The Low Glutamate Diet Effectively Improves Pain and Other Symptoms of Gulf War Illness

Kathleen F. Holton; Anna E. Kirkland; Michael Baron; Shalini S. Ramachandra; Mackenzie T. Langan; Elizabeth T. Brandley; James N. Baraniuk

doi:10.3390/nu12092593

The Low Glutamate Diet Effectively Improves Pain and Other Symptoms of Gulf War Illness

Nutrients ◽

10.3390/nu12092593 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2593

Author(s):

Kathleen F. Holton ◽

Anna E. Kirkland ◽

Michael Baron ◽

Shalini S. Ramachandra ◽

Mackenzie T. Langan ◽

...

Keyword(s):

Symptom Score ◽

Effect Size ◽

Monosodium Glutamate ◽

Tender Point ◽

Gulf War ◽

Control Group ◽

Individual Response ◽

Gulf War Illness ◽

Diet Intervention ◽

Gastrointestinal Problems

Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen’s d. Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms (p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry (p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p < 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.

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The Low Glutamate Diet Significantly Improves Pain and Other Symptoms in Veterans with Gulf War Illness

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_027 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1211-1211

Author(s):

Kathleen Holton ◽

Anna Kirkland ◽

Elizabeth Brandley ◽

John VanMeter ◽

James Baraniuk

Keyword(s):

Chronic Pain ◽

Effect Size ◽

Dietary Intervention ◽

Monosodium Glutamate ◽

Gulf War ◽

Diet Group ◽

Control Group ◽

Diet Change ◽

Gulf War Illness ◽

Double Blind

Abstract Objectives The objective was to examine if a low glutamate diet can reduce symptoms in Gulf War Illness (GWI), a multi-symptom chronic pain condition. Methods Forty GW veterans were recruited from across the US. Baseline measures included assessment of symptoms, myalgic score, tender point count, and dolorimetry. Subjects were randomized to the low glutamate diet, or to a wait-listed control group, starting the diet one month later. Measures were evaluated post-diet, and then subjects were randomized to a double-blind placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to assess whether symptoms return/worsen in each condition. Challenge data have not yet been un-blinded, and thus are not included in this abstract. Symptom scores were compared between those randomized to immediate dietary intervention versus wait-listed controls (independent t-tests). After everyone completed the 1-month diet, change scores were analyzed for the whole group (Wilcoxon Signed Rank tests). Improvement was defined as ‘much’ or ‘very much’ improved on the patient global impression of change (PGIC) score, and the effect size was calculated (Cohen's d). Results After 1-month, overall symptom number (mean (SD)) significantly differed between the diet group (11(6)) and the wait-listed controls (18(6)), P = 0.0007. The diet had a very large effect size, d = 1.17, with no adverse effects reported. When comparing pre-post scores after all subjects followed the 1-month diet, the number of symptoms went from a mean(SD) of 21(5) at baseline to 12(6) post-diet, P < 0.0001. The severity of remaining symptoms was also significantly reduced (all P < 0.0001). Seventy-two % of subjects met the PGIC criteria for improvement. Highly significant improvements in pain measures were also observed for myalgic score (P < 0.0001), number of tender points (P < 0.0001), and average dolorimetry (P < 0.001). Conclusions These striking results suggest that the low glutamate diet may be an effective treatment for chronic pain and symptoms associated with Gulf War Illness. Funding Sources Department of Defense (DoD), US Army Medical Research Acquisition Activity, Office of the Assistant Secretary of Defense for Health Affairs through the GWI Research Program. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the DoD.

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The Effects of a Low Glutamate Dietary Intervention on Anxiety and PTSD in Veterans with Gulf War Illness (FS15-08-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.fs15-08-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Elizabeth Brandley ◽

Anna Kirkland ◽

Gabrielle Sarlo ◽

John VanMeter ◽

James Baraniuk ◽

...

Keyword(s):

