The global spread of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the pandemic outbreak of coronavirus disease 2019 (COVID-19), an inflammatory disease that is primarily affecting the respiratory system. However, gastrointestinal symptoms in COVID-19 patients suggests that the gut may present another viral target organ. Disease development and severity is dependent on viral interaction with two cell surface human proteins, ACE2 and TMPRSS2, and on antiviral response which may lead to systemic hyperinflammatory syndrome and multiorgan dysfunction. Understanding the host response to SARS-CoV-2 infection and the pathology of the disease will be greatly enhanced by the development of appropriate animal models. Laboratory mice have been the mainstay of therapeutic and vaccine development, however, the virus does not grow in wild type mice and only induced mild disease in transgenic animals expressing human ACE2. As there are known differences between immune response in laboratory mice and humans we evaluated the response of human gut developed as xenografts and host mouse gut following systemic LPS injections as a hyperinflammation model system. The orthologous gene expression levels in the mouse and human gut were highly correlated (Spearman’s rank correlation coefficient: 0.28–0.76) and gene set enrichment analysis of significantly upregulated human and mouse genes revealed that a number of inflammatory and immune response pathways are commonly regulated in the two species. However, species differences were also observed, most importantly, in the inflamed human gut but not in the mouse gut, there was clear upregulation of mRNAs coding for TMPRSS2, ADAM17 and for RIG-I-like receptors, which are involved in the recognition of viruses and in antiviral innate immune response. Moreover, using species-specific immunofluorescence microscopy, we demonstrated the expression and localization of human ACE2 and TMPRSS2 proteins, which are essential elements of the molecular machinery that enables SARS-CoV-2 to infect and replicate in human gut cells. Our findings demonstrate that the intestinal immune response to inflammation in humans and mice are generally very similar. However, certain human-specific diseases, such as COVID-19, can only be successfully studied in an experimental model of human tissue, such as the gut xenograft.