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Long-chain saturated fatty acids in breast milk are associated with the pathogenesis of atopic dermatitis via inducing inflammatory ILC3s

ABSTRACT: Breastfeeding is thought to influence the immune system development of infants and may even affect various immunological responses later in life. Breast milk provides a rich source of early nutrition for the growth and developmental of infants. However, the presence of certain compounds in breast milk related to an unhealthy lifestyle or the diet of lactating mothers may negatively impact infants6. Based on a cohort study, we found that the composition of mother’s milk containing high amount of long-chain saturated fatty acids (LCSFAs) was related to a higher incidence of atopic dermatitis (AD) in children. Similarly, a mouse model in which breastfed offspring were fed milk high in LCSFAs also resulted in AD onset later in life. We showed that LCSFAs are damage-associated molecular patterns, which initiate a series of inflammatory events in the gut involving type 3 innate lymphoid cells (ILC3s). A remarkable increase in inflammatory ILC3s was observed in the gut, and the migration of these ILC3s to the skin contributed to the pathogenesis of AD. Gene expression analysis of ILC3s isolated from the gut revealed up-regulation of genes that increase ILC3s and chemokines, which may play a role in ILC migration to the skin. Even in the absence of adaptive immunity, Rag1 knockout mice fed a high-LCSFA milk diet developed eczema, accompanied by increased gut ILC3s. Here, we propose that early exposure to LCSFAs in infants may affect the balance of intestinal innate immunity, inducing a highly inflammatory environment with the proliferation of ILC3s and production of interleukin-17 and interleukin-22, which are attributed to the pathogenesis of AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE124182 | GEO | 2020/09/30

REPOSITORIES: GEO

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Project description:Background: Maternal pre-pregnancy BMI is a critical factor influencing the composition of breast milk. Breast milk has abundant extracellular vesicles (EVs) containing various biological molecules (cargo), including miRNAs. EVs are not degraded in the gastrointestinal system and circulation; thus, breast milk EVs (bEVs) interact with other organs in breastfed infants and modify the gene expression of recipient cells using miRNAs. In maternal obesity, miRNAs in bEVs are deregulated, which might be associated with adverse health outcomes in infants. In this study, we examined 798 miRNAs to determine which miRNAs are altered in the bEVs of obese mothers and their potential impact on breastfed infants. Methods: We recruited healthy nursing mothers who were either obese (BMI≥30) or lean (BMI<25) based on their pre-pregnancy BMI, and delivered a singleton baby in the prior six months. EVs were isolated from breast milk with ultracentrifugation. bEV characteristics were examined by flow cytometry and fluorescence imaging of EV markers. A total of 798 miRNAs were screened using a NanoString human miRNA panel to find deregulated miRNAs in bEVs of obese mothers compared to lean mothers. Results: We included 65 nursing mothers: 47 lean and 18 obese mothers based on pre-pregnancy BMI. After bEV isolation, we confirmed the expression of general EV markers. Out of 37 EV markers, CD326 was the most highly expressed marker in bEVs. From miRNA analysis using NanoString, we found that the most abundant miRNAs include miR-30b-5p, miR-494-3p, and let-7 families, and the list of top 10 miRNAs was not different between lean and obese mothers. Target genes of the top 10 miRNAs were associated with the EGFR, ErbB, and FoxO signaling pathway. Nineteen miRNAs were deregulated in bEVs of obese mothers (adjusted p < 0.05 cut-off), including miR-575, miR-548g-3p, miR-582-3p, and miR-652-5p. The target genes of these miRNAs are associated with lipid metabolism, inflammatory diseases, and nervous/cardiovascular system development. Conclusion: In this study, we demonstrated altered miRNAs in bEVs of obese mothers and identified the pathways of their potential target genes. Our findings will provide insight for future studies investigating the role of bEVs in breastfed infants.

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Long-chain saturated fatty acids in breast milk are associated with the pathogenesis of atopic dermatitis via inducing inflammatory ILC3s

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