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

Gastrointestinal (GI) symptoms are a prominent feature of Gulf War Illness (GWI). Animal models attribute them to pyridostigmine bromide (PB) exposure, which induces smooth muscle hypertrophy, neuroinflammation, and motility impairment. However, animal studies only provide static snapshots of disease progression and can only partially resolve how inflammatory, neuronal, and biomechanical processes interact dynamically over time. To address this gap, we developed a computational model that couples cytokine kinetics, macrophage activation, and an excitatory-inhibitory neuronal imbalance to predict smooth muscle hypertrophy and colonic motility changes in GWI. The model was calibrated using data from mice exposed to PB under acute (7-day exposure and measurement) and chronic (7-day exposure and 30-day measurement) conditions, reproducing measured cytokine IL-6 elevations, macrophage accumulation, circular muscle thickening, and shifts in excitatory and inhibitory gene expression. Simulations captured reduced excitatory stress, and sustained loss of inhibitory relaxation, consistent with organ-bath recordings. Sensitivity analyses identified macrophage persistence as a dominant regulator of chronic inhibitory dysfunction, whereas excitatory pathways exhibited relative robustness and recovery. Thus, our model provides a systems-level view of how acute PB-induced inflammation evolves into chronic dysmotility and establishes a first step towards a virtual platform for testing hypotheses and interventions translatable to neuroimmune GI disorders.