There is emerging evidence that non-coding RNAs (ncRNAs) within maternal breast milk (MBM) impart unique metabolic and immunologic effects on developing infants. Most studies examining ncRNAs in MBM have focused on microRNAs. It remains unclear whether microRNA levels are related to other ncRNAs, or whether they are impacted by maternal characteristics. This longitudinal cohort study examined 503 MBM samples from 192 mothers to: 1) identify the most abundant ncRNAs in MBM; 2) examine the impact of milk maturity on ncRNAs; and 3) determine whether maternal characteristics affect ncRNAs. MBM was collected at 0, 1, and 4 months post-delivery. High throughput sequencing quantified ncRNAs within the lipid fraction. There were 3069 ncRNAs and 238 microRNAs with consistent MBM presence (≥10 reads in ≥10% samples). Levels of 17 ncRNAs and 11 microRNAs accounted for 80% of the total RNA content. Most abundant microRNAs displayed relationships ([R]>0.2, adj p< 0.05) with abundant ncRNAs. A large proportion of ncRNAs (1269/3069; 41%) and microRNAs (206/238; 86%) were affected by MBM maturity. The majority of microRNAs (111/206; 54%) increased from 0-4 months. Few ncRNAs and microRNAs were affected (adj p < 0.05) by maternal age, race, parity, body mass index, gestational diabetes, or collection time. However, nearly half of abundant microRNAs (4/11) were impacted by diet. To our knowledge this is the largest study of MBM ncRNAs, and the first to demonstrate a relationship between MBM microRNAs and maternal diet. Such knowledge could guide nutritional interventions aimed at optimizing metabolic and immunologic microRNA profiles within MBM.
Background Human milk is thought to reduce infant atopy risk. The biologic mechanism for this protective effect is not fully understood. Objectives We tested the hypothesis that infant consumption of four microRNAs (miR-146b-5p, miR-148b-3p, miR-21–5p, and miR-375–3p) in human milk would be associated with reduced atopy risk. Design The Breast Milk IMPACT Study involved a cohort of mother-infant dyads who planned to breastfeed beyond four months. Infant consumption of the four human milk microRNAs in the first six months was calculated as the product of milk microRNA concentration and the number of human milk feeds, across three lactation stages: early milk (0–4 weeks), transitional milk (4–16 weeks), and mature milk (16–24 weeks). The primary outcome was infant atopy in the first year, defined as atopic dermatitis, food allergies, or wheezing. The final analysis included 432 human milk samples and 7,824 weeks of longitudinal health data from 163 dyads. Results Seventy-three infants developed atopy. Forty-one were diagnosed with atopic dermatitis (25%), 33 developed food allergy (20%), and 10 had wheezing (6%). Eleven developed > 1 condition (7%). Infants who did not develop atopy consumed higher levels of miR-375–3p (d = 0.18, P = 0.022, adj P = 0.044) and miR-148b-3p (d = 0.23, P = 0.007, adj P = 0.028). Consumption of miR-375–3p (X2 = 5.7, P = 0.017, OR = 0.92, 95% CI = 0.86, 0.99) was associated with reduced atopy risk. Levels of miR-375–3p increased throughout lactation (r = 0.46, F = