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Aging Neurosci."],"abstract":"<jats:p>Long COVID (LC) is a multisystem, post-infectious conditions diagnosed \u22653 months after acute SARS-CoV-2 infection and marked by relapsing, persistent, or progressive symptoms, especially fatigue, post-exertional symptom exacerbation and neuropsychiatric syndromes. We synthesized evidence suggesting that LC arises from intersecting pathways including viral persistence, intestinal dysbiosis and barrier compromise with microbial translocation, innate immune activation with neutrophil extracellular traps (NET) and thromboinflammation, and immune dysregulation with features of exhaustion and autoimmunity. These processes adversely impact blood-brain barrier (BBB) function and lead to neuroinflammation. We propose a mechanistic model in which viral antigens and translocated microbial products amplify pro-inflammatory networks promoting immunothrombosis and tissue hypoperfusion. Hematogenous and gut-brain pathways may then deliver inflammatory mediators to the central nervous system (CNS), resulting in BBB disruption and glial activation that underpin nervous system disorders in LC. Treatment regimens aimed at lowering antigen load, restoring mucosal barrier integrity and modulating myeloid\/coagulation pathways may warrant investigation as novel therapeutic strategies to treat LC.<\/jats:p>","DOI":"10.3389\/fnagi.2025.1744415","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T06:32:07Z","timestamp":1768890727000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID"],"prefix":"10.3389","volume":"17","author":[{"given":"Laurence","family":"Leclerc","sequence":"first","affiliation":[{"name":"Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute (IRCM)","place":["Montreal, QC, Canada"]},{"name":"Department of Microbiology, Infectious Diseases and Immunology, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Poudrier","sequence":"additional","affiliation":[{"name":"Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute (IRCM)","place":["Montreal, QC, Canada"]},{"name":"Department of Microbiology, Infectious Diseases and Immunology, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Power","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace Y.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Division of Pulmonary Medicine, Department of Medicine, University of Alberta and Alberta Health Services","place":["Edmonton, AB, Canada"]},{"name":"Alberta Respiratory Centre, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Women and Children's Health Research Institute, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia Liana","family":"Falcone","sequence":"additional","affiliation":[{"name":"Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute (IRCM)","place":["Montreal, QC, Canada"]},{"name":"Department of Microbiology, Infectious Diseases and Immunology, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]},{"name":"Division of Microbiology and Infectious Diseases, Department of Medicine, Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al (CHUM)","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1344862","DOI":"10.3389\/fneur.2024.1344862","article-title":"Dysautonomia following Lyme disease: a key component of post-treatment Lyme disease syndrome?","volume":"15","author":"Adler","year":"2024","journal-title":"Front. 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