Data Sheet 1_A compartmental model for simulating the gut-brain axis in gastric function regulation.pdf

Introduction Gastric function is regulated by the gut-brain axis, which integrates vagal and enteric nervous system (ENS) pathways. The parasympathetic circuit within the vagal pathway promotes digestion by stimulating peristaltic activity and relaxing the pyloric sphincter (PS) through motor and sensory neurons. In contrast, the sympathetic pathway inhibits digestion by suppressing peristalsis and constricting the PS, highlighting the complex neural coordination involved in gastric regulation. Methods We introduce a novel mathematical model of the gut-brain axis using a computationally efficient compartmental modeling framework. The model simulates the vagal and ENS pathways and their corresponding effects on gastric function to enhance our understanding of gut-brain axis regulation. We employ the Michaelis-Menten equation with a Hill coefficient to capture neurotransmitter release at neuromuscular junctions by stimulation of motor neurons and its effects on gastric cells. Motor, or efferent, neurons are modeled for three key stomach regions: the fundus, which exhibits tonic activity; the antrum, which exhibits phasic activity; and the PS, which exhibits both tonic and phasic activity. Thus, the stomach is represented as a three-compartment model. The stomach model extends our previous work by incorporating passive stress and dynamic changes in stomach geometry. Sensory, or afferent, inputs are represented through linear equations that account for chemo- and mechanoreceptor activity, while a binary variable captures the sympathetic response. Afferent and efferent firing rates are linked via fitted curves to effectively close the gut-brain axis feedback loop, borrowing from a similar approach used to model cardiovascular regulation. Results The simulation results align with physiological observations, demonstrating inhibitory digestive activity during sympathetic responses and excitatory activity, such as gastric emptying, during parasympathetic responses. During gastric emptying, the interstitial cells of Cajal activity shows constant amplitude for low to medium gastric volumes but exhibits an increase in amplitude at very high gastric volumes. Furthermore, gastric emptying rates decrease with high-calorie liquids due to PS regulation. Discussion The flexibility of the model allows for future enhancements based on newly discovered signaling pathways in gut-brain circuitry. The computational efficiency of the model suggests its potential use in developing vagal stimulation therapies for gastrointestinal disorders using closed-loop model-based control.