Anxiety Disorders ◽

Dietary Intervention ◽

Monosodium Glutamate ◽

Gulf War ◽

Rank Test ◽

Control Group ◽

Controlled Clinical Trial ◽

Gulf War Illness ◽

Double Blind ◽

Funding Sources

Abstract Objectives Glutamate is an amino acid and also serves as the most ubiquitous neurotransmitter in the human body. Previous work has shown that dysregulated glutamatergic neurotransmission is implicated in the etiology of anxiety disorders. Objective: To examine the effect of a low glutamate dietary intervention on anxiety and Posttraumatic Stress Disorder (PTSD) in veterans with Gulf War Illness (GWI). Methods Forty veterans with GWI are being recruited for a randomized-controlled clinical trial testing the effects of a low glutamate diet on neurological symptoms. After consent, subjects complete baseline measures, then subjects are randomized to the low-glutamate diet or a wait-listed control group. For the active intervention phase, they follow a 1-month low glutamate diet and then are re-tested prior to entering a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG) or placebo, to test for return of symptoms. Preliminary data are presented here for changes observed on the Generalized Anxiety Disorder 7-item (GAD-7) scale and the PTSD Checklist (PCL-C) after one month on the diet in subjects recruited to date. Pre-post diet scores were compared for anxiety and PTSD using a Wilcoxon Signed Rank test in SAS. Results Seventeen veterans (M = 15; F = 2) with GWI have been recruited to date (mean age = 50 ± 4 yrs). Preliminary analyses demonstrate that after one month on the diet, significant improvements were noted for anxiety (score reduced from a median (IQ range) of 9 (13) to 5 (10), p = 0.01) and for PTSD (median (IQ) score reduced from 58 (33) to 43 (28), p = 0.04). Conclusions This study suggests that consuming a low glutamate diet may improve anxiety and PTSD in veterans suffering from Gulf War Illness. More research is needed to further explore the role of dietary glutamate in anxiety disorders. Funding Sources U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Gulf War Illness Research Program under Award No. W81XWH-17-1-0457. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

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Diagnosis of Gulf War Illness Using Laser-Induced Spectra Acquired from Blood Samples

Applied Spectroscopy ◽

10.1177/00037028211042049 ◽

2021 ◽

pp. 000370282110420

Author(s):

Rosalba Gaudiuso ◽

Sirui Chen ◽

Efi Kokkotou ◽

Lisa Conboy ◽

Eric Jacobson ◽

...

Keyword(s):

Blood Plasma ◽

Correct Diagnosis ◽

Difference Spectrum ◽

Gulf War ◽

Classification Model ◽

Control Group ◽

Plasma Samples ◽

Gulf War Illness ◽

Breakdown Spectroscopy ◽

The Difference

Gulf War illness (GWI) is a chronic illness with no known validated biomarkers that affects the lives of hundreds of thousands of people. As a result, there is an urgent need for the development of an untargeted and unbiased method to distinguish GWI patients from non-GWI patients. We report on the application of laser-induced breakdown spectroscopy (LIBS) to distinguish blood plasma samples from a group of subjects with GWI and from subjects with chronic low back pain as controls. We initially obtained LIBS data from blood plasma samples of four GWI patients and four non-GWI patients. We used an analytical method based on taking the difference between a mean LIBS spectrum obtained with those of GWI patients from the mean LIBS spectrum of those of the control group, to generate a “difference” spectrum for our classification model. This model was cross-validated using different numbers of differential LIBS emission peaks. A subset of 17 of the 82 atomic and ionic transitions that provided 70% of correct diagnosis was selected test in a blinded fashion using 10 additional samples and was found to yield 90% classification accuracy, 100% sensitivity, and 83.3% specificity. Of the 17 atomic and ionic transitions, eight could be assigned unambiguously to species of Na, K, and Fe.

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Gulf War Illness-associated increases in blood levels of interleukin 6 and C-reactive protein: biomarker evidence of inflammation

BMC Research Notes ◽

10.1186/s13104-019-4855-2 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Tammy A. Butterick ◽

Janeen H. Trembley ◽

Laura L. Hocum Stone ◽

Clemma J. Muller ◽

Rebecca R. Rudquist ◽

...

Keyword(s):

Chronic Inflammation ◽

Interleukin 6 ◽

Well Being ◽

Gulf War ◽

Blood Levels ◽

C Reactive Protein ◽

Gulf War Illness ◽

Memory Impairments ◽

Reactive Protein ◽

Gastrointestinal Problems

Abstract Objective Gulf War Illness is a chronic multisymptom disorder severely impacting the health and well-being of many Veterans of the 1990–1991 Gulf War. Symptoms that define the disease include pain, fatigue, mood and memory impairments, gastrointestinal problems, lung disorders, and skin rashes. In our previous biomarker study, we discovered Gulf War Illness-associated proinflammatory blood biomarkers. Therefore, we hypothesized that chronic inflammation causes the symptoms that define this disorder. Testing the chronic inflammation hypothesis is the objective of this study. Results The biomarker fingerprint of Gulf War Illness is the end-product of a cascade of proinflammatory cytokine signals. In particular, the observed increase in C-reactive protein predicts a corresponding increase in interleukin 6, the cytokine that stimulates hepatocytes to produce C-reactive protein. Therefore, in this study we measured potential upstream cytokine signals in plasma samples from Gulf War Veterans. As predicted, a positive correlation between interleukin 6 and C-reactive protein was observed.

