C. Cockrell1, S. Christley1, E. Chang2, G. An1 1University Of Chicago,Surgery,Chicago, IL, USA 2University Of Chicago,Medicine/Gastroenterology,Chicago, IL, USA
Introduction: Pouchitis following proctocolectomy for ulcerative colitis is a significant source of morbidity, with long-term incidence rates of up to 95%. The pathogenesis of pouchitis is a multiscale process involving the dysregulated intestinal inflammation, abnormal mucosal tissue response, and alterations in gut microflora due to stasis resulting from the anatomic configuration of the illeal pouch. We have previously developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) to dynamically represent existing knowledge of the behavior of enteric epithelial tissue. Given that the progression of pouchitis and the spatial distribution of inciting stimuli are not homogenous throughout the pouch, anatomic scale simulations are required in order to plausibly simulate the clinical manifestations of the interplay of ileal and residual rectal cuff tissue with a dynamic microbiome. To achieve clinically relevant simulations we have implemented a supercomputing version of SEGMEnT, SEGMEnT_HPC, with the ability to generate anatomic-scale simulations of intestinal mucosa in response to inflammation.
Methods: SEGMEnT_HPC is an expansion of our prior SEGMEnT model to a High Performance Computing (HPC) platform, incorporating gut epithelial cells, inflammatory cells and their effects on the extracellular matrix with consequent changes in crypt-villus morphology. Luminal inflammatory stimuli are represented by the fecal microbiome as a dynamically flowing liquid. Simulation experiments were performed to investigate the role of fecal flow dynamics and host inflammatory potential on the development of anatomically realistic pouchitis, including anatomic transition zones at the proximal end of the pouch and the residual rectal cuff.
Results: SEGMEnT_HPC simulations suggested a putative role for Phosphotase and tensin homolog/phosphoinositide 3-kinase (PTEN/PI3K) as a key point of crosstalk between inflammation and morphogenesis, and demonstrated that differential flow dynamics associated with the creation of the ileal pouch promoted chronic inflammation due to fecal stasis in simulations in with impaired inflammatory suppression. We also noted the potential for the residual rectal cuff to “seed” the inflammatory propagation, seen in a heterogeneous continuum effect in terms of the anatomic patterning of metaplasia and inflammation in susceptible conditions.
Conclusion: SEGMEnT_HPC can serve as an integrating platform for the study of inflammation in gastrointestinal disease by generating clinically relevant and anatomic scale phenotypes from cellular and molecular mechanisms. Simulations of pouchitis demonstrated a complex interplay between the inflammatory potential of the host, the effect of fecal stasis and alterations in the resident microbiome affected by the flow dynamics of the pouch and rectal cuff. We suggest that SEGMEnT_HPC will be a vital adjunct in our future exploration of this and other complex, multi-factorial processes