Thursday, March 30, 2017

BOSTON UNIVERSITY: Identifying Biomarkers of Gulf War Illness



SOURCE:  Boston University School of Public Health, by Lisa Chedekel, March 29, 2017

https://www.bu.edu/sph/2017/03/29/identifying-biomarkers-of-gulf-war-illness/


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Identifying Biomarkers of Gulf War Illness

POSTED ON: March 29, 2017 TOPICS: gulf war illness, veteran health, veterans
serviceman-flagTwenty-five years after the first Gulf War, scientists still do not know the exact biological mechanisms that are making about one-third of the 697,000 veterans who served in the war sick.
But a new multi-institution study in the journal Neurotoxicology & Teretology, co-authored by a School of Public Health researcher, provides evidence that Gulf War Illness (GWI) stems from neuronal and glial injury affecting both the gray and white matter cells of the brain, and identifies serum autoantibodies that may prove useful as biomarkers of the illness.
The research team found “significantly elevated levels” of eight autoantibodies linked to certain central-nervous system cytoskeletal proteins (including tau, tubulin, myelin basic protein and glial fibrillary acidic protein) in a sample group of 20 Gulf War veterans, compared to a control group—a finding that suggests a “possible new avenue” for identifying an objective biomarker of Gulf War Illness. Glial fibrillary acidic protein—a marker of glial astrocyte injury—completely distinguished between the GWI cases and the controls in the study.
“These results confirm the presence of neuronal injury/glial activation in these veterans, and are in agreement with the recent reports indicating that 25 years after the war, the health of veterans with GWI is not improving and may be getting worse,” the authors said.
The serum autoantibodies “may prove useful as biomarkers of GWI, upon validation of the findings using larger cohorts in our ongoing multi-site study.”
Study co-principal investigator Kimberly Sullivan, a research assistant professor of environmental health and principal investigator on the Gulf War Illness Consortium project, which includes nine study sites, said the new study provides “objective, blood-based evidence of damage to the brains of sick Gulf War veterans. It indicates that, at least at some point, these veterans had a leaky blood-brain barrier that allowed these CNS proteins to enter their bloodstream and activate the immune system.”
Sullivan said she was hopeful that the work would lead to a simple blood test for GWI, and perhaps other toxicant-induced disorders, “if our larger, ongoing study shows the same promising results as this initial study.”
The complex of symptoms known as Gulf War Illness includes memory and attention problems, fatigue, chronic muscle and joint pain, headaches, persistent diarrhea, respiratory difficulties and skin rashes.  
Past research has shown that exposure to pesticides, the nerve gas agent sarin, and ingestion of pyridostigmine bromide (PB)—prophylactic pills intended to protect troops against the effects of possible nerve gas—are associated with GWI and neurological dysfunction. These so-called “toxic wounds” resulted in damage to veterans’ nervous systems and immune systems, including reduced white and gray matter in veterans’ brains, past studies have shown.
Combined with prior findings, the new study indicates that alterations in the brain’s cytoskeletal proteins, as evidenced by circulating autoantibodies, appear to be associated with chronic neuro-inflammation and oxidative stress, which cause the chronic health problems reported by sick veterans.
There is no treatment for GWI, and veterans’ advocates have complained that the Department of Veterans Affairs has been reluctant to recognize the illness as a toxicant-induced disorder.
The new study found significant increases in the levels of some of the eight autoantibodies among GWI veterans, including a 9.27-fold increase for calcium—calmodulin kinase II (CaMKIII); a six-fold increase for glial fibrillary acidic protein (GFAP); and a 4.83-fold increase in tau protein. Those elevated levels are consistent with the veterans’ exposure during their deployments to compounds such as pesticides and sarin gas, the research team said. Similar effects have been found in GWI animal models.
The study was led by Mohamed Abou-Donia of Duke University Medical Center, with co-authors from: Beth Israel Deaconess Medical Center, Harvard Medical School, Zagazig University in Egypt, and Menoufia University in Egypt.
The Gulf War Illness Consortium, which has developed blood and stem cell repositories, recently received nearly $3 million in funding from the Department of Defense for four additional “New Investigator” studies aimed at identifying biomarkers and genetic risk factors involved in the illness. Sullivan said that utilizing the GWIC biorepositories will allow for faster results in the new research. The new studies include:
  • Research to be conducted in collaboration with the Naval Research Laboratory that will examine epigenetic DNA changes in affected veterans to identify “altered gene expression markers”—meaning that protective genes may have been turned off by environmental exposures, causing the chronic health symptoms.
  • Exploring the association between development of GWI and exposure to cholinergic compounds (pesticides and nerve agents) in subgroups of veterans with specific combinations of genotypes that are less able to detoxify these chemicals. The study will be led by Patricia Janulewicz, SPH assistant professor of environmental health.
  • Developing a computerized diagnostic system for GWI using “machine learning” that incorporates multiple biomarker data, in order to generate probability scores at the individual veteran level and gauge potential risks for symptoms of GWI. The study will be led by researcher Bang-bon Koo, a postdoctoral associate in the BU School of Medicine.
  • Using a stem cell biorepository bank to determine whether GW-relevant chemical exposures cause the cytoskeletal protein, tau, in neurons to go awry, and if so, whether the resulting symptoms can be reversed with several FDA-approved medicines. The study will be led by Drexel University investigators.

