Gastrointestinal neuroimmune disruption in a mouse Gulf War Illness model

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 effects of PB in vivo by exposing male and female mice to 9 μg/mL or 90 μg/mL PB for 7 and 30 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 and immune responses were studied using multiplex cytokine and chemokine arrays in the gut and brain. Acutely exposing whole mount preparations of myenteric plexus to PB drove calcium responses in enteric glia (181.0%, p<0.001). In vivo, exposure to PB acutely increased fecal pellet output (44.3%, p<0.05) and increased fecal fluid content (13.2%, p<0.05) in male mice, but decreased fecal pellet output (62.5%, p<0.05) and reduced fecal fluid content (18.1%, p<0.05) in females. Regardless of sex, PB treatment altered neuromuscular control, slower colonic bead expulsion (male 504.4%, p<0.001; female 275.8%, p<0.01), and reduced colon length (male 9.4%, p<0.05; female 9.9%, p<0.05). PB also drove enteric neurodegeneration in male mice (15.5% neuronal loss, p<0.05) and increased the proportion of excitatory enteric neurons (by 67.7% in 90 μg/mL group, p<0.05) in females. Despite having no effect on colonic permeability, exposure to PB caused major shifts in the expression of pro‐inflammatory cytokines and chemokines in the colon and brain that suggest immunosuppressive effects. Interestingly, immune disruption was still evident in the colon and brain of female animals at one month following exposure to PB. Our results show that the paradigm of PB exposure experienced by veterans of the Persian Gulf War contributes to long‐lasting pathophysiology by driving enteric neuroinflammation, promoting immunosuppression, and altering functional anatomy of the colon in a sex‐dependent manner.Support or Funding InformationDepartment of Defense (DOD) W81XWH1610631This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.