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Open AccessArticle

Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness

1
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
2
Center for Fundamental and Applied Microbiomics, The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
3
School of Public Health, Boston University, Boston MA 02118, USA
4
NOVA Southeastern University, Fort Lauderdale, FL 33314, USA
5
Department of Health Services Policy and Management, University of South Carolina, Columbia, SC 29208, USA
6
Dorn VA Medical Center, Columbia, SC 29209, USA
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(10), 968; https://doi.org/10.3390/v11100968
Received: 5 September 2019 / Revised: 17 October 2019 / Accepted: 17 October 2019 / Published: 21 October 2019
(This article belongs to the Section Animal Viruses)
Gulf War illness (GWI) is characterized by the persistence of inflammatory bowel disease, chronic fatigue, neuroinflammation, headache, cognitive impairment, and other medically unexplained conditions. Results using a murine model show that enteric viral populations especially bacteriophages were altered in GWI. The increased viral richness and alpha diversity correlated positively with gut bacterial dysbiosis and proinflammatory cytokines. Altered virome signature in GWI mice also had a concomitant weakening of intestinal epithelial tight junctions with a significant increase in Claudin-2 protein expression and decrease in ZO1 and Occludin mRNA expression. The altered virome signature in GWI, decreased tight junction protein level was followed by the presence an activation of innate immune responses such as increased Toll-like receptor (TLR) signaling pathways. The altered virome diversity had a positive correlation with serum IL-6, IL-1β, and IFN-γ, intestinal inflammation (IFN-γ), and decreased Brain-Derived Neurotrophic Factor (BDNF), a neurogenesis marker. The co-exposure of Gulf War chemical and antibiotic (for gut sterility) or Gulf War chemical and Ribavirin, an antiviral compound to suppress virus alteration in the gut showed significant improvement in epithelial tight junction protein, decreased intestinal-, systemic-, and neuroinflammation. These results showed that the observed enteric viral dysbiosis could activate enteric viral particle-induced innate immune response in GWI and could be a novel therapeutic target in GWI. View Full-Text
Keywords: Gulf war illness; Virome; microbiome; next-generation sequencing; intestinal inflammation; neuroinflammation; Ribavirin; IL6 Gulf war illness; Virome; microbiome; next-generation sequencing; intestinal inflammation; neuroinflammation; Ribavirin; IL6
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Seth, R.K.; Maqsood, R.; Mondal, A.; Bose, D.; Kimono, D.; Holland, L.A.; Janulewicz Lloyd, P.; Klimas, N.; Horner, R.D.; Sullivan, K.; Lim, E.S.; Chatterjee, S. Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness. Viruses 2019, 11, 968.

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