UC Irvine

Understanding the complex pathology of Gulf War Illness (GW), with its multisymptomatic condition, and identifying an efficient treatment has been a longstanding challenge for researchers. Researchers have made significant efforts in conducting mechanistic studies using different combinations of representative Gulf War (GW) chemicals in various experimental animal models in an attempt to create a translatable GWI pre-clinical model. However, there remain confounding factors like paucity of information regarding the actual amount of exposure among the GW Veterans, route, and duration of exposure impede the process.Our lab has been pioneering GWI research for the past decade. From the very first report about the association of altered gut microbiome in GWI pathology, we have attempted to approach the condition considering the translatable impact of the results on present-day Veterans. In the first study, the impact of metabolic disorders in underlying GWI conditions has been studied. GW Veterans living in a sedentary lifestyle now have an increased risk of xii developing conditions like obesity. The results showed that administration of a Western diet in a mouse model pre-exposed to GW chemicals decreased the abundance of beneficial gut bacteria. A decrease in bacterial diversity is strongly associated with gastrointestinal, hepatic, and systemic inflammation along with increased neurodegeneration. This study further provides cues of pleiotropic marker IL-6 being responsible for GWI pathology via the microbiome-gut-brain axis. In the second study, the alteration of gut resistome profile due to GW chemical exposure is long-lasting and closely associated with bacterial dysbiosis. In this study, a similar trend in resistome profile has been observed in an experimental murine model and GW Veterans. It was also observed that the altered antibiotic resistance genes were associated with gastrointestinal and systemic inflammation and decreased synaptic plasticity in the brain. In the third study, a double humanized mouse model have been designed in an approach to have a more translatable GWI murine model. The model has been designed to have both human microbiome and immune system. Exposure to GW chemicals resulted in alteration of gut microbiome and expression of host immune markers which were similar to the results observed in GW Veterans in an earlier study.