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.

Milk Exosomes: Perspective Agents for Anticancer Drug Delivery

“…In a study of the microRNA profile in exosomes of human milk during type I diabetes mellitus, 631 exosomal microRNAs were identified, including immune-related ones such as hsa-let-7c, hsa-miR-21, hsa-miR-34a, hsa-miR- 146b, and hsa-miR-200b. Differential expression was described for nine miRNAs in healthy and diabetic groups [ 67 ]. MircroRNAs, highly represented in milk exosomes, are reviewed in Table 2 .…”

The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles

“…This is often associated with the development of cancer, and cells that undergo this transition are generally invasive [106]. Additionally, mothers with Type-1 diabetes have an altered BM-EV miRNA profile, of which some of the differentially-expressed miRNAs are capable of inducing pro-inflammatory cytokine expression [107].…”

Circulating microRNAs in Breast Milk and Their Potential Impact on the Infant

“…Mirza [ 84 ] found a disrupted pattern in the concentrations of breast milk exosomal miRNAs in mothers with type 1 diabetes mellitus, compared to healthy mothers. Whereas has-miR-4497, has-miR-1246, has-miR-133a-3p, has-miR-3178, has-miR-1290, and has-miR-320d were upregulated, has-miR-518e-3p, has-miR-29-3p, and has-miR-200c-5p were downregulated.…”