Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID
Plain-Language Summary
This review synthesizes a large body of evidence to explain how Long COVID (LC) can arise as a chronic, multisystem condition following SARS-CoV-2 infection. Rather than a single cause, the authors describe LC as the result of multiple interacting biological processes, including persistence of viral material, disruption of the gut microbiome and intestinal barrier, sustained immune activation, abnormal blood clotting, and inflammation affecting the brain and nervous system.
The paper highlights how viral proteins or RNA that remain in the body after acute infection may continue to stimulate the immune system. At the same time, damage to the intestinal lining (“leaky gut”) can allow microbial products from the gut to enter the bloodstream, further amplifying inflammation. These circulating inflammatory signals, together with immune cell activation and clotting abnormalities, may impair blood flow and disrupt the blood–brain barrier, a protective layer that normally limits what enters the brain.
According to the authors, these combined processes help explain common Long COVID symptoms such as fatigue, post-exertional symptom exacerbation, cognitive difficulties (“brain fog”), and neuropsychiatric symptoms. The review also compares Long COVID to other post-infectious and neuroinflammatory conditions, such as HIV-related neurological disease and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), to identify shared biological patterns that may guide future research.
Key Findings
- Long COVID appears to result from interacting mechanisms rather than a single pathological process.
- Persistent viral antigens (proteins or RNA) may continue to stimulate immune responses months after infection.
- Intestinal dysbiosis and impaired gut barrier integrity can allow microbial products to enter the bloodstream and promote systemic inflammation.
- Sustained activation of innate immune cells, including monocytes and neutrophils, is associated with inflammatory signaling and abnormal blood clotting.
- Inflammation, microvascular injury, and clot-related hypoxia may contribute to blood–brain barrier disruption and neuroinflammation.
- Neurological symptoms in Long COVID likely reflect combined effects of immune dysregulation, vascular dysfunction, and altered gut–brain signaling.
Study Type
Narrative review article synthesizing evidence from clinical, immunological, and experimental studies.
What This Means (and Doesn’t Mean)
The findings support a model in which Long COVID is driven by overlapping immune, vascular, and neuroinflammatory processes that can persist after the initial SARS-CoV-2 infection. This framework helps explain why symptoms can be diverse, long-lasting, and difficult to attribute to a single organ or mechanism.
However, the review does not establish direct causality for any single pathway, nor does it identify proven treatments. Many proposed mechanisms remain under investigation, and the paper does not provide clinical guidance or confirm that targeting these pathways will improve outcomes.
Source
- Full text (Frontiers): https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1744415/full
Disclaimer
This summary was created with the assistance of artificial intelligence and reviewed by a human prior to publication. While care is taken to ensure accuracy, errors are possible. If you notice any issues, have questions, or would like to request coverage of a specific research paper, please contact admin@long-covid.org.
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