Fig. 1: Evidence of SARS-CoV-2 intestinal infection.

This figure shows the putative mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) intestinal infection. Angiotensin-converting enzyme 2 (ACE2) is mainly expressed on the brush border of enterocytes in the ileum and colon. Cell entry by SARS-CoV-2 (1) begins with the binding of spike (S) proteins to ACE2. Host cell transmembrane serine protease 2 (TMPRSS2) cleaves the S protein. Subsequently, the cell membrane fuses with the viral membrane and SARS-CoV-2 genomic RNA is released into the cytoplasm. Based on human intestinal organoid studies, SARS-CoV-2 primarily infects enterocytes but not goblet cells. The double membrane structure produced by virus replication (2) can be observed in the infected cells and the virus protein can be detected in the endoplasmic reticulum (ER). Newly assembled viral particles were released predominantly from the apical side into the lumen. The detection of subgenomic mRNA (sgmRNA) can serve as evidence of active viral replication in the intestine. SARS-CoV-2 infection activates an interferon-mediated immune response (3) in human organoids. Levels of the intestinal epithelial cell-specific inflammatory factor IL-18, which is activated by inflammasomes, have been shown to increase in patients with severe coronavirus disease 2019 (COVID-19). However, how SARS-CoV-2 triggers immune response in the gut in humans is not yet well understood, including the role of inflammatory factors caused by intestinal infection and their contribution to cytokine release syndrome (CRS), and requires further investigation. The histological examination of human intestinal samples revealed that lymphocytes and inflammatory cells infiltrated the lamina propria (4). Patients with diarrhoea exhibited increased faecal calprotectin levels, released mainly by infiltrated neutrophils. However, whether intestinal infiltrations of T cells, B cells, macrophages and neutrophils as well as of their secreted cytokine and IgA are correlated with disease severity is still unknown. SARS-CoV-2 infection altered the gut microbiota community structure (5). The enrichment of opportunistic pathogens and the depletion of beneficial commensals was observed in patients with COVID-19. These changes were correlated with the expression of inflammatory factors in the serum of these patients. However, whether the microbiota profile can predict the occurrence of CRS and whether modulation of the microbiota can resolve CRS need further study. IEL, intraepithelial lymphocyte.