Persistent enteric neuroinflammation chronically impairs colonic motility in a pyridostigmine bromide-induced mouse model of Gulf War illness.

Neuroplasticity in the adult colon enables the enteric nervous system (ENS) to adaptively remodel in response to acute inflammation, preserving motility. However, chronic inflammation may drive maladaptive neuroplasticity, resulting in gastrointestinal dysmotility, a hallmark of functional gastrointestinal disorders, including Gulf War illness (GWI). GWI affects ∼30% of Gulf War veterans and has been linked to oral toxic exposures during combat, such as pyridostigmine bromide (PB). To explore mechanisms of persistent dysmotility, we developed a PB exposure model relevant to GWI. In the colon, we observed structural and functional ENS changes, including an imbalance in excitatory and inhibitory motor neurons and altered motility patterns. These were accompanied by a sustained influx of pro-inflammatory macrophages and elevated cytokine levels, indicating persistent low-grade enteric neuroinflammation. Inflammatory macrophages were found near enteric neural stem cells (ENSCs), impairing their regenerative potential. Transcriptomic analyses corroborated the presence of chronic neuroinflammation and dysregulated repair pathways. Together, our findings suggest that persistent enteric neuroinflammation and impaired neurogenesis contribute to long-term colonic dysmotility in GWI. This model offers new insights into chronic ENS dysfunction and may guide therapeutic strategies for GWI and related disorders.