Long‐term gastrointestinal motility disruption in a mouse Gulf War Illness model treated with palmitoylethanolamide

Abstract

Gulf War Illness (GWI) is a chronic disorder characterized by a spectrum of six symptoms that include gastrointestinal (GI) disorders. Exposure to the anti‐nerve gas drug pyridostigmine bromide (PB) is linked with the development of GWI, but the exact mechanisms remain unclear. Our prior data show that PB exposure contributes to long‐lasting pathophysiology by driving enteric neuroinflammation, promoting immunosuppression, and altering physiological function of the colon. Here, we tested the hypothesis that palmitoylethanolamide (PEA), an endogenous anti‐inflammatory mediator, is sufficient to reduce the detrimental effects of PB in the gut and brain of mice. We tested the effects of PB in vivo by exposing male and female mice to 90 μg/mL PB for 7 days and assessing gut function using in vivo and ex vivo tests of colonic motility and barrier function for 5 months. After 2 months of treatment mice were treated with 0.07 mg/mL of PEA. Immune responses were studied using multiplex cytokine and chemokine arrays in the gut and brain. Male, but not female, mice exposed to PB gained less weight during exposure of PEA (4%, p<0.05). Regardless of sex, exposure to PEA cause a decrease in fecal pellet output (male 66.5%, p<0.01; female 66.1%, p<0.05) and fecal fluid content (male 29.3%, p<0.01; female 23.7%, p<0.05). The combination of PB and PEA treatment altered neuromuscular control and slowed colonic bead expulsion (577.7%, p<0.001) in male mice, but only PB treatment caused slower expulsion in females (777.7%, p<0.001). Colonic permeability was not altered in male mice, but females treated with PEA trended towards increased permeability (39.1%, p=0.0534). Exposure to PEA caused major shifts in the expression of pro‐inflammatory cytokines and chemokines in the colon and brain. Interestingly, immune disruption was still evident in the colon and brain of male and female animals at 2 months following exposure to PEA. Our results show that PEA alters the functional anatomy of the colon and promotes immune disruption in a sex dependent manner and provides no tangible benefit for neuroimmune disruptions driven by PB.Support or Funding InformationDepartment of Defense (DOD) W81XWH1610631