Project Summary/Abstract: Gulf War Illness (GWI) continues to plague a subsection of the veterans deployed in the Persian Gulf war even 30 years after they returned home. The illness has taken a heavy toll on the overall quality of life of our deployed veterans. We still do not have a definitive treatment regimen for Gulf War Illness even though several drug candidates have shown promise. Recent research in the last five years have revealed the role of host gut microbiome in gastrointestinal disturbance, systemic inflammation and neurotrophic abnormalities in Gulf War Illness mouse models. A recent study from our laboratory and our collaborators at Boston University showed that veterans with GWI exhibit microbial dysbiosis with decreased butyrogenic bacterial profile. We have preliminary data that the host virome signature is altered in GWI veterans. In addition, we showed that gut virome alteration in a mouse model of GWI is strongly associated with increased serum levels of IL6, a proinflammatory cytokine known to cause systemic and neurocognitive disease. Results showed that short chain fatty acids such as butyrate restored healthy microbiome, improved microbial metabolism in the gut apart from attenuating GWI symptom persistence in preclinical studies. Butyrate, a nutraceutical that is endogenously produced in the host gut following bacterial fermentation also has shown promise in gastrointestinal disturbances such as IBS and IBD and is a good treatment choice among gastroenterologists. Butyrate is also effective as a strong anti-inflammatory molecule in preclinical studies. The FDA has long approved the use of butyrate as a safe food additive and use of it as enemas for GI disturbances. Interestingly, Gulf War Illness patients show gastrointestinal disturbances (constipation, diarrhea, bloating, acid reflux, pain), chronic fatigue and neurocognitive abnormalities. The GWI patients also have an altered microbiome that is associated with systemic inflammation. Objective of the trial: The goal of this clinical trial is to determine if a Butyrate formulation that consists of butyric acid as calcium and magnesium derivatives in a single oral capsule administered twice a day is effective in increasing physical functioning for Veterans with Gulf War Illness. The secondary outcome will focus on the drug's role in (a) restoring gut microbiome and virome (that have been found altered in GWI veterans), (b) decreasing gastrointestinal disturbances (constipation, diarrhea, pain) (c) decreasing chronic fatigue, (d) decreasing systemic inflammation such a blood levels of proinflammatory cytokines and (d) a decrease in cognitive deficits. The clinical trial involving butyrate on Gulf War Illness veterans will be conducted in three sites across the nation. The sites of Columbia SC (primary-Columbia VA medical center), Salt Lake City, Utah and Miami VA will work in tandem and in total concert to conduct this trial. This is a randomized, two group, double blin...