Breast Milk-Derived Extracellular Vesicles Enriched in Exosomes From Mothers With Type 1 Diabetes Contain Aberrant Levels of microRNAs.

ABSTRACT

The breast milk plays a crucial role in shaping the initial intestinal microbiota and mucosal immunity of the infant. Interestingly, breastfeeding has proven to be protective against the early onset of immune-mediated diseases including type 1 diabetes. Studies have shown that exosomes from human breast milk are enriched in immune-modulating miRNAs suggesting that exosomal miRNAs (exomiRs) transferred to the infant could play a critical role in the development of the infant's immune system. We extracted exomiRs from breast milk of 52 lactating mothers (26 mothers with type 1 diabetes and 26 healthy mothers), to identify any differences in the exomiR content between the two groups. Small RNA-sequencing was performed to identify known and novel miRNAs in both groups. A total of 631 exomiRs were detected by small RNA sequencing including immune-related miRNAs such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR-146b, and hsa-miR-200b. In addition, ~200 novel miRNAs were identified in both type 1 diabetes and control samples. Among the known miRNAs, nine exomiR's were found differentially expressed in mothers with type 1 diabetes compared to healthy mothers. The highly up-regulated miRNAs, hsa-miR-4497, and hsa-miR-3178, increased lipopolysaccharide-induced expression and secretion of tumor necrosis factor α (TNFα) in human monocytes. The up-regulated miRNA target genes were significantly enriched for longevity-regulating pathways and FoxO signaling. Our findings suggest a role of breast milk-derived exomiRs in modulating the infant's immune system.