Persistent Gut-Immune Axis dysregulation in long-term Post-COVID Syndrome: Insights from a prospective, observational, cross-sectional case-control study

Post-COVID syndrome (PCS) is a complex condition that can emerge after recovery from SARS-CoV-2 infection, even in young, healthy individuals with mild acute illness. While the underlying mechanisms remain unclear, viral persistence and immune dysregulation are considered key contributors. This study investigates whether the persistence of viral proteins in gut-associated lymphoid tissue (GALT) is linked to PCS and how it may influence immune cell populations in the terminal ileum (TI). Peripheral blood (PB) and TI biopsies were obtained 15 to 22 months after acute SARS-CoV-2 infection from 43 SARS-CoV-2 convalescent patients (20 with (PCS + ) and 23 without PCS symptoms (PCS − )). Mononuclear cells were isolated from PB and TI for flow cytometric and histological analysis. PCS + individuals exhibited a distinct immune profile characterized by increased mast cell activity, and elevated zonulin levels, indicating compromised gut barrier function alongside with elevated SARS-CoV-2 nucleocapsid protein expression in the TI. Additional findings included expansion of plasmacytoid dendritic cells, alterations in NK cell subsets, and higher proportions of central memory T-cells with low PD-1 expression in TI. Elevated MMP-9 levels further indicated localized gut inflammation and tissue remodeling. These results highlight the gut-immune interface as potential driver of PCS and support therapeutic strategies targeting viral persistence and intestinal immune homeostasis.