Friday, March 24, 2017

New research links Gulf War Illness to gastrointestinal disturbances




SOURCE:  Press Release, University of South Carolina (EurekaAlerts)

https://www.eurekalert.org/pub_releases/2017-03/uosc-nrl032317.php


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PUBLIC RELEASE: 

New research links Gulf War Illness to gastrointestinal disturbances

Findings may point to new treatments for elusive disorder
UNIVERSITY OF SOUTH CAROLINA
A new study from the University of South Carolina has found a gastrointestinal link that could help explain many of the health issues facing those with Gulf War Illness (GWI) as well as opening new pathways to treatment options that may improve both gastrointestinal and neurological symptoms associated with the disorder. 
The research is the first study to link the gastrointestinal disturbances of GWI with changes in the intestinal microbiota. This connection potentially explains both the gastrointestinal inflammation and the neurological abnormalities (e.g., impairments to cognition, memory, learning) that define GWI. 
GWI exposures alter the microbiome (i.e., bacterial content in the gut), and the affected microbiota then produce endotoxins, which pass through a thinned lining of the gut (i.e., leaky gut) and into the blood where they circulate throughout the body. These compounds trigger an inflammatory response that, in turn, initiates several neurological abnormalities commonly observed in GWI. 
The findings were published by PLOS ONE and led by Saurabh Chatterjee, associate professor of environmental health sciences at USC's Arnold School of Public Health. The study looked at how the various exposures experienced by Gulf War veterans might have changed the microbiome. "Humans and animals have specific types of bacteria that help aid various physiological processes, including digestion, absorption, immunity and gut integrity, and when external factors change the bacterial composition in our digestive systems, we have problems," says Chatterjee. "Obesity, metabolic syndrome, inflammatory bowel syndrome, and liver disease have already been linked with changes in bacterial composition of the gut."
Characterized by symptoms such as chronic headache, cognitive difficulties, debilitating fatigue, widespread pain, respiratory problems, sleep problems, gastrointestinal problems, and other unexplained medical abnormalities, GWI continues to affect 25-32 percent of the 700,000 U.S. veterans who served in the 1990-1991 Persian Gulf War. Twenty years of scientific research has traced these symptoms to Gulf War chemical exposures and the drugs taken during deployment that were meant to prevent or counteract these exposures. However, the vast majority of these studies have focused on neurological effects (rather than gastrointestinal), and none of them have successfully revealed the pathways through which GWI affects the brain. 
The study showed that not only did exposures to the suspected GWI agents lead to inflammation in the intestines, but to neuroinflammation as well. "Usually, the gut is very selective about letting only certain elements from what we eat and drink into our blood--thanks to good bacteria," explains Chatterjee. "But when the composition changes due to an increase in certain bad bacteria, this causes disruption to the mucosal lining of the intestinal walls--leading more intestinal contents to leak into the blood."
Once in the blood, the toxins travel throughout the body to affect the different organ systems. It is through this path that the toxins reach the brain, causing the neuroinflammation and corresponding neurological symptoms that previous studies have extensively linked to GWI. Now that scientists can explain the neurological symptoms that characterize GWI, a new paradigm of research has been unlocked--one related to treatment options.
"We know that many diseases like obesity, liver disease, and inflammatory bowel syndrome can be cured or at least decreased by consuming good bacteria, like probiotics," says Chatterjee. "Now that this connection has been established, it opens the door to new studies where GWI patients take probiotics for a longer period of time and, hopefully, see improvement in symptoms connected with metabolic syndrome, gastrointestinal disturbances, and maybe even neuroinflammation."
###
FULL JOURNAL ARTICLE:
SOURCE:  PLOSone, March 22, 2017
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172914

PLOS 
x

Abstract

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.

