https://doi.org/10.1039/D0FO00518E [8] Shim, J. V., Rehberg, M., Wagenhuber, B., van der Graaf, P. H., & Chung, D. W. (2025). Combining mechanistic modeling with machine learning as a strategy to predict inflammatory bowel disease clinical scores. Frontiers in Pharmacology, 16, 1479666. https://doi.org/10.3389/FPHAR.2025.1479666/BIBTEX
