Investigation of Inflammation and Tissue Patterning in the Gut Using a Spatially Explicit General-Purpose Model of Enteric Tissue (SEGMEnT)

Abstract

The mucosa of the intestinal tract represents a finely tuned system where tissue structure strongly influences, and is turn influenced by, its function as both an absorptive surface and a defensive barrier. Mucosal architecture and histology plays a key role in the diagnosis, characterization and pathophysiology of a host of gastrointestinal diseases. Inflammation is a significant factor in the pathogenesis in many gastrointestinal diseases, and is perhaps the most clinically significant control factor governing the maintenance of the mucosal architecture by morphogenic pathways. We propose that appropriate characterization of the role of inflammation as a controller of enteric mucosal tissue patterning requires understanding the underlying cellular and molecular dynamics that determine the epithelial crypt-villus architecture across a range of conditions from health to disease. Towards this end we have developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) to dynamically represent existing knowledge of the behavior of enteric epithelial tissue as influenced by inflammation with the ability to generate a variety of pathophysiological processes within a common platform and from a common knowledge base. In addition to reproducing healthy ileal mucosal dynamics as well as a series of morphogen knock-out/inhibition experiments, SEGMEnT provides insight into a range of clinically relevant cellular-molecular mechanisms, such as a putative role for Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) as a key point of crosstalk between inflammation and morphogenesis, the protective role of enterocyte sloughing in enteric ischemia-reperfusion and chronic low level inflammation as a driver for colonic metaplasia. These results suggest that SEGMEnT can serve as an integrating platform for the study of inflammation in gastrointestinal disease.

Author Summary

Mucosal histology plays a key role in the diagnosis, characterization and propagation of a host of gastrointestinal diseases, and the development of computational models capable of producing spatial architecture comparable to histology will enhance the evaluation of hypotheses for those diseases. Inflammation is a significant factor in the pathogenesis of a series of gastrointestinal diseases, and affects the maintenance of the mucosal architecture by morphogenic pathways. We have developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) to investigate the behavior of enteric epithelial tissue as influenced by inflammation. SEGMEnT integrates cellular and molecular pathways governing morphogenesis and inflammation to generate a variety of pathophysiological processes from a common platform and knowledge base. Beyond reproducing healthy and disease ileal mucosal dynamics, SEGMEnT provides insight into a range of clinically relevant cellular-molecular mechanisms, including a novel putative role for Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) as a key point of crosstalk between enteric inflammation and morphogenesis, the protective role of enterocyte sloughing in enteric ischemia-reperfusion and the mechanism of chronic low level inflammation as a driver for colonic metaplasia. These results suggest that SEGMEnT can serve as an integrating platform for the study of inflammation in gastrointestinal disease.