Enteric Neuroinflammation Driven by Exposure to Pyridostigmine Bromide is a Possible Contributing Factor to Gulf War Illness

Abstract

Gulf War Illness (GWI) is a chronic disorder characterized by a spectrum of six symptoms that include gastrointestinal disorders. Exposure to the anti‐nerve gas drug pyridostigmine bromide (PB) is linked with the development of GWI, but the exact mechanisms remain unclear. We hypothesize that PB disrupts gut functions by creating persistent neuroinflammation within the enteric nervous system (ENS). We tested the acute effects of PB on the ENS in situ with calcium imaging recordings and in vivo by exposing mice to 9 μg/mL or 90 μg/mL PB (low‐ or high‐PB) for 7 days and subsequently assessing gut function using in vivo and ex vivo tests of colonic motility and barrier function. Neurochemistry of the ENS was assessed by immunohistochemistry. Our results show that glial calcium responses were significantly increased in the presence of PB (181.0%, p<0.001) when compared to ADP response. Mice exposed to high‐PB exhibited increased fecal pellet output (80.7%, p<0.05), higher fecal fluid content (19.1%, p<0.05), slower colonic bead expulsion (218.3%, p<0.001), altered neuromuscular control, and neurodegeneration in the ENS (18.3% neuronal loss, p<0.05) in comparison with control. Mice exposed to low‐PB showed an increase in the proportion of inhibitory enteric neurons (35%, p<0.05), while PB treatment caused reduced colon length (10.4%, p=0.0704 low‐PB; 9.8%, p=0.0908 high‐PB) and increased colonic fluid transport (31.0% low‐PB, 32.7% high=PB, p<0.05 both) regardless of the dose. Our results show that the acute exposure to PB significantly alters the anatomy and functions of the ENS. We propose that these changes contribute to the pathophysiology of GWI.Support or Funding InformationDepartment of Defense (DOD) W81XWH1610631This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.