Zonulin and claudin‐5 levels in multisystem inflammatory syndrome and SARS‐CoV‐2 infection in children

Abstract

Aim: SARS-CoV-2 infection in children is generally asymptomatic or mild; however, it can lead to a life-threatening clinical condition, multisystem inflammatory syndrome in children (MIS-C), days or weeks after the infection. Increased intestinal permeability isa possible triggering factor at the onset of the hyperinflammation associated with MIS-C. Zonulin and claudin-5 are involved in intestinal permeability. In this study, we aimed to investigate serum zonulin and claudin-5 levels in SARS-CoV-2 infection and MIS-C disease. Methods: The study group consisted of children diagnosed with MIS-C or SARS-CoV-2 infection who presented to a university hospital paediatric emergency or infectious diseases departments. The control group included well patients seen at the General Pediatrics units for routine follow-up. Serum zonulin and claudin-5 levels were measured at the time of diagnosis. Results: Fifteen patients were included in the MIS-C group, 19 in the SARS-CoV-2 infection group and 21 in the control group. The mean zonulin level in the MIS-C group was significantly higher than in the control group (P < 0.001). Mean Claudin-5 levels were Psignificantly lower in the SARS-CoV-2 infection group than in the control group (P < 0.001). Conclusion:These results indicate that increased intestinal permeability may be involved in the pathogenesis of SARS-CoV-2 infection and MIS-C disease. Larger clinical trials are needed to clarify the role of serum zonulin and claudin-5 on intestinal permeability in MIS-C and SARS-CoV-2 infection in children.

Zonulin, a marker of gut permeability, is associated with mortality in a cohort of hospitalised peruvian COVID-19 patients

“…In another study, Oliva et al ( Oliva et al., 2021 ) found median zonulin values similar to those in our study on comparing COVID-19 patients and matched healthy controls. In addition, it is important to highlight the role of zonulin in children with multisystem inflammatory syndrome (MIS), related to the persistence of the virus in the gastrointestinal tract ( Kılıç et al., in press ; Josyabhatla et al., 2021 ). Therefore, zonulin might be associated with a translocation of viral proteins into the bloodstream, contributing to increased inflammation.…”

“…Moreover, population-associated variation of responses to viral infections is differentiated by genetic ancestry ( Randolph et al., 2021 ). The few published studies on serum zonulin levels and COVID-19 come from cohorts/case series of United States of America ( Giron et al., 2021 ; Josyabhatla et al., 2021 ; Yonker et al., 2022 ), Italy ( Oliva et al., 2021 ) and Turkey ( Kılıç et al., in press ) only. Therefore, data from studies with subjects from a different genetic and geographic background are important for external validity issues.…”

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

“…Claudin-5 is the most enriched member of TJ proteins in the BBB, and its integrity is crucial for neuroprotection [ 174 ]. Several studies have shown that increased intestinal zonulin release and permeability are associated with high serum levels of claudin-5 in patients with neuroinflammatory or neurodegenerative disorders [ 73 , 166 , 167 , 175 , 176 ].…”

“…Partly due to the intensified research on the SARS-CoV-2 pandemic, emerging data have recently revealed the role of the zonulin pathway in viral infections, which, in addition, often have CNS involvement. Elevated zonulin levels were demonstrated in patients with SARS-CoV-2 infection, which was associated with more severe outcomes [ 175 , 177 , 178 , 179 , 180 , 181 ]. These studies suggest that the prolonged presence of undigested SARS-CoV-2 viruses leads to enhanced zonulin release in the gastrointestinal tract, resulting in impaired intestinal permeability, which goes together with the accelerated trafficking of viral antigens into the bloodstream, leading to hyperinflammation (causing multisystem inflammatory syndrome—MIS).…”