Gut infection and dysbiosis are hallmarks of severe SARS-CoV-2 variants.

SARS-CoV-2, the virus behind the COVID-19 pandemic, is primarily a respiratory pathogen, with host entry mediated by the ACE2 receptor that determines viral tropism. Notably, in humans, ACE2 is highly expressed in the gastrointestinal (GI) tract, particularly the small intestine (SI), prompting us to examine GI infectivity of SARS-CoV-2 variants of concern (VOCs). We found that ACE2 expression in Syrian hamsters closely resembles humans, supporting their use in studying GI tropism. Using this model, we compared infection and pathology of the ancestral Wuhan-like strain (Hong Kong), Delta, and Omicron variants. Despite high ACE2 expression, GI infection and pathology were generally low relative to the respiratory tract. However, the Delta variant showed markedly enhanced GI infectivity and pathology, especially in the SI, and caused the greatest disruption of the gut microbiome. These findings link SARS-CoV-2 virulence with GI infection and microbiome disturbance, establishing Syrian hamsters as a relevant model.