Date of Award

Spring 2020

Document Type

Open Access Dissertation

Department

Environmental Health Sciences

First Advisor

Saurabh Chatterjee

Abstract

Gulf war illness (GWI) is a chronic multisymptomatic disorder affecting about 30% of veterans of the 1990-1991 Persian Gulf war. Affected veterans complain of chronic symptoms which begun during or shortly after the war and persist 30 years later. This dissertation is a report of three studies which use a murine model to investigate the microbiome as a therapeutic target in GWI. Mice were exposed to pesticides and the prophylactic drug pyridostigmine bromide (PB) and studied these chemical’s impact on the microbiome in both an acute and persistence model of GWI.

The first study looks at the effect of altered microbiome on metabolism and proposes short chain fatty acids as a therapy for GWI. Results show that mice exposed to GWI showed toll like receptor activation, inflammation and metabolic reprogramming in the liver. These symptoms were alleviated with sodium butyrate, a short chain fatty acid. The second study looked at the effect of altered microbiome on the enteric nervous system and proposes the use of SsnB a TLR4 antagonist in combination with sodium butyrate as a possible therapy. Results show that mice which were treated with GW chemicals had reactive enteric glia which produced reactive oxygen species and proinflammatory cytokines, thereby modulating the expression of tight junction proteins in the intestine. Further, administration of SsnB and butyrate led improved EGC states and therefore improving tight junction protein integrity. The third study looks at the altered microbiome in the persistence of GWI neurological symptoms. Results show that mice exposed to GW chemicals presented with decreased relative abundance of Akkermansia muciniphila, a probiotic bacterium associated with good health, and this correlated with HMGB1 levels, neuroinflammation and neurotrophins level such as BDNF which are key players in maintaining neurological health

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