BACKGROUND: Long-term immunosuppressive therapy typically increases the risk of viral infection, yet during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, inflammatory bowel disease (IBD) patients showed reduced severe coronavirus disease 2019 (COVID-19) susceptibility. This suggests potential overlapping molecular mechanisms between IBD and COVID-19 that warrant investigation. METHODS: From April 2020 to April 2022, we enrolled 363 IBD patients and 146 healthy donors. Serum samples were analyzed by enzyme-linked immunoadsorption assay to determine the presence of anti-SARS-CoV-2 antibodies and to measure concentrations of the host-soluble factors sACE2 and mannose-binding lectin (MBL), which have SARS-CoV-2 neutralizing activity. Furthermore, colonic mucosa biopsies were analyzed by real-time PCR to confirm the upregulation of MBL2 as well as to assess the expression of genes encoding SARS-CoV-2 entry molecules (ie, ACE2, TMPRSS2, TMPRSS4, ADAM17, AGTR1). RESULTS: Intestinal mucosa expression of ACE2, TMPRSS2, and TMPRSS4 genes was significantly lower in IBD than in healthy individuals, regardless of the type of medication, while ADAM17 and AGT1R were similar across groups. Serum sACE2 levels changed minimally, whereas circulating MBL levels were significantly higher in CD and somewhat elevated in UC patients versus controls. Parallel trends in MBL2 gene expression were observed in IBD patients' intestinal mucosa. CONCLUSIONS: Overall, our study indicates that the presence of higher basal circulating levels of MBL in CD patients and the decreased intestinal mucosa expression of the SARS-CoV-2 receptor ACE2 and the host cell priming proteases TMPRSS2 and TMPRSS4 in both CD and UC patients may reduce COVID-19 risk, underscoring the potential protective role of these biomarkers in IBD populations against SARS-CoV-2 infection.