Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness
Ratanesh K. Seth,
Rabia Maqsood,
Ayan Mondal,
Dipro Bose,
Diana Kimono,
LaRinda A. Holland,
Patricia Janulewicz Lloyd,
Nancy Klimas,
Ronnie D. Horner,
Kimberly Sullivan,
Efrem S. Lim,
Saurabh Chatterjee
Affiliations
Ratanesh K. Seth
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
Rabia Maqsood
Center for Fundamental and Applied Microbiomics, The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
Ayan Mondal
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
Dipro Bose
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
Diana Kimono
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
LaRinda A. Holland
Center for Fundamental and Applied Microbiomics, The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
Patricia Janulewicz Lloyd
School of Public Health, Boston University, Boston MA 02118, USA
Nancy Klimas
NOVA Southeastern University, Fort Lauderdale, FL 33314, USA
Ronnie D. Horner
Department of Health Services Policy and Management, University of South Carolina, Columbia, SC 29208, USA
Kimberly Sullivan
School of Public Health, Boston University, Boston MA 02118, USA
Efrem S. Lim
Center for Fundamental and Applied Microbiomics, The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
Saurabh Chatterjee
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA
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.
