Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness
Open Access
- 21 October 2019
- Vol. 11 (10), 968
- https://doi.org/10.3390/v11100968
Abstract
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.Keywords
Funding Information
- U.S. Department of Defense (W81XWH1810374, W81XWH-13-2-0072)
- U.S. Department of Veterans Affairs (CX001923-01)
This publication has 70 references indexed in Scilit:
- Targeting Intracellular Calcium Stores Alleviates Neurological Morbidities in a DFP-Based Rat Model of Gulf War IllnessToxicological Sciences, 2019
- Interactions between Bacteriophage, Bacteria, and the Mammalian Immune SystemViruses, 2018
- The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain InjuryBrain Sciences, 2018
- The effect of systemic inflammation on human brain barrier functionBrain, Behavior, and Immunity, 2016
- MEGAN Community Edition - Interactive Exploration and Analysis of Large-Scale Microbiome Sequencing DataPLoS Computational Biology, 2016
- A Chronic Longitudinal Characterization of Neurobehavioral and Neuropathological Cognitive Impairment in a Mouse Model of Gulf War Agent ExposureFrontiers in Integrative Neuroscience, 2016
- Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced DepressionInternational Journal of Neuropsychopharmacology, 2015
- VirSorter: mining viral signal from microbial genomic dataPeerJ, 2015
- Anti‐IL‐6 neutralizing antibody modulates blood‐brain barrier function in the ovine fetusThe FASEB Journal, 2015
- Resident viruses and their interactions with the immune systemNature Immunology, 2013