Blocking intestinal permeability within this murine model of Kawasaki disease with the zonulin inhibitor AT1001 (larazotide acetate, currently in a phase III clinical trial for celiac disease) significantly reduced the development of cardiovascular lesions, suggesting a possible involvement of zonulin in this process (24). 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 patients clinical response. == RESULTS == We showed that in children ALW-II-41-27 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 experienced a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently ALW-II-41-27 available treatments. == CONCLUSION == These mechanistic data on MIS-C ALW-II-41-27 pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this progressively common severe COVID-19related disease in children. Keywords:COVID-19, Inflammation Keywords:Antigen, Tight junctions == Introduction == Most children who are acutely infected with SARS-CoV-2 develop moderate upper respiratory symptoms or experience asymptomatic contamination. Several days to weeks after resolution of the initial contamination, some of these children will develop a severe life-threatening illness, termed multisystem inflammatory syndrome in children (MIS-C), which is an immune activation syndrome associated with prior SARS-CoV-2 contamination or exposure. Patients with MIS-C present with prolonged fever, marked gastrointestinal (GI) symptoms, cytokine storm, myocardial dysfunction, and cardiogenic shock with ventricular dysfunction in the setting of multisystem inflammation, reminiscent of, yet distinct from, harmful shock syndrome or ALW-II-41-27 Kawasaki disease (1). Eighty percent of these hospitalized children develop cardiac pathology (2), including coronary artery dilations, myocardial dysfunction, or ventricular failure with hypotensive shock (3). The cause of this late-phase severe illness in children has not previously been recognized, leaving treatment options and prevention strategies nebulous. As the prevalence of SARS-CoV-2 infections among children and adolescents is usually increasing (4), MIS-C cases are increasing as HDM2 well. A better understanding of this life-threatening illness is usually urgently needed. Children with MIS-C display increased monocyte recruitment and hyperphagocytosis (5) with a cytokine storm (6), T cell activation (7), and inflammation driven by growth of immunoglobulins (5,8). A recently discovered superantigen-like motif near the S1/S2 cleavage site around the SARS-CoV-2 spike protein (9,10) is usually hypothesized to drive this hyperinflammatory response in MIS-C. However, in most MIS-C cases, SARS-CoV-2 is usually undetectable by reverse transcription PCR (RT-PCR) of the nasopharyngeal swab, leaving the etiology and timing of this hyperinflammatory response yet to be elucidated (2,11). In adults, there is increased recognition that this gut serves as a nidus for SARS-CoV-2 (12) and that in severe COVID-19, dysbiosis and disruption of the GI barrier drive inflammatory activation (13,14). Although GI symptoms predominate MIS-C symptomatology (2), the role of the GI tract in the pathogenesis of MIS-C has not been evaluated. In this study, we provide evidence that GI sources of SARS-CoV-2 viral antigenemia may instigate and drive MIS-C. We demonstrate that weeks after the initial contamination, SARS-CoV-2 RNA remains in the GI tract, and zonulin-instigated hyperpermeability of the mucosal barrier coincides with SARS-CoV-2 antigenemia. Current treatment strategies are targeted at dampening the inflammatory response but do not address mucosal permeability or antigenemia. Here, we provide insight into the mechanism of disease pathogenesis and present evidence related to the trigger of MIS-C, thereby offering biomarkers for early detection of disease and avenues for the prevention and treatment of MIS-C. == Results == This study included biospecimens from 100 children: 19 children were clinically diagnosed with MIS-C as defined by CDC criteria (Supplemental Table 1; supplemental material available online with this short article;https://doi.org/10.1172/JCI149633DS1); 26 children had COVID-19 confirmed by RT-PCR; and 55 children served as nonCOVID-19 controls (32 pre-pandemic). The average age of the children with MIS-C (8 years old) was more youthful than that of the children who presented with COVID-19 (14 years old), which is usually consistent with the national averages (2,15). The patients with MIS-C presented with a median of 3 days of acute symptoms associated with MIS-C (range, 128 days), after a previous COVID-19 exposure or SARS-CoV-2 contamination 26.