Toxic Exposure of Pyridostigmine Bromide Chronically Impairs Colonic Motility Via Low Grade Enteric Neuroinflammation

Combat veterans from the Persian Gulf War have unexplained yet persistent impairment in colonic motility due to combat-related toxic exposures. Central to Gulf War-related toxic exposures was the unmitigated ingestion of Pyridostigmine bromide (PB). We previously developed a Gulf War Illness (GWI) mouse model, where acute PB exposure led to immediate disruptions in colonic motility. Here, we explore mechanisms by which acute enteric neuroinflammation produces peristent impairment in colonic motility. GWI mice were exposed to PB transiently, and allowed to recover with no exposures for 1 month. GWI mice had significantly increased amplitudes of colonic contraction and diminished nerve-stimulated colonic relaxation, compared to naive controls. Immunohistological characterization demonstrated persistent chronic damage in enteric neuronal network integrity, accompanied by a significant imbalance in excitatory and inhibitory motor neuronal populations. Inflammatory CD40+ tissue- resident macrophages were identified with enteric neural stem cells in GWI colons, with an increase in secreted inflammatory cytokines. Unbiased transcriptomic analysis corroborated peristent low grade enteric neuroinflammation, overall resulting in impaired repair and regeneration of neural circuity in GWI. Our learnings can be leveraged to design new regenerative therapies for Gulf War veterans, and broadly impact our understanding of severeal inflammatory disorders of the gut.