Modeling Inflammation-Driven Colon Hypertrophy and Motility Changes in Gulf War Illness

Area of Science:

• Computational biology
• Neuroimmunology
• Gastroenterology

Background:

• Gastrointestinal symptoms are common in Gulf War Illness (GWI).
• Pyridostigmine bromide (PB) exposure in animal models links to smooth muscle hypertrophy, neuroinflammation, and impaired motility.
• Existing animal studies offer limited insight into the dynamic interactions of inflammatory, neuronal, and biomechanical processes over time.

Purpose of the Study:

• To develop a computational model predicting smooth muscle hypertrophy and colonic motility changes in GWI.
• To couple cytokine kinetics, macrophage activation, and neuronal imbalance to simulate GWI pathophysiology.
• To provide a systems-level understanding of acute inflammation evolving into chronic dysmotility.

Main Methods:

• Developed a computational model integrating cytokine kinetics, macrophage activation, and neuronal imbalance.
• Calibrated the model using data from mice exposed to PB under acute (7-day) and chronic (30-day) conditions.
• Performed simulations to predict smooth muscle hypertrophy and colonic motility, validated against experimental data.

Main Results:

• The model accurately reproduced measured IL-6 elevations, macrophage accumulation, and circular muscle thickening.
• Simulations captured reduced excitatory stress and sustained loss of inhibitory relaxation, aligning with organ-bath recordings.
• Sensitivity analyses identified macrophage persistence as a key factor in chronic inhibitory dysfunction.

Conclusions:

• The computational model offers a dynamic, systems-level view of GWI pathophysiology.
• Macrophage persistence is a critical regulator of chronic colonic dysmotility following PB exposure.
• The model serves as a foundation for a virtual platform to test interventions for neuroimmune GI disorders.