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REVIEW ARTICLE

Gluten-related disorders and brain–heart interactions: Pathophysiological links, clinical manifestations, and translational implications

Giustino Varrassi1,2* ,  Y Van Tran3 ,  Phong Van Pham3 ,  Ameen Abdulhasan Al Alwany2 ,  Dariusz Myrcik4 ,  Annalisa Caruso5 ,  Matteo Luigi Giuseppe Leoni6
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1 Department of Research, Fondazione Paolo Procacci, Rome, Italy
2 Department of Research and Cardiolgy, College of Medicine, University of Baghdad, Baghdad, Iraq
3 Department of Anesthesiology, Tam Anh General hospital, Ho Chi Minh City, Vietnam
4 Department of Propaedeutics of Internal Diseases and Emergency Medicine, Medical University of Silesia, Katowice, Silesian Voivodeship, Poland
5 Department of Surgery, Azienda Socio-Sanitaria Territoriale di Lodi, Lodi, Italy
6 Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy
Brain & Heart, 026050005 https://doi.org/10.36922/BH026050005
Received: 26 January 2026 | Revised: 5 February 2026 | Accepted: 24 February 2026 | Published online: 17 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Gluten-related disorders (GRDs), including celiac disease, non-celiac gluten sensitivity, and wheat allergy, are increasingly recognized as systemic immune-mediated conditions with clinically significant neurological, psychiatric, and cardiovascular manifestations that extend beyond their classical gastrointestinal phenotype. Epidemiological and clinical evidence have linked GRDs to gluten ataxia, peripheral neuropathy, cognitive dysfunction, affective disorders, increased cardiovascular risk, and autonomic dysregulation. Mechanistic research implicates convergent pathways involving intestinal barrier disruption, systemic immune activation, autoantibody cross-reactivity, blood–brain barrier dysfunction, and endothelial injury mediated by chronic inflammation. This narrative review synthesizes current evidence on the pathophysiology of brain–heart involvement in GRDs through the lens of the gut– brain–heart axis, integrating neuroimmune, autonomic, and vascular mechanisms. We examine the potential for reversibility of selected neurocardiac manifestations through dietary and adjunctive interventions, alongside critical knowledge gaps in mechanistic understanding, biomarker development, and therapeutic targeting. A systems-level framework for understanding GRDs may improve diagnostic recognition, cardiovascular and neurological risk stratification, and inform more integrated clinical management strategies.

Keywords
Gluten-related disorders
Celiac disease
Gut–brain–heart axis
Neuroimmune interactions
Autonomic dysfunction
Cardiovascular involvement
Blood–brain barrier dysfunction
Funding
This research received no external funding.
Conflict of interest
Giustino Varrassi and Matteo Luigi Giuseppe Leoni are Editorial Board Member and Guest Editor of this journal, but were not in any way involved in the editorial peer-review process conducted for this paper, directly or indirectly. The authors declare no conflicts of interest.
References
  1. Taraghikhah N, Ashtari S, Asri N, et al. An updated overview of spectrum of gluten-related disorders: clinical and diagnostic aspects. BMC Gastroenterol. 2020;20(1):258. doi: 10.1186/s12876-020-01390-0

 

  1. Giuffre M, Gazzin S, Zoratti C, et al. Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation. Int J Mol Sci. 2022;23(24):15564. doi: 10.3390/ijms232415564

 

  1. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi: 10.1016/j.cgh.2017.06.037

 

  1. Galli G, Amici G, Conti L, Lahner E, Annibale B, Carabotti M. Sex-Gender Differences in Adult Coeliac Disease at Diagnosis and Gluten-Free-Diet Follow-Up. Nutrients. 2022;14(15):3192. doi: 10.3390/nu14153192

 

  1. Santonicola A, Wieser H, Gizzi C, Soldaini C, Ciacci C. Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview. Nutrients. 2024;16(12):1814. doi: 10.3390/nu16121814

 