Thursday, March 23, 2017

Gulf War Illness linked to gastrointestinal disturbances; Findings may point to new treatments for elusive disorder

SOURCE:  Science Daily, March 17, 2017

https://www.sciencedaily.com/releases/2017/03/170323125513.htm 


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Gulf War Illness linked to gastrointestinal disturbances

Findings may point to new treatments for elusive disorder

Date:
March 23, 2017
Source:
University of South Carolina
Summary:
A new study has linked gastrointestinal disturbances in those suffering from Gulf War illness with changes intestinal microbiota. The findings open up new treatment options that may improve both gastrointestinal and neurological symptoms among soldiers and veterans.
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FULL STORY

A new study from the University of South Carolina has found a gastrointestinal link that could help explain many of the health issues facing those with Gulf War Illness (GWI) as well as opening new pathways to treatment options that may improve both gastrointestinal and neurological symptoms associated with the disorder.
The research is the first study to link the gastrointestinal disturbances of GWI with changes in the intestinal microbiota. This connection potentially explains both the gastrointestinal inflammation and the neurological abnormalities (e.g., impairments to cognition, memory, learning) that define GWI.
GWI exposures alter the microbiome (i.e., bacterial content in the gut), and the affected microbiota then produce endotoxins, which pass through a thinned lining of the gut (i.e., leaky gut) and into the blood where they circulate throughout the body. These compounds trigger an inflammatory response that, in turn, initiates several neurological abnormalities commonly observed in GWI.
The findings were published by PLOS ONE and led by Saurabh Chatterjee, associate professor of environmental health sciences at USC's Arnold School of Public Health. The study looked at how the various exposures experienced by Gulf War veterans might have changed the microbiome. "Humans and animals have specific types of bacteria that help aid various physiological processes, including digestion, absorption, immunity and gut integrity, and when external factors change the bacterial composition in our digestive systems, we have problems," says Chatterjee. "Obesity, metabolic syndrome, inflammatory bowel syndrome, and liver disease have already been linked with changes in bacterial composition of the gut."
Characterized by symptoms such as chronic headache, cognitive difficulties, debilitating fatigue, widespread pain, respiratory problems, sleep problems, gastrointestinal problems, and other unexplained medical abnormalities, GWI continues to affect 25-32 percent of the 700,000 U.S. veterans who served in the 1990-1991 Persian Gulf War. Twenty years of scientific research has traced these symptoms to Gulf War chemical exposures and the drugs taken during deployment that were meant to prevent or counteract these exposures. However, the vast majority of these studies have focused on neurological effects (rather than gastrointestinal), and none of them have successfully revealed the pathways through which GWI affects the brain.
The study showed that not only did exposures to the suspected GWI agents lead to inflammation in the intestines, but to neuroinflammation as well. "Usually, the gut is very selective about letting only certain elements from what we eat and drink into our blood -- thanks to good bacteria," explains Chatterjee. "But when the composition changes due to an increase in certain bad bacteria, this causes disruption to the mucosal lining of the intestinal walls -- leading more intestinal contents to leak into the blood."
Once in the blood, the toxins travel throughout the body to affect the different organ systems. It is through this path that the toxins reach the brain, causing the neuroinflammation and corresponding neurological symptoms that previous studies have extensively linked to GWI. Now that scientists can explain the neurological symptoms that characterize GWI, a new paradigm of research has been unlocked -- one related to treatment options.
"We know that many diseases like obesity, liver disease, and inflammatory bowel syndrome can be cured or at least decreased by consuming good bacteria, like probiotics," says Chatterjee. "Now that this connection has been established, it opens the door to new studies where GWI patients take probiotics for a longer period of time and, hopefully, see improvement in symptoms connected with metabolic syndrome, gastrointestinal disturbances, and maybe even neuroinflammation."
Story Source:
Materials provided by University of South CarolinaNote: Content may be edited for style and length.

Journal Reference:
  1. Firas Alhasson, Suvarthi Das, Ratanesh Seth, Diptadip Dattaroy, Varun Chandrashekaran, Caitlin N. Ryan, Luisa S. Chan, Traci Testerman, James Burch, Lorne J. Hofseth, Ronnie Horner, Mitzi Nagarkatti, Prakash Nagarkatti, Stephen M. Lasley, Saurabh Chatterjee. Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activationPLOS ONE, 2017; 12 (3): e0172914 DOI: 10.1371/journal.pone.0172914

Cite This Page:
University of South Carolina. "Gulf War Illness linked to gastrointestinal disturbances: Findings may point to new treatments for elusive disorder." ScienceDaily. ScienceDaily, 23 March 2017. <www.sciencedaily.com/releases/2017/03/170323125513.htm>.

