IL-22 is a good candidate to play a critical role in regulating gut microbiota because it is an important inducer of antimicrobial peptides and mucins in the gut. However, whether IL-22 participates in immune homeostasis by way of modulating gut microbiota remains to be elucidated. In this study, we find, through 16S rRNA gene-pyrosequencing analysis, that healthy IL-22–deficient mice had altered colonic microbiota, notably with decreased abundance of some genera, including Lactobacillus, and increased levels of others. Mice harboring this altered microbiota exhibited more severe disease during experimentally induced colitis. Interestingly, this altered gut microbiota can be transmitted to cohoused wild-type animals along with the increased susceptibility to this colitis, indicating an important role for IL-22 in shaping the homeostatic balance between immunity and colonic microbiota for host health.