REVIEW article
Front. Aging Neurosci.
Sec. Neuroinflammation and Neuropathy
This article is part of the Research TopicLong- and Post-COVID Syndromes: Immune Mechanisms and Therapeutic StrategiesView all 14 articles
Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID
Provisionally accepted
Laurence Leclerc1,2
Johanne Poudrier1,2
Christopher Power3
Grace Y. Lam4,5,6,7*
Emilia Liana Falcone1,2,8,9*- 1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute (IRCM), Montréal, Canada
- 2Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, Canada
- 3Division of Neurology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
- 4Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
- 5Division of Pulmonary Medicine, Department of Medicine, University of Alberta and Alberta Health Services, Edmonton, Canada
- 6Alberta Respiratory Centre, University of Alberta, Edmonton, Canada
- 7Women and Children’s Health Research Institute, University of Alberta, Edmonton, Canada
- 8Department of Medicine, Universite de Montreal, Montreal, Canada
- 9Division of Microbiology and Infectious Diseases, Centre Hospitalier de l'Universite de Montreal, Montreal, Canada
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Long COVID (LC) is a multisystem, post-infectious conditions diagnosed ³3 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 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.
Keywords: gut dysbiosis, intestinal barrierdysfunction, Long Covid, microbial translocation, myeloid activation, Neuroinflammation, SARS-CoV-2, viral persistence
Received: 14 Nov 2025; Accepted: 18 Dec 2025.
Copyright: © 2025 Leclerc, Poudrier, Power, Lam and Falcone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Grace Y. Lam
Emilia Liana Falcone
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