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Exosomes and exosome-like vesicles participate in cell-to-cell communication in animals, plant and bacteria. Dietary exosomes in bovine milk are bioavailable in non-bovine species, but a fraction of milk exosomes reaches the large intestine. We hypothesized that milk exosomes alter the composition of the gut microbiome in mice. C57BL/6 mice were fed AIN-93G diets, defined by their content of bovine milk exosomes and RNA cargos: exosome/RNA depleted (ERD) versus exosome/RNA-sufficient (ERS) diets. Feeding was initiated at age three weeks and cecum content was collected at ages 7, 15 and 47 weeks. Microbial communities were identified by 16S rRNA gene sequencing. The dietary intake of exosomes and age had significant effects on the microbial communities in the cecum. At the phylum level, the abundance of Verrucomicrobia was greater in mice fed ERD compared to ERS, and the abundance of both Firmicutes and Tenericutes was smaller in mice fed ERD compared to ERS at age 47 weeks. At the family level, the abundance of Anaeroplasmataceae was greater in mice fed ERD compared to ERS, and the abundance of Bifidobacteriaceae, Lachnospiraceae, and Dehalobacteriaceae was significantly greater in mice fed ERS than mice fed ERD at age 15 weeks. Exosome feeding significantly altered the abundance of 52 operational taxonomic units; diet effects were particularly strong in the Lachnospiraceae, Ruminococcaceae and the Verrucomicrobiaceae families. We conclude that exosomes in bovine milk alter microbial communities in non-bovine species, suggesting that exosomes and their cargos participate in the crosstalk between bacterial and animal kingdoms.IMPORTANCEVirtually all living cells, including bacteria communicate through exosomes, which can be found in all body fluids. Exosomes and the RNA cargos have been implicated in all aspects of health and disease, e.g., metastasis of cancer, neuronal signaling and embryonic development. Previously, we reported that exosomes and their microRNA cargos are not solely derived from endogenous synthesis, but may also be obtained from dietary sources such as bovine milk in non-bovine mammals. Here, we report for the first time that bovine milk exosomes communicate with the intestinal microbiome and alters microbial communities in mice. This is the first report suggesting that the gut microbiome facilitates the signaling by dietary exosomes across kingdoms: animal (cow) → bacteria → animal (mouse).