Physiological insights into electrodiffusive maintenance of gastric mucus through sensitivity analysis and simulations

Abstract

It is generally accepted that the gastric mucosa and adjacent mucus layer are critical in the maintenance of a pH gradient from stomach lumen to stomach wall, protecting the mucosa from the acidic environment of the lumen and preventing auto-digestion of the epithelial layer. No conclusive study has shown precisely which physical, chemical, and regulatory mechanisms are responsible for maintaining this gradient. However, experimental work and modeling efforts have suggested that concentration dependent ion-exchange at the epithelial wall, together with hydrogen ion/mucus network binding, may produce the enormous pH gradients seen in vivo . As of yet, there has been no exhaustive study of how sensitive these modeling results are with respect to variation in model parameters, nor how sensitive such a regulatory mechanism may be to variation in physical/biological parameters. In this work, we perform sensitivity analysis (using Sobol’ Indices) on a previously reported model of gastric pH gradient maintenance. We quantify the sensitivity of mucosal wall pH (as a proxy for epithelial health) to variations in biologically relevant parameters and illustrate how variations in these parameters affects the distribution of the measured pH values. In all parameter regimes, we see that the rate of cation/hydrogen exchange at the epithelial wall is the dominant parameter/effect with regards to variation in mucosal pH. By careful sensitivity analysis, we also investigate two different regimes representing high and low hydrogen secretion with different physiological interpretations. By complementing mechanistic modeling and biological hypotheses testing with parametric sensitivity analysis we are able to conclude which biological processes must be tightly regulated in order to robustly maintain the pH values necessary for healthy function of the stomach.

Pharmacological targeting of gastric mucosal barrier with traditional Chinese medications for repairing gastric mucosal injury

“…The inhibitory activity of burdock is stronger than ranitidine at the same concentration and is comparable to omeprazole ( Silva, et al, 2018 ). In addition, a study evidenced that as the rate of H + /Na + exchange decreased, the average pH of gastric juice subsequently decreased as well ( Aggarwal, et al, 2021 ). From the above studies on parietal cells, it can be inferred that TCMs ameliorate alterations and dysregulation in gastric acid secretion through the modulation of agonists, antagonists and ion channels that stimulate parietal cell activity.…”

Exploring how ecological and epidemiological processes shape multi-host disease dynamics using global sensitivity analysis

“…Global sensitivity analysis is a well developed methodology that has been widely applied in engineering settings where understanding reliability is very important (Saltelli, 2002;Saltelli et al, 2005;Wu, 1994). Within the past few decades, sensitivity analysis has begun to be used to assess model predictions, experimental design, and robustness in a variety of biological applications (Blower and Dowlatabadi, 1994;Jarrett et al, 2015Jarrett et al, , 2017bRenardy et al, 2019;Aggarwal et al, 2019Aggarwal et al, , 2021Marino et al, 2008;Wentworth et al, 2016;Hanthanan Arachchilage and Hussaini, 2021). One of the differences between more traditional applications and biological applications is in the interpretation of the rankings.…”