The study demonstrates that SARS-CoV-2 can infect human gut enterocytes, which are highly expressing the receptor angiotensin-converting enzyme 2 (ACE2). Using human small intestinal organoids (hSIOs), the researchers found that both SARS-CoV and SARS-CoV-2 could productively infect enterocytes, as evidenced by the production of infectious viral particles and induction of a generic viral response program. Confocal and electron microscopy confirmed the infection of enterocytes, with viral particles detected in the lumen and at the apical and basolateral sides of the cells. Ultrastructural analysis revealed double-membrane vesicles, the site of viral replication. RNA expression analysis showed that SARS-CoV-2 induced a broader signature of cytokines and interferon-stimulated genes compared to SARS-CoV, suggesting a stronger innate immune response. These findings indicate that the intestinal epithelium supports SARS-CoV-2 replication and that hSIOs can serve as an experimental model for studying coronavirus infection and biology.The study demonstrates that SARS-CoV-2 can infect human gut enterocytes, which are highly expressing the receptor angiotensin-converting enzyme 2 (ACE2). Using human small intestinal organoids (hSIOs), the researchers found that both SARS-CoV and SARS-CoV-2 could productively infect enterocytes, as evidenced by the production of infectious viral particles and induction of a generic viral response program. Confocal and electron microscopy confirmed the infection of enterocytes, with viral particles detected in the lumen and at the apical and basolateral sides of the cells. Ultrastructural analysis revealed double-membrane vesicles, the site of viral replication. RNA expression analysis showed that SARS-CoV-2 induced a broader signature of cytokines and interferon-stimulated genes compared to SARS-CoV, suggesting a stronger innate immune response. These findings indicate that the intestinal epithelium supports SARS-CoV-2 replication and that hSIOs can serve as an experimental model for studying coronavirus infection and biology.