SARS-CoV-2 can infect human gut enterocytes, as shown by experiments using human small intestinal organoids (hSIOs). The virus uses the ACE2 receptor, which is highly expressed in enterocytes. SARS-CoV and SARS-CoV-2 readily infect hSIOs, producing infectious viral particles. The study shows that the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology. SARS-CoV-2 infects both proliferating cells and enterocytes, with ACE2 expression varying depending on the culture conditions. Transmission electron microscopy revealed viral replication in enterocytes, with viral particles found in the lumen of the organoid. RNA sequencing analysis showed that SARS-CoV-2 induces a broader interferon response than SARS-CoV in hSIOs. The study also shows that SARS-CoV-2 can infect enterocyte lineage cells in an hSIO model, with ACE2 expression increasing significantly upon differentiation. The findings suggest that the gut may be another target organ for SARS-CoV-2, and that hSIOs are a valuable tool for studying coronavirus infection and pathogenesis. The study highlights the importance of understanding coronavirus pathogenesis and transmission, as well as the need for accurate in vitro models to study these viruses.SARS-CoV-2 can infect human gut enterocytes, as shown by experiments using human small intestinal organoids (hSIOs). The virus uses the ACE2 receptor, which is highly expressed in enterocytes. SARS-CoV and SARS-CoV-2 readily infect hSIOs, producing infectious viral particles. The study shows that the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology. SARS-CoV-2 infects both proliferating cells and enterocytes, with ACE2 expression varying depending on the culture conditions. Transmission electron microscopy revealed viral replication in enterocytes, with viral particles found in the lumen of the organoid. RNA sequencing analysis showed that SARS-CoV-2 induces a broader interferon response than SARS-CoV in hSIOs. The study also shows that SARS-CoV-2 can infect enterocyte lineage cells in an hSIO model, with ACE2 expression increasing significantly upon differentiation. The findings suggest that the gut may be another target organ for SARS-CoV-2, and that hSIOs are a valuable tool for studying coronavirus infection and pathogenesis. The study highlights the importance of understanding coronavirus pathogenesis and transmission, as well as the need for accurate in vitro models to study these viruses.