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Gulf War Veterans with Psychiatric Symptoms (Anxiety, Depression, and PTSD) Significantly Improve on a Low Glutamate Diet

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_008 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1192-1192

Author(s):

Elizabeth Brandley ◽

Anna Kirkland ◽

Kathleen Holton

Keyword(s):

Dietary Intervention ◽

Psychiatric Symptoms ◽

Gulf War ◽

Control Group ◽

Gulf War Illness ◽

War Veterans ◽

Double Blind ◽

Double Blind Placebo ◽

Gulf War Veterans ◽

Anxiety Depression

Abstract Objectives The objective of this study was to assess the effects of a low glutamate dietary intervention on measures of anxiety, depression, and PTSD in veterans with Gulf War Illness (GWI). Methods Forty Gulf War veterans were recruited from across the U.S. for a clinical trial examining the effects of a low glutamate diet on symptoms of GWI. During baseline testing, subjects completed the GAD-7 anxiety measure, the PCL-C PTSD scale, and the Center for Epidemiologic Studies Depression Scale (CES-D), and then were randomized to immediate dietary intervention or a wait-listed control group. All participants received intensive dietary training before starting the diet. After one month on the diet, post-diet testing was completed, then subjects were randomized into a double-blind, placebo-controlled crossover challenge with MSG/placebo to test for a return of symptoms. The challenge data has not yet been un-blinded; therefore, it will not be discussed in this abstract. Pre-post diet change scores were analyzed using the Wilcoxon Signed Rank tests via SPSS®v26. Results Results demonstrate highly significant improvements in psychiatric symptoms associated with GWI after one-month on a low glutamate diet. Scores were reduced from a median (IQ range) of 9(13) to 4(8), P = 0.001 for anxiety; from 27(15) to 19(10), P < 0.001 for depression; and from 57(32) to 39(32), P < 0.001 for PTSD. Conclusions These results suggest that a low glutamate diet may improve depression, anxiety, and PTSD in veterans with GWI. Future analysis of the double-blind, placebo-controlled crossover challenge data will provide a better understanding of whether challenge with glutamate can significantly increase anxiety, depression and PTSD relative to placebo. Funding Sources The US Army Medical Research Acquisition Activity, 820 Chandler St, Fort Detrick MD 21,702–5014 is the awarding and administering acquisition office. This work is supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

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Gastrointestinal problems, mechanisms and possible therapeutic directions in Gulf war illness: a mini review

Military Medical Research ◽

10.1186/s40779-021-00341-4 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Diana A. Kimono

Keyword(s):

Chronic Fatigue ◽

Gulf War ◽

The Body ◽

Gulf War Illness ◽

Potential Therapeutic Target ◽

Organ Systems ◽

Gastrointestinal Problems ◽

High Prevalence ◽

Important Player

AbstractBy its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target.

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Restorative potential of (−)-epicatechin in a rat model of Gulf War illness muscle atrophy and fatigue

Scientific Reports ◽

10.1038/s41598-021-01093-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Israel Ramirez-Sanchez ◽

Viridiana Navarrete-Yañez ◽

Alejandra Garate-Carrillo ◽

Modesto Lara-Hernandez ◽

Judith Espinosa-Raya ◽

...

Keyword(s):

Muscle Atrophy ◽

Rat Model ◽

Inflammatory Cytokine ◽

Gulf War ◽

Plasma Metabolites ◽

Control Group ◽

Loss Of Function ◽

Gulf War Illness ◽

Mediators Of Inflammation ◽

Male Wistar Rats

AbstractWe examined in a rat model of Gulf War illness (GWI), the potential of (−)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

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Restorative Effects of (-)-Epicatechin in a Rat Model of Gulf War Illness Muscle Atrophy and Fatigue

10.21203/rs.3.rs-516148/v1 ◽

2021 ◽

Author(s):

Israel Ramirez-Sanchez ◽

Viridiana Navarrrete ◽

Alejandra Garate-Carrillo ◽

Modesto Lara-Hernandez ◽

Judith Espinosa-Raya ◽

...

Keyword(s):

Muscle Atrophy ◽

Rat Model ◽

Inflammatory Cytokine ◽

Gulf War ◽

Plasma Metabolites ◽

Control Group ◽

Loss Of Function ◽

Gulf War Illness ◽

Mediators Of Inflammation ◽

Male Wistar Rats

Abstract We examined in a rat model of Gulf War illness (GWI), the potential of (-)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicles and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

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