Filamentous bacteriophages induce proinflammatory responses in intestinal epithelial cells

Bacteriophages are the dominant members of the human enteric virome and can shape bacterial communities in the gut; however, our understanding of how they directly impact health and disease is limited. Previous studies have shown that specific bacteriophage populations are expanded in patients with Crohns disease (CD) and ulcerative colitis (UC), suggesting that fluctuations in the enteric virome may contribute to intestinal inflammation. Based on these studies, we hypothesized that a high bacteriophage burden directly induces intestinal epithelial responses. We found that filamentous inoviruses M13 and Fd induced dose-dependent IL-8 expression in the human intestinal epithelial cell line HT-29 to a greater degree than their lytic counterparts T4 and {phi}X174 did. We also found that M13, but not Fd, reduced bacterial internalization in HT-29 cells. This led us to investigate the mechanism underlying M13-mediated inhibition of bacterial internalization by examining the antiviral and antimicrobial responses in these cells. M13 upregulated Type I and III IFN expression and augmented short-chain fatty acid (SCFA)-mediated LL-37 expression in HT-29 cells. Taken together, our data establish that inoviruses directly affect human intestinal epithelial cells. These results provide new insights into the complex interactions between bacteriophages and the intestinal mucosa, which may underlie disease pathogenesis.