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 Crohn's 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 bacteriophages 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 ϕX174. 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 expressions and augmented short-chain fatty acid (SCFA)-mediated LL-37 expression in HT-29 cells. Taken together, our data establish that filamentous bacteriophages 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.