MicroRNAs in Bovine Milk Exosomes Are Bioavailable in Humans but Do Not Elicit a Robust Pro-inflammatory Cytokine Response

Exosomes are cargo-containing nanovesicles secreted by virtually all cell types to facilitate intercellular communication. Among exosome cargos microRNAs have drawn much attention in recent years because of their role in post-transcriptional gene regulation. Recently, our laboratory has shown that, in addition to endogenous biosynthesis, exosomes and their microRNA cargos are also obtained from dietary sources such as bovine milk in humans, mice and pigs. There is evidence that bovine milk exosomes contain microRNAs implicated in immune function. However, the effects of immune-related microRNAs in bovine milk exosomes on regulation of the human immune system are unknown. The first two chapters of this dissertation focus on the bioavailability of immune-related microRNAs from bovine milk exosomes and immune responses to milk feeding in healthy adults. Human feeding studies are the gold standard used in this work to assess nutritional relevance of bovine milk exosomes and their suitability as vehicles for drug delivery. Results from the first two chapters provide strong evidence that some of the immune-related microRNAs in bovine milk exosomes are bioavailable in humans. In addition, bovine milk exosomes do not elicit a robust pro-inflammatory cytokine response following oral administration. The final chapter will focus on assessment of bioavailability and distribution of exosomes and their microRNA cargos from bovine, porcine and murine milk within and across species boundaries. Milk exosomes labeled with fluorophores or fluorescent fusion proteins accumulated in various peripheral tissues following suckling, oral gavage and intravenous administration in mice and pigs. Overall, the conclusion of this work is that microRNAs in bovine milk exosomes are bioavailable and can regulate gene expression in non-bovine species. The absence of adverse immunogenic response to bovine milk exosomes suggest that they should be considered further as a viable option for the delivery of drugs. While accumulating evidence suggests that dietary exosomes and their cargos are bioavailable, much more work will need to be performed to determine the mechanisms by which dietary exosomes elicit strong phenotypes in humans and animals. Ongoing studies in our laboratory to advance this work and to test some of the concepts are also briefly described