The virtual intestine: in silico modeling of small intestinal electrophysiology and motility and the applications

Abstract

The intestine comprises a long hollow muscular tube organized in anatomically and functionally discrete compartments, which digest and absorb nutrients and water from ingested food. The intestine also plays key roles in the elimination of waste and protection from infection. Critical to all of these functions is the intricate, highly-coordinated motion of the intestinal tract, known as motility, which is co-regulated by hormonal, neural, electrophysiological and other factors. The Virtual Intestine encapsulates a series of mathematical models of intestinal function in health and disease, with a current focus on motility, and particularly electrophysiology. The Virtual Intestine is being cohesively established across multiple physiological scales, from sub/cellular functions to whole organ levels, facilitating quantitative evaluations that present an integrative in-silico framework. The models are also now finding broad physiological applications, including in evaluating hypotheses of slow wave pacemaker mechanisms, smooth muscle electrophysiology, structure-function relationships, and electromechanical coupling. Clinical applications are also beginning to follow, including in the pathophysiology of motility disorders, diagnosing intestinal ischemia, and visualizing colonic dysfunction. These advances illustrate the emerging potential of the Virtual Intestine to effectively address multi-scale research challenges in interdisciplinary gastrointestinal sciences.

Intra‐operative high‐resolution mapping of slow wave propagation in the human jejunum: Feasibility and initial results

“…19,24 These new data update existing quantitative physiology knowledge, and can now be applied to usefully inform computational models of electrical activity and electro-mechanical coupling in the human small intestine. [32][33][34] Such models have been restricted to date by a void of spatiotemporal human slow wave data, but hold significant potential for in silico hypothesis testing. 32 Recording and analyzing human intestine slow wave activity, even at low-resolution with sparse electrodes, is challenging, and there have therefore been very few detailed studies to guide physiological understanding.…”

“…These new data update existing quantitative physiology knowledge, and can now be applied to usefully inform computational models of electrical activity and electro‐mechanical coupling in the human small intestine . Such models have been restricted to date by a void of spatiotemporal human slow wave data, but hold significant potential for in silico hypothesis testing …”

Electrical stimulation of gut motility guided by anin silicomodel

“…Previous work modelled motility anatomically in three dimensions, although such anatomical models often lacked the physiological behavior to model electrical stimulation (Randhawa et al, 1996, Parsons and Huizinga, 2015, Du et al, 2016, Cheng et al, 2013). In this work, a virtual pellet was modeled as a 1-cm-long, 2D rigid object with position determined by fundamental mechanics.…”

“…Additional models were developed to study neural control of motility, including models for segmentation and migrating motor complexes (Chambers et al, 2008, Thomas et al, 2004). Separate models captured electrical slow waves that arise from the interaction between interstitial cells of Cajal (ICC) and smooth muscle fibers, but these models did not consider enteric neurons or neuromuscular junctions (Edwards and Hirst, 2003, Edwards and Hirst, 2006, Edwards and Hirst, 2005, Edwards et al, 1999, Hirst et al, 2006, Du et al, 2016, Du et al, 2011). Despite these efforts, there is no model that includes all the components necessary to capture the effect of electrical stimulation on gut motility, including conductance-based models of the electrical activity of enteric neurons and ICC-driven slow wave propagation through smooth muscle.…”

Original Research: Combined model of bladder detrusor smooth muscle and interstitial cells

“…Similar approach was already repeatedly employed in the field of gastrointestinal physiology on several levels of biological complexity, from (sub)cellular models to tissue and whole organ levels providing a complex in silico organ modeling framework for addressing complex clinical problems. 29,30 The interactions between IC and SMC were ....................................................................................................................... recently modeled also in uterine tissue. 36 In a system consisting of myocytes coupled to passive (IC-like) cells, which was extended to a simple two-dimensional lattice model of the tissue, they were able to demonstrate that an increase in inter-cellular electrical coupling strongly facilitated the appearance of spontaneous action potentials that may eventually lead to parturition.…”