ArticleThe Journal of clinical investigation2021
Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05576714 (Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 Associated Encephalopathy/Encephalitis and Multi-systemic Inflammatory Syndrome in Children), which is not on this map. Cited by 154 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 Associated Encephalopathy/Encephalitis and Multi-systemic Inflammatory Syndrome in Children
Who cites it
154 citing papers in PubMed, 2 syntheses or guidelines pooled it, 251 citations in OpenAlex.
- Long-Term Complications of Multisystem Inflammatory Syndrome in Children and Adults Post-COVID-19: A Systematic Review.International journal of molecular sciences · 2025Pooled it
- Characterization of a Hepatitis Outbreak in Children, 2021 to 2022.JAMA network open · 2022Pooled it
- Intestinal Barrier Loss Enables Microbiota-Mediated Purinergic Suppression During Malaria.bioRxiv : the preprint server for biology · 2026Article
- SARS-CoV-2 spike S1-mediated HIF-2α activation in retinal endothelial cells suggests a mechanism contributing to post-COVID endothelial dysfunction.Frontiers in immunology · 2026Article
- A perfect storm: the immunological and pathophysiological landscape of pediatric post-COVID-19 condition.Frontiers in immunology · 2026Review
- Mass spectrometry combined with machine learning identifies novel protein signatures as demonstrated with multisystem inflammatory syndrome in children.Scientific reports · 2025Article
- Unravelling γδ T-cell dysregulation in the gut and its implications for immune-mediated diseases.Disease models & mechanisms · 2025Article
- Pulmonary and Immune Dysfunction in Pediatric Long COVID: A Case Study Evaluating the Utility of ChatGPT-4 for Analyzing Scientific Articles.Journal of clinical medicine · 2025Review
- Alterations of the Intestinal Barrier and Inflammatory Response, Caused by Chronic Ozone Exposure in a Rat Model.Antioxidants (Basel, Switzerland) · 2025Article
- Altered Gut Microbiota and Predicted Immune Dysregulation in Early Childhood SARS-CoV-2 Infection.Microorganisms · 2025Article
- Article
- Children with Post COVID-19 Multisystem Inflammatory Syndrome Display Unique Pathophysiological Metabolic Phenotypes.Journal of proteome research · 2025Article
- CharacterizingInternational journal of molecular sciences · 2025Article
- Gastrointestinal and hepatic manifestations among hospitalized COVID-19 children.BMC pediatrics · 2025Article
- Article
- Loss of tricellular tight junction tricellulin leads to hyposalivation in Sjögren's syndrome.International journal of oral science · 2025Article
- A review of gut failure as a cause and consequence of critical illness.Critical care (London, England) · 2025Review
- Observational
- An Update on Multi-System Inflammatory Syndrome in Children.Current rheumatology reports · 2025Review
- Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways.Inflammatory bowel diseases · 2025Review
94 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
33 authors at 5 institutions in 3 countries.
Funding
Abstract
BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.
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