About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of
gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal
inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several
functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of
dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered
tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of
antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused
dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of
nitric oxide and activation of NOX2 since gut
sterility with
antibiotics prevented this change. The resulting
peroxynitrite generation led to increased oxidative stress that triggered
inflammation as shown by increased NLRP-3
inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in
tight junction protein occludin and selective
water channel aquaporin-3 with a concomitant increase in
Claudin-2. The
tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and
butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.