{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:15:31Z","timestamp":1760145331714,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T00:00:00Z","timestamp":1720828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Army Medical Research Acquisition Activity","award":["W81XWH-17-1-0457"],"award-info":[{"award-number":["W81XWH-17-1-0457"]}]},{"name":"Office of the Assistant Secretary of Defense for Health Affairs","award":["W81XWH-17-1-0457"],"award-info":[{"award-number":["W81XWH-17-1-0457"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-\u03b3, IL-6, IL-1\u03b2, TNF-\u03b1) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression (p &lt; 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), (p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (\u03b2 = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-\u03b3 was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), (p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-\u03b3, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work.<\/jats:p>","DOI":"10.3390\/nu16142255","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T08:35:17Z","timestamp":1721032517000},"page":"2255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biomarkers Associated with Depression Improvement in Veterans with Gulf War Illness Using the Low-Glutamate Diet"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-0674","authenticated-orcid":false,"given":"Amy A.","family":"Maury","sequence":"first","affiliation":[{"name":"Department of Neuroscience, American University, Washington, DC 20016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-7983","authenticated-orcid":false,"given":"Kathleen F.","family":"Holton","sequence":"additional","affiliation":[{"name":"Department of Health Studies, American University, Washington, DC 20016, USA"},{"name":"Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/JOM.0000000000000627","article-title":"Physical and Mental Health Status of Gulf War and Gulf Era Veterans: Results from a Large Population-Based Epidemiological Study","volume":"58","author":"Dursa","year":"2016","journal-title":"J. Occup. Environ. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1017\/S0033291714001913","article-title":"Depression in Gulf War Veterans: A Systematic Review and Meta-Analysis","volume":"45","author":"Blore","year":"2015","journal-title":"Psychol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1192\/bjp.188.5.453","article-title":"Military Deployment to the Gulf War as a Risk Factor for Psychiatric Illness among US Troops","volume":"188","author":"Fiedler","year":"2006","journal-title":"Br. J. Psychiatry J. Ment. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1177\/0033354916676278","article-title":"All-Cause Mortality Among US Veterans of the Persian Gulf War","volume":"131","author":"Barth","year":"2016","journal-title":"Public Health Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Brandley, E.T., Kirkland, A.E., Baron, M., Baraniuk, J.N., and Holton, K.F. (2022). The Effect of the Low Glutamate Diet on the Reduction of Psychiatric Symptoms in Veterans with Gulf War Illness: A Pilot Randomized-Controlled Trial. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.926688"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neuro.2020.07.001","article-title":"Dietary Glutamate and the Brain: In the Footprints of a Jekyll and Hyde Molecule","volume":"80","author":"Onaolapo","year":"2020","journal-title":"NeuroToxicology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.neuro.2020.06.008","article-title":"Neurotoxicity in Gulf War Illness and the Potential Role of Glutamate","volume":"80","author":"Joyce","year":"2020","journal-title":"Neurotoxicology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.5498\/wjp.v11.i7.297","article-title":"Glutamate and Depression: Reflecting a Deepening Knowledge of the Gut and Brain Effects of a Ubiquitous Molecule","volume":"11","author":"Onaolapo","year":"2021","journal-title":"World J. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1136\/jnnp.69.2.228","article-title":"Homocysteine, Folate, Methylation, and Monoamine Metabolism in Depression","volume":"69","author":"Bottiglieri","year":"2000","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1093\/ageing\/afr086","article-title":"Testing Homocysteine-Induced Neurotransmitter Deficiency, and Depression of Mood Hypothesis in Clinical Practice","volume":"40","author":"Gariballa","year":"2011","journal-title":"Age Ageing"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e13486","DOI":"10.1111\/eci.13486","article-title":"The Association between Serum Homocysteine and Depression: A Systematic Review and Meta-Analysis of Observational Studies","volume":"51","author":"Moradi","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232640981770147","DOI":"10.1177\/2326409817701471","article-title":"Homocysteine and Psychiatric Disorders","volume":"5","author":"Silva","year":"2017","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1176\/ajp.2007.164.6.861","article-title":"The Homocysteine Hypothesis of Depression","volume":"164","author":"Folstein","year":"2007","journal-title":"Am. J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1159\/000330247","article-title":"Neuroinflammation: A Common Pathway in CNS Diseases as Mediated at the Blood-Brain Barrier","volume":"19","author":"Erickson","year":"2012","journal-title":"Neuroimmunomodulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.psyneuen.2010.09.012","article-title":"Inflammation-Associated Depression: From Serotonin to Kynurenine","volume":"36","author":"Dantzer","year":"2011","journal-title":"Psychoneuroendocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nri.2015.5","article-title":"The Role of Inflammation in Depression: From Evolutionary Imperative to Modern Treatment Target","volume":"16","author":"Miller","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"743","DOI":"10.2174\/1570159X14666160106155129","article-title":"Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem","volume":"14","author":"Pinto","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2174\/1389200003339063","article-title":"Interferon-Gamma-Induced Tryptophan Degradation: Neuropsychiatric and Immunological Consequences","volume":"1","author":"Widner","year":"2000","journal-title":"Curr. Drug Metab."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Harsanyi, S., Kupcova, I., Danisovic, L., and Klein, M. (2022). Selected Biomarkers of Depression: What Are the Effects of Cytokines and Inflammation?. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010578"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.biopsych.2008.11.029","article-title":"Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression","volume":"65","author":"Miller","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Holton, K.F., Kirkland, A.E., Baron, M., Ramachandra, S.S., Langan, M.T., Brandley, E.T., and Baraniuk, J.N. (2020). The Low Glutamate Diet Effectively Improves Pain and Other Symptoms of Gulf War Illness. Nutrients, 12.","DOI":"10.3390\/nu12092593"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1001\/jama.280.11.981","article-title":"Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War","volume":"280","author":"Fukuda","year":"1998","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mawson, A.R., and Croft, A.M. (2019). Gulf War Illness: Unifying Hypothesis for a Continuing Health Problem. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16010111"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Vilagut, G., Forero, C.G., Barbaglia, G., and Alonso, J. (2016). Screening for Depression in the General Population with the Center for Epidemiologic Studies Depression (CES-D): A Systematic Review with Meta-Analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155431"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/oxfordjournals.aje.a112455","article-title":"Assessing Depressive Symptoms in Five Psychiatric Populations: A Validation Study","volume":"106","author":"Weissman","year":"1977","journal-title":"Am. J. Epidemiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v059.i05","article-title":"Mediation: R Package for Causal Mediation Analysis","volume":"59","author":"Tingley","year":"2014","journal-title":"J. Stat. Softw."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0749-3797(18)30622-6","article-title":"Screening for Depression in Well Older Adults: Evaluation of a Short Form of the CES-D (Center for Epidemiologic Studies Depression Scale)","volume":"10","author":"Andresen","year":"1994","journal-title":"Am. J. Prev. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.lfs.2014.04.032","article-title":"Monosodium Glutamate, a Food Additive, Induces Depressive-like and Anxiogenic-like Behaviors in Young Rats","volume":"107","author":"Quines","year":"2014","journal-title":"Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1073\/pnas.94.11.5923","article-title":"Neurotoxicity Associated with Dual Actions of Homocysteine at the N-Methyl-d-Aspartate\u2009Receptor","volume":"94","author":"Lipton","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100087","DOI":"10.1016\/j.jadr.2021.100087","article-title":"Plasma Homocysteine Concentrations and Depression: A Twin Study","volume":"4","author":"Bremner","year":"2021","journal-title":"J. Affect. Disord. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1176\/appi.ajp.159.12.2099","article-title":"Vitamin B12, Folate, and Homocysteine in Depression: The Rotterdam Study","volume":"159","author":"Tiemeier","year":"2002","journal-title":"Am. J. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/camh.12387","article-title":"The Relationship of Severity of Depression with Homocysteine, Folate, Vitamin B12, and Vitamin D Levels in Children and Adolescents","volume":"25","author":"Esnafoglu","year":"2020","journal-title":"Child Adolesc. Ment. Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1001\/archpsyc.60.6.618","article-title":"Folate, Vitamin B12, Homocysteine, and the MTHFR 677C\u2192T Polymorphism in Anxiety and Depression: The Hordaland Homocysteine Study","volume":"60","author":"Bjelland","year":"2003","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1192\/bjp.bp.107.039511","article-title":"Predictive Value of Folate, Vitamin B12 and Homocysteine Levels in Late-Life Depression","volume":"192","author":"Kim","year":"2008","journal-title":"Br. J. Psychiatry J. Ment. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.intimp.2019.05.039","article-title":"Interaction of the Immune-Inflammatory and the Kynurenine Pathways in Rats Resistant to Antidepressant Treatment in Model of Depression","volume":"73","author":"Duda","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1684\/ecn.2015.0362","article-title":"TNF\u03b1 Mediates Stress-Induced Depression by Upregulating Indoleamine 2,3-Dioxygenase in a Mouse Model of Unpredictable Chronic Mild Stress","volume":"26","author":"Liu","year":"2015","journal-title":"Eur. Cytokine Netw."},{"key":"ref_37","first-page":"198","article-title":"A Link between Stress and Depression: Shifts in the Balance between the Kynurenine and Serotonin Pathways of Tryptophan Metabolism and the Etiology and Pathophysiology of Depression","volume":"11","author":"Miura","year":"2008","journal-title":"Stress Amst. Neth."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0306-9877(03)00207-X","article-title":"Cytokine-Serotonin Interaction through IDO: A Neurodegeneration Hypothesis of Depression","volume":"61","author":"Myint","year":"2003","journal-title":"Med. Hypotheses"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/7854_2016_6","article-title":"Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches","volume":"31","author":"Dantzer","year":"2017","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"72","DOI":"10.2337\/db06-0617","article-title":"Induction of Indoleamine 2,3-Dioxygenase by Interferon-Gamma in Human Islets","volume":"56","author":"Sarkar","year":"2007","journal-title":"Diabetes"},{"key":"ref_41","first-page":"2516","article-title":"Relationship between Interferon-Gamma, Indoleamine 2,3-Dioxygenase, and Tryptophan Catabolism","volume":"5","author":"Taylor","year":"1991","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Castro, F., Cardoso, A.P., Gon\u00e7alves, R.M., Serre, K., and Oliveira, M.J. (2018). Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00847"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0889-1591(03)00057-6","article-title":"Pathways Linking Depression, Adiposity, and Inflammatory Markers in Healthy Young Adults","volume":"17","author":"Miller","year":"2003","journal-title":"Brain Behav. Immun."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/14\/2255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:16:12Z","timestamp":1760109372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/14\/2255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,13]]},"references-count":43,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["nu16142255"],"URL":"https:\/\/doi.org\/10.3390\/nu16142255","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2024,7,13]]}}}