Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation.
Many of the symptoms of Gulf War Illness (GWI) that include neurological abnormalities, neuroinflammation, chronic fatigue and gastrointestinal disturbances have been traced to Gulf War chemical exposure. Though the association and subsequent evidences are strong, the mechanisms that connect exposure to intestinal and neurological abnormalities remain unclear. Using an established rodent model of Gulf War Illness, we show that chemical exposure caused significant dysbiosis in the gut that included increased abundance of phylum Firmicutes and Tenericutes, and decreased abundance of Bacteroidetes. Several gram negative bacterial genera were enriched in the GWI-model that included Allobaculum sp. Altered microbiome caused significant decrease in tight junction protein Occludin with a concomitant increase in Claudin-2, a signature of a leaky gut. Resultant leaching of gut caused portal endotoxemia that led to upregulation of toll like receptor 4 (TLR4) activation in the small intestine and the brain. TLR4 knock out mice and mice that had gut decontamination showed significant decrease in tyrosine nitration and inflammatory mediators IL1β and MCP-1 in both the small intestine and frontal cortex. These events signified that gut dysbiosis with simultaneous leaky gut and systemic endotoxemia-induced TLR4 activation contributes to GW chemical-induced neuroinflammation and gastrointestinal disturbances.
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Firas
F
Alhasson
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Suvarthi
S
Das
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Ratanesh
R
Seth
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Diptadip
D
Dattaroy
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Varun
V
Chandrashekaran
Second Genome Inc., San Francisco, California, United States of America.
Caitlin N
CN
Ryan
Second Genome Inc., San Francisco, California, United States of America.
Luisa S
LS
Chan
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
Traci
T
Testerman
Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
James
J
Burch
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America.
Lorne J
LJ
Hofseth
Department of Health Services, Policy and Management, Arnold School of Public Health, University of South Carolina. Columbia, South Carolina, United States of America.
Ronnie
R
Horner
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
Mitzi
M
Nagarkatti
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
Prakash
P
Nagarkatti
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
Stephen M
SM
Lasley
Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina, United States of America.
Saurabh
S
Chatterjee
D000818:Animals; D062446:Claudin-2 / Q000378:metabolism; D004195:Disease Models, Animal; D064806:Dysbiosis / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D047830:Gulf War; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology; D007410:Intestinal Diseases / Q000378:metabolism* / Q000382:microbiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018923:Persian Gulf Syndrome / Q000378:metabolism / Q000382:microbiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D062446:Claudin-2; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4