Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID.

ingentiumby ingentium

In Coronavirus Literature.

Intestinal barrier compromise, viral persistence, and immune dysregulation converge on neurological sequelae in Long COVID.

Publication date: Nov 14, 2025

Long COVID (LC) is a multisystem, post-infectious conditions diagnosed ≥3 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.

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Concepts Keywords
Covid gut dysbiosis
Immunothrombosis intestinal barrier dysfunction
Months Long COVID
Pro microbial translocation
Viral myeloid activation
neuroinflammation
SARS-CoV-2
viral persistence

Semantics

Type Source Name
disease MESH Long COVID
disease MESH SARS-CoV-2 infection
pathway REACTOME SARS-CoV-2 Infection
disease MESH fatigue
disease MESH symptom exacerbation
disease MESH syndromes
disease MESH dysbiosis
disease MESH traps
disease MESH thromboinflammation
disease MESH neuroinflammation
disease MESH nervous system disorders
disease MESH Lam
pathway REACTOME Reproduction
disease MESH Inflammation
disease MESH Infectious Diseases
disease MESH Severe acute respiratory syndrome
drug DRUGBANK Angiotensin II
drug DRUGBANK Serine
pathway KEGG Endocytosis
pathway REACTOME Translation
disease MESH infection
disease MESH diarrhea
disease MESH nausea
disease MESH vomiting
disease MESH ulcerative colitis
drug DRUGBANK Isoxaflutole
disease MESH HIV infection
pathway REACTOME HIV Infection
drug DRUGBANK Factor IX Complex (Human)
disease MESH PCC
disease MESH chronic condition
disease MESH cognitive dysfunction
disease MESH brain fog
disease MESH death
disease MESH chronic fatigue syndrome
disease MESH viremia
drug DRUGBANK Coenzyme M
pathway KEGG Tight junction
disease MESH LPS
pathway KEGG Platelet activation
drug DRUGBANK Ritonavir
drug DRUGBANK L-Tryptophan
pathway REACTOME Antimicrobial peptides
disease MESH viral infections
drug DRUGBANK Serotonin
disease MESH injury
disease MESH hyperglycemia
pathway REACTOME Immune System
disease MESH strain
disease MESH PRRs
disease MESH malaria
pathway KEGG Malaria
drug DRUGBANK Butyric Acid
pathway REACTOME Neutrophil degranulation
disease MESH fibrosis
drug DRUGBANK Von Willebrand Factor Human
drug DRUGBANK Beroctocog alfa
disease MESH Amyloid deposit
disease MESH hypoxia
disease MESH lymphocytic choriomeningitis
disease MESH headache
disease MESH neuropathic pain
disease MESH anxiety
disease MESH postural orthostatic tachycardia syndrome
disease MESH tachycardia
disease MESH dizziness
disease MESH demyelination
disease MESH multiple sclerosis
disease MESH ischemia
drug DRUGBANK Fibrinogen Human
pathway KEGG Viral replication
disease MESH cognitive symptoms
disease MESH gliosis
disease MESH blood clot
disease MESH neurodegenerative diseases
pathway REACTOME Neurodegenerative Diseases
disease MESH stroke
disease MESH traumatic brain injury
disease MESH CNS infection
disease MESH measles
pathway KEGG Measles
disease MESH influenza
disease MESH neurocognitive disorders
disease MESH AIDS
drug DRUGBANK Gold
disease MESH autoimmune diseases
disease MESH Varicella
disease MESH zoster
disease MESH Herpes simplex
disease MESH encephalitis
drug DRUGBANK Ilex paraguariensis leaf
disease MESH Lassa fever
disease MESH Borrelia burgdorferi infection
disease MESH dysautonomia
disease MESH fibromyalgia
drug DRUGBANK Carboxyamidotriazole
disease MESH atherosclerosis
disease MESH macrophage activation syndrome
disease MESH lfs
disease MESH Dis
disease MESH Allergy
disease MESH coronavirus infection
disease MESH Neurological manifestations
disease MESH Mas
disease MESH viral hemorrhagic fevers
disease MESH malnutrition
drug DRUGBANK (S)-Des-Me-Ampa
disease MESH colorectal cancer
pathway KEGG Colorectal cancer
disease MESH Cancers
disease MESH SLE
disease MESH intestinal disease
pathway KEGG Primary immunodeficiency
drug DRUGBANK Tocilizumab
disease MESH Kos
disease MESH Ham
pathway REACTOME Apoptosis
drug DRUGBANK Tolbutamide
disease MESH ebola virus disease
disease MESH atrophy
drug DRUGBANK Tretamine
pathway REACTOME Fatty acids

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