In this study, we have demonstrated that short-chain fatty acids (SCFAs), derived from fiber-fermenting commensal bacteria, downregulate ACE2 and reduce infection by a VSV pseudovirus expressing SARS-CoV-2 spike in both mice and hamsters, promote antiviral T cell responses and the formation of spike-specific B and T cells, and dampen the coagulation response. Here, ACE2 is linked to infection.