  1. Rodrigo L. Celiac Disease and Associated Extraintestinal Manifestations, with Special Reference to Neurological Disorders. OBM Neurobiol. 2020;04(04):074. doi: 10.21926/obm.neurobiol.2004074

 

  1. Guo X, Liu H, Song YJ, et al. Neuro-Immune Crosstalk: Molecular Mechanisms, Biological Functions, Diseases, and Therapeutic Targets. MedComm. 2026;7(2):e70497. doi: 10.1002/mco2.70497

 

  1. Eng S, Gabr A, Raghav S, Frishman WH, Aronow WS. The Gut-Heart Connection: Unraveling Cardiovascular Risks in Celiac Disease. Cardiol Rev. 2025. doi: 10.1097/CRD.0000000000000988

 

  1. Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells. 2019;8(7):670. doi: 10.3390/cells8070670

 

  1. Baethge C, Goldbeck-Wood S, Mertens S. SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4(1):5. doi: 10.1186/s41073-019-0064-8

 

  1. Aboulaghras S, Piancatelli D, Taghzouti K, et al. Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease. Int J Mol Sci. 2023;24(2):1188. doi: 10.3390/ijms24021188

 

  1. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol. 2002;2(9):647–655. doi: 10.1038/nri885

 

  1. Caputo I, Barone MV, Martucciello S, Lepretti M, Esposito C. Tissue transglutaminase in celiac disease: role of autoantibodies. Amino Acids. 2009;36(4):693–699. doi: 10.1007/s00726-008-0120-z

 

  1. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10(1):13.doi: 10.1186/1741-7015-10-13

 

  1. Manza F, Lungaro L, Costanzini A, et al. Non-Celiac Gluten/Wheat Sensitivity—State of the Art: A Five-Year Narrative Review. Nutrients. 2025;17(2):220. doi: 10.3390/nu17020220

 

  1. Catassi C, Catassi G, Naspi L. Nonceliac gluten sensitivity. Curr Opin Clin Nutr Metab Care. 2023;26(5):490–494. doi: 10.1097/MCO.0000000000000925

 

  1. Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291-307.e5. doi: 10.1016/j.jaci.2013.11.020

 

  1. Cianferoni A. Wheat allergy: diagnosis and management. J Asthma Allergy. 2016;9:13–25. doi: 10.2147/JAA.S81550

 

  1. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151–175. doi: 10.1152/physrev.00003.2008

 

  1. Serena G, D’Avino P, Fasano A. Celiac Disease and Nonceliac Wheat Sensitivity: State of Art of Non-dietary Therapies. Front Nutr. 2020;7:152. doi: 10.3389/fnut.2020.00152

 

  1. Wei G, Helmerhorst EJ, Darwish G, Blumenkranz G, Schuppan D. Gluten Degrading Enzymes for Treatment of Celiac Disease. Nutrients. 2020;12(7):2095. doi: 10.3390/nu12072095

 

  1. Tye-Din JA, Daveson AJM, Goel G, et al. Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study. Lancet Gastroenterol Hepatol. 2023;8(5):446–457. doi: 10.1016/S2468-1253(22)00428-9

 

  1. Varrassi G, Leoni MLG, Fari G, Al-Alwany AA, Al-Sharie S, Fornasari D. Neuromodulatory Signaling in Chronic Pain Patients: A Narrative Review. Cells. 2025;14(17):1320. doi: 10.3390/cells14171320

 

  1. Leoni MLG, Mercieri M, Viswanath O, et al. Neuropathic Pain: A Comprehensive Bibliometric Analysis of Research Trends, Contributions, and Future Directions. Curr Pain Headache Rep. 2025;29(1):73. doi: 10.1007/s11916-025-01384-1

 

  1. Therrien A, Kelly CP, Silvester JA. Celiac Disease: Extraintestinal Manifestations and Associated Conditions. J Clin Gastroenterol. 2020;54(1):8–21. doi: 10.1097/MCG.0000000000001267

