Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier

J Clin Invest. 2021 Jul 15;131(14):e149633. doi: 10.1172/JCI149633.


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.

Keywords: Antigen; COVID-19; Inflammation; Tight junctions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antigens, Viral / blood
  • Biomarkers / blood
  • COVID-19 / etiology*
  • COVID-19 / physiopathology*
  • COVID-19 / virology
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Female
  • Haptoglobins / antagonists & inhibitors
  • Haptoglobins / physiology*
  • Humans
  • Infant
  • Infant, Newborn
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / physiopathology*
  • Intestinal Mucosa / virology
  • Male
  • Oligopeptides / pharmacology
  • Permeability / drug effects
  • Proof of Concept Study
  • Protein Precursors / antagonists & inhibitors
  • Protein Precursors / blood
  • Protein Precursors / physiology*
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / pathogenicity
  • Spike Glycoprotein, Coronavirus / blood
  • Spike Glycoprotein, Coronavirus / immunology
  • Systemic Inflammatory Response Syndrome / etiology*
  • Systemic Inflammatory Response Syndrome / physiopathology*
  • Systemic Inflammatory Response Syndrome / virology
  • Young Adult


  • Antigens, Viral
  • Biomarkers
  • Haptoglobins
  • Oligopeptides
  • Protein Precursors
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • zonulin
  • larazotide acetate

Supplementary concepts

  • pediatric multisystem inflammatory disease, COVID-19 related