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.
Highlights
The gut epithelium faces unique challenges in striking a balance between its receptive role in the absorption of nutrients and fostering synergistic interactions with commensal microbes versus retaining sufficient defensive barrier function to prevent microbial invasion and heal tissue injury effectively within this complex environment
While Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) does not generate the spatial architecture de novo, it is able to produce the appropriate cell distributions and spatial morphogen gradients leading to homeostasis
SEGMEnT dynamically represents and integrates existing knowledge concerning homeostasis and inflammation in the ileum and provides a computational platform to augment the exploration of the cellular/molecular processes involved in intestinal wound repair, ischemia/reperfusion injury, and colonic metaplasia/ pouchitis
Summary
The gut epithelium faces unique challenges in striking a balance between its receptive role in the absorption of nutrients and fostering synergistic interactions with commensal microbes versus retaining sufficient defensive barrier function to prevent microbial invasion and heal tissue injury effectively within this complex environment. We propose that a broad spectrum of intestinal disease can be unified by a view that the mucosal tissue architecture, as maintained by morphogenesis pathways, is subject to a series of control modules that effectively balance the complex interplay of multiple functional objectives when in a state of health, but can become disturbed to generate pathological conditions (Figure 1) Of these control modules, inflammatory pathways are among the most clinically significant, playing an important pathophysiological role in a host of intestinal diseases ranging from environmental enteropathy [2], necrotizing enterocolitis [3], inflammatory bowel disease [4], gut-derived sepsis [5] and cancer [6]. SEGMEnT models the spatial dynamics of the crypt-villus tissue architecture as generated by the behavior of gut epithelial cells as they undergo replication, migration and differentiation, with the novel incorporation of the effect of inflammation on those morphogenic processes (Figure 1)
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