Acute Cytomegalovirus Infection Modulates the Intestinal Microbiota and Targets Intestinal Epithelial Cells

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to probe into the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected within the first 5 days post-infection as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes incited with high-titer MCMV replication in the colon, mild crypt necrosis and increased colonic pro-inflammatory cytokine levels. Further analyses revealed that murine and human intestinal epithelial cell line as well as primary intestinal crypt cells/ organoids represent direct targets of CMV accompanied by increased cell mortality upon infection. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV induces colitis in immunocompetent hosts by altering the intestinal homeostasis.