Research links Gulf War Illness to gastrointestinal disturbances and uncovers pathways to how this condition causes neuroinflammation

SOURCE:  University of South Carolina, Arnold School of Public Health, March 23, 2017

https://www.sc.edu/study/colleges_schools/public_health/about/news/2017/gwi_study.php#.W-8h9C2ZPOR


****

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Research links Gulf War Illness to gastrointestinal disturbances and uncovers pathways to how this condition causes neuroinflammation



March 23, 2017 | Erin Bluvas, bluvase@sc.edu 
A team of researchers* led by Associate Professor of Environmental Health Sciences (ENHS) Saurabh Chatterjee have published the first study to link the gastrointestinal disturbances (e.g., bloating, flatulence, indigestion) of  Gulf War Illness (GWI) with changes in the intestinal microbiota. This connection potentially explains both the gastrointestinal inflammation and the neurological abnormalities (e.g., impairments to cognition, memory, learning) that define GWI.
GWI exposures alter the microbiome (i.e., bacterial content in the gut). The affected microbiota then produce endotoxins, which pass through a thinned lining of the gut (i.e., leaky gut) and into the blood where they circulate throughout the body. These compounds trigger an inflammatory response that, in turn, initiates several neurological abnormalities commonly observed in GWI. These findings open up new treatment options that may improve both gastrointestinal and neurological symptoms among soldiers and veterans with GWI.
Characterized by symptoms such as chronic headache, cognitive difficulties, debilitating fatigue, widespread pain, respiratory problems, sleep problems, gastrointestinal problems, and other unexplained medical abnormalities, GWI continues to affect 25-32 percent of the 700,000 U.S. veterans who served in the 1990-1991 Persian Gulf War. Twenty years of scientific research has traced these symptoms to Gulf War chemical exposures and the drugs taken during deployment that were meant to prevent or counteract these exposures. However, the vast majority of these studies have focused on neurological effects (rather than gastrointestinal), and none of them have successfully revealed the pathways through which GWI affects the brain.
The present study, published in PLOS ONE, looked at how the various exposures experienced by Gulf War veterans might have changed the microbiome. “Humans and animals have specific types of bacteria that help aid various physiological processes, including digestion, absorption, immunity and gut integrity, and when external factors change the bacterial composition in our digestive systems, we have problems,” says Chatterjee. “Obesity, metabolic syndrome, inflammatory bowel syndrome, and liver disease have already been linked with changes in bacterial composition of the gut.”
The scientists observed that not only did exposures to the suspected GWI agents lead to inflammation in the intestines, but to neuroinflammation as well. Changes to the frontal cortex, which controls many physical activities, alerted them to the connection, which they investigated further.
“Usually, the gut is very selective about letting only certain elements from what we eat and drink into our blood—thanks to good bacteria,” explains Chatterjee. “But when the composition changes due to an increase in certain bad bacteria, this causes disruption to the mucosal lining of the intestinal walls—leading more intestinal contents to leak into the blood.”
“We know that many diseases like obesity, liver disease, and inflammatory bowel syndrome can be cured or at least decreased by consuming good bacteria, like probiotics,” says Chatterjee. “Now that this connection has been established, it opens the door to new studies where GWI patients take probiotics for a longer period of time and, hopefully, see improvement in symptoms connected with metabolic syndrome, gastrointestinal disturbances, and maybe even neuroinflammation.”  
These findings and treatments may also be applicable to other veterans who have served in subsequent conflicts in the Gulf region. Even soldiers who have served as recently as the War in Afghanistan have begun to emerge with similar, though not as pronounced, symptoms. The team is already pursuing next steps in this line of research in Chatterjee’s Arnold School-based lab, the Environmental Health & Disease Laboratory, which specializes in how environmental toxins contribute to liver disease, metabolic syndrome, and obesity.
In addition to collaborators in California and Illinois, the lab’s location at the University of South Carolina positions it to benefit from collaborators from the School of Medicine, College of Pharmacy, and Arnold School experts such as Associate Professor Jim Burch (Department of Epidemiology and Biostatistics), who specializes in veterans research, and Professor and Associate Dean for Clinical Public Health Ronnie Horner (Department of Health Services Policy Management), who has studied neurological conditions among Gulf War veterans and briefly served on the Department of Veterans Affairs’ Research Advisory Committee on Gulf War Veterans’ Illness.
*Co-authors include: Firas Alhasson (Environmental Health Sciences), Suvarthi Das (Environmental Health Sciences), Ratanesh Seth (Environmental Health Sciences), Diptadip Dattoroy (Environmental Health Sciences), Varun Chandrashekaran (Environmental Health Sciences), Caitlin Ryan (Second Genome Inc.), Louisa Chan (Second Genome Inc.), Traci Testerman (USC School of Medicine), Jim Burch (Epidemiology and Biostatistics), Lorne Hofseth (USC College of Pharmacy), Ronnie Horner (Health Services Policy and Management), Mitzi Nagarkatti (USC School of Medicine), Prakash Nagarkatti (USC School of Medicine), Stephen Lasley (University of Illinois)
This work has been supported by NIH Pathway to Independence Award, R00ES019875 to Saurabh Chatterjee.