Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation.
Ontology highlight
ABSTRACT:
SUBMITTER: Bose D
PROVIDER: S-EPMC9174162 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation.
Bose Dipro D Chatterjee Somdatta S Older Ethan E Seth Ratanesh R Janulewicz Patricia P Saha Punnag P Mondal Ayan A Carlson Jeffrey M JM Decho Alan W AW Sullivan Kimberly K Klimas Nancy N Lasley Stephen S Li Jie J Chatterjee Saurabh S
Communications biology 20220607 1
Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resis ...[more]
Similar Datasets
Project description:BackgroundMore than twenty years following the end of the 1990-1991 Gulf War it is estimated that approximately 300,000 veterans of this conflict suffer from an unexplained chronic, multi-system disorder known as Gulf War Illness (GWI). The etiology of GWI may be exposure to chemical toxins, but it remains only partially defined, and its case definition is based only on symptoms. Objective criteria for the diagnosis of GWI are urgently needed for diagnosis and therapeutic research.ObjectiveThis study was designed to determine if blood biomarkers could provide objective criteria to assist diagnosis of GWI.DesignA surveillance study of 85 Gulf War Veteran volunteers identified from the Department of Veterans Affairs Minnesota Gulf War registry was performed. All subjects were deployed to the Gulf War. Fifty seven subjects had GWI defined by CDC criteria, and 28 did not have symptomatic criteria for a diagnosis of GWI. Statistical analyses were performed on peripheral blood counts and assays of 61 plasma proteins using the Mann-Whitney rank sum test to compare biomarker distributions and stepwise logistic regression to formulate a diagnostic model.ResultsLymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI subjects. Six serum proteins associated with inflammation were significantly different in GWI subjects. A diagnostic model of three biomarkers-lymphocytes, monocytes, and C reactive protein-had a predicted probability of 90% (CI 76-90%) for diagnosing GWI when the probability of having GWI was above 70%.SignificanceThe results of the current study indicate that inflammation is a component of the pathobiology of GWI. Analysis of the data resulted in a model utilizing three readily measurable biomarkers that appears to significantly augment the symptom-based case definition of GWI. These new observations are highly relevant to the diagnosis of GWI, and to therapeutic trials.
| S-EPMC4924830 | biostudies-literature
Project description:Long term consequences of combined pyridostigmine bromide and permethrin exposure in C57BL6/J mice using a well characterized mouse model of exposure to these Gulf War agents. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semi-acute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches – stable isotope dimethyl labeling (SIDL) and isobaric tags for relative and absolute quantitation (iTRAQ). The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW-agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at five months post exposure to PB+PER
2017-02-01 | PXD005185 | Pride
Project description:Altered gut microbiome in a mouse model of gulf war illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation
| PRJEB19474 | ENA
Project description:Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.
| S-EPMC11172868 | biostudies-literature
Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.
2019-03-15 | GSE112905 | GEO
Project description:Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.
| S-EPMC10338554 | biostudies-literature
Project description:Low level sarin nerve gas and other anti-cholinesterase agents have been implicated in Gulf War illness (GWI), a chronic multi-symptom disorder characterized by cognitive, pain and fatigue symptoms that continues to afflict roughly 32% of veterans from the 1990-1991 Gulf War. How disrupting cholinergic synaptic transmission could produce chronic illness is unclear, but recent research indicates that acetylcholine also mediates communication between axons and oligodendrocytes. Here we investigated the hypothesis that oligodendrocyte development is disrupted by Gulf War agents, by experiments using the sarin-surrogate acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP). The effects of corticosterone, which is used in some GWI animal models, were also investigated. The data show that DFP decreased both the number of mature and dividing oligodendrocytes in the rat prefrontal cortex (PFC), but differences were found between PFC and corpus callosum. The differences seen between the PFC and corpus callosum likely reflect the higher percentage of proliferating oligodendroglia in the adult PFC. In cell culture, DFP also decreased oligodendrocyte survival through a non-cholinergic mechanism. Corticosterone promoted maturation of oligodendrocytes, and when used in combination with DFP it had protective effects by increasing the pool of mature oligodendrocytes and decreasing proliferation. Cell culture studies indicate direct effects of both DFP and corticosterone on OPCs, and by comparison with in vivo results, we conclude that in addition to direct effects, systemic effects and interruption of neuron-glia interactions contribute to the detrimental effects of GW agents on oligodendrocytes. Our results demonstrate that oligodendrocytes are an important component of the pathophysiology of GWI.
| S-EPMC6899710 | biostudies-literature
Project description:BackgroundMore than 230,000 veterans-about 1/3 of US personnel deployed in the 1990-1991 Persian Gulf War-developed chronic, multi-symptom health problems now called "Gulf War illness" (GWI), for which mechanisms and objective diagnostic signatures continue to be sought.MethodsTargeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. 40 male participants, included 20 veterans who met both Kansas and CDC diagnostic criteria for GWI and 20 nonveteran controls without similar symptoms that were 1:1 matched to GWI cases by age, sex, and ethnicity. Serum samples were collected and archived at -80° C prior to testing. 358 metabolites from 46 biochemical pathways were measured by hydrophilic interaction liquid chromatography and tandem mass spectrometry.ResultsVeterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Lipid abnormalities accounted for 78% of the metabolic impact. Fifteen ceramides and sphingomyelins, and four phosphatidylcholine lipids were increased. Five of the 8 pathways were shared with the previously reported metabolic phenotype of males with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, 4 of the 5 shared pathways were regulated in opposite directions; key pathways that were up-regulated in GWI were down-regulated in ME/CFS. The single pathway regulated in the same direction was purines, which were decreased.ConclusionsOur data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Metabolomic differences between GWI and ME/CFS show that common clinical symptoms like fatigue can have different chemical mechanisms and different diagnostic implications. Larger studies will be needed to validate these findings.
| S-EPMC6660083 | biostudies-literature
Project description:Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI), by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in theater have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water (20mg%, w/v) for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate (DFP, 4mg/kg, i.p.). Control mice were maintained under normal husbandry. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genomic methylation analysis by MBD-seq. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.
2023-06-01 | GSE225179 | GEO
Project description:Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key. This Boston University-based Gulf War Illness Consortium (GWIC) study investigated the impact of single nucleotide polymorphisms (SNPs) in variants of immune and pain genetic markers IL1B, IL2, IL6, IL6R, IL10, TNF, TGF, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, COMT and OPRM1 on GWI occurrence in a Caucasian subset of Gulf War (GW) veterans with (cases, n = 170) and without (controls, n = 34) GWI. Logistic regression modeling created a prediction model of GWI risk that associated genetic variability in TGF (rs1800469, p = 0.009), IL6R (rs8192284, p = 0.004) and TLR4 (rs4986791, p = 0.013) with GWI occurrence. This prediction model was specific and sensitive, with a receiver operator characteristic area under the curve of 71.4%. This is the first report of immune genetic variability being predictive of GWI and warrants validation in larger independent cohorts. Future reports will present interactions of these genetic risk factors with other characteristics of GW service.
| S-EPMC8615505 | biostudies-literature