Attenuated replication and damaging effects of SARS-CoV-2 Omicron variants in an intestinal epithelial barrier model

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Many COVID-19 patients suffer from gastrointestinal symptoms and impaired intestinal barrier function may play a key role in harmful inflammatory responses and Long COVID. Despite its importance, the impact of SARS-CoV-2 on intestinal epithelia is poorly understood. To address this, we established an intestinal barrier model integrating epithelial Caco-2 cells and mucus-secreting HT29 cells in the presence or absence of human Raji cells. We show that this gut epithelial model allows efficient differentiation of Caco-2 cells into M (microfold) cell-like cells and faithfully mimics intestinal barrier function. It is highly permissive to SARS-CoV-2 infection due to high expression of the viral entry factors ACE2 and TMPRSS2. Early strains of SARS-CoV-2 and the Delta variant replicated with high efficiency, severely disrupted barrier function and depleted tight junction proteins, such as claudin-1, occludin and ZO-1. In comparison, Omicron subvariants also depleted ZO-1 from tight junctions but had less damaging effects on mucosal integrity and barrier function. Remdesivir and the TMPRSS2 inhibitor Camostat prevented SARS-CoV-2 replication and thus epithelial barrier damage, while the Cathepsin inhibitor E64d was ineffective. Our results support that SARS-CoV-2 disrupts intestinal barrier function but further suggest that circulating Omicron variants are less damaging than earlier viral strains.

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