 

  1. Hadjivassiliou M, Sanders DD, Aeschlimann DP. Gluten related disorders: gluten ataxia. Dig Dis. 2015;33(2):264–268. doi: 10.1159/000369509

 

  1. Yelland GW. Gluten-induced cognitive impairment (“brain fog”) in coeliac disease. J Gastroenterol Hepatol. 2017;32 Suppl 1:90–93. doi: 10.1111/jgh.13706

 

  1. Addolorato G, Leggio L, D’Angelo C, et al. Affective and psychiatric disorders in celiac disease. Dig Dis. 2008;26(2):140–148. doi: 10.1159/000116772

 

  1. Hadjivassiliou M, Sanders DS, Grunewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9(3):318–330. doi: 10.1016/S1474-4422(09)70290-X

 

  1. Kounatidis D, Pavlou A, Evangelopoulos A, et al. Rethinking Celiac Disease Management: Treatment Approaches Beyond the Gluten-Free Diet. Biomedicines. 2026;14(1):29. doi: 10.3390/biomedicines14010029

 

  1. Huang J. Assessment of the causal association between celiac disease and cardiovascular diseases. Front Cardiovasc Med. 2022;9:1017209. doi: 10.3389/fcvm.2022.1017209

 

  1. Wang Y, Chen B, Ciaccio EJ, et al. Celiac Disease and the Risk of Cardiovascular Diseases. Int J Mol Sci. 2023;24(12):9974. doi: 10.3390/ijms24129974

 

  1. Ludvigsson JF, James S, Askling J, Stenestrand U, Ingelsson E. Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease. Circulation. 2011;123(5):483– 490. doi: 10.1161/CIRCULATIONAHA.110.965624

 

  1. Emilsson L, Smith JG, West J, Melander O, Ludvigsson JF. Increased risk of atrial fibrillation in patients with coeliac disease: a nationwide cohort study. Eur Heart J. 2011;32(19):2430–2437. doi: 10.1093/eurheartj/ehr167

 

  1. Batty M, Bennett MR, Yu E. The Role of Oxidative Stress in Atherosclerosis. Cells. 2022;11(23):3843. doi: 10.3390/cells11233843

 

  1. Hadithi M, Mulder CJ, Stam F, et al. Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. World J Gastroenterol. 2009;15(8):955–960. doi: 10.3748/wjg.15.955

 

  1. Furgala A, Przybylska-Felus M, Ciesielczyk K, Gil K, Zwolinska-Wcislo M. Effects of water ingestion on autonomic activity and gastric motility in patients with celiac disease. J Physiol Pharmacol. 2023;74(2):185–194. doi: 10.26402/jpp.2023.2.06

 

  1. Giorgetti GM, Tursi A, Iani C, et al. Assessment of autonomic function in untreated adult coeliac disease. World J Gastroenterol. 2004;10(18):2715–2718. doi: 10.3748/wjg.v10.i18.2715

 

  1. Calvillo L, Vanoli E, Ferrara F, Caradonna E. Interplay Among Gut Microbiota-Derived TMAO, Autonomic Nervous System Dysfunction, and Heart Failure Progression. Int J Mol Sci. 2025;27(1):203. doi: 10.3390/ijms27010203

 

  1. Banks WA. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des. 2005;11(8):973–984. doi: 10.2174/1381612053381684

 

  1. Inayat N, Zahir A, Hashmat AJ, et al. Gut Microbiota as a Key Modulator of Chronic Disease: Implications for Diabetes, Autoimmunity, and Cancer. Cureus. 2025;17(5):e84687. doi: 10.7759/cureus.84687

 

  1. Wacklin P, Laurikka P, Lindfors K, et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am J Gastroenterol. 2014;109(12):1933–1941. doi: 10.1038/ajg.2014.355

 

  1. Chen WG, Schloesser D, Arensdorf AM, et al. The Emerging Science of Interoception: Sensing, Integrating, Interpreting, and Regulating Signals within the Self. Trends Neurosci. 2021;44(1):3–16. doi: 10.1016/j.tins.2020.10.007

 

  1. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68(10):988–1001. doi: 10.1016/S0025-6196(12)62272-1

 

  1. Varrassi G, Paladini A, Tran YV, et al. Advances in the Pathophysiology and Management of Cancer Pain: A Scoping Review. Cancers. 2026;18(2):259. doi: 10.3390/cancers18020259

 

  1. Melo E, Fiel J, Milhomens R, et al. Dynamic coupling between the central and autonomic cardiac nervous systems in patients with refractory epilepsy: A pilot study. Front Neurol. 2022;13:904052. doi: 10.3389/fneur.2022.904052

 

  1. Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61(3):201–216. doi: 10.1016/s0165-0327(00)00338-4

 

  1. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853–859. doi: 10.1038/nature01321

 

  1. Marcuello C, Lim K, Nisini G, Pokrovsky VS, Conde J, Ruggeri FS. Nanoscale Analysis beyond Imaging by Atomic Force Microscopy: Molecular Perspectives on Oncology and Neurodegeneration. Small Sci. 2025;5(11):2500351. doi: 10.1002/smsc.202500351

 

  1. Huang J, Liu S, Li P, et al. Multi-omics analysis of gut-brain axis reveals novel microbial and neurotransmitter signatures in patients with arteriosclerotic cerebral small vessel disease. Pharmacol Res. 2024;208:107385. doi: 10.1016/j.phrs.2024.107385

 

  1. Mazzola AM, Zammarchi I, Valerii MC, et al. Gluten- Free Diet and Other Celiac Disease Therapies: Current Understanding and Emerging Strategies. Nutrients. 2024;16(7):1006. doi: 10.3390/nu16071006

 

  1. Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease. Gastroenterology. 2021;160(1):63–75. doi: 10.1053/j.gastro.2020.06.098

 

  1. Hall NJ, Rubin G, Charnock A. Systematic review: adherence to a gluten-free diet in adult patients with coeliac disease. Aliment Pharmacol Ther. 009;30(4):315–330. doi: 10.1111/j.1365-2036.2009.04053.x

 

  1. Varrassi G, Cereda E, Ruoppolo GA, Mercieri M, Muscaritoli M. The drug called food and its role as a therapy for chronic patients: a comprehensive narrative review. Adv Health Res. 2024;1(1):6. doi: 10.4081/ahr.2024.6

 

  1. Schmucker C, Eisele-Metzger A, Meerpohl JJ, et al. Effects of a gluten-reduced or gluten-free diet for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2022;2022(2):CD013556. doi: 10.1002/14651858.CD013556.pub2

 

  1. Dota M, Rubbini L, Massetti G, et al. Work Impairment in Patients with Celiac Disease and Its Relationship with Persistence of Symptoms, Dietary Adherence, Quality of Life, and Psychological Morbidity. Dig Dis Sci. 2025;71(1):129– 137. doi: 10.1007/s10620-025-09183-9

 

  1. Rubio-Tapia A, Hill ID, Semrad C, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023;118(1):59–76. doi: 10.14309/ajg.0000000000002075

 

  1. Blom JJ, Gidrewicz D, Turner J, Duerksen DR, Pinto- Sanchez MI. Diagnosis and management of celiac disease. CMAJ. 2025;197(38):E1258–E1265. doi: 10.1503/cmaj.230091

 

  1. Daponte A, Koros C, Skarlis C, et al. Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice. Int J Mol Sci. 2025;26(19):9739. doi: 10.3390/ijms26199739

 

  1. Everett BM, Moorthy MV, Tikkanen JT, Cook NR, Albert CM. Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death. Circulation. 2020;142(12):1148–1158. doi: 10.1161/CIRCULATIONAHA.120.046947
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Brain & Heart, Electronic ISSN: 2972-4139 Published by AccScience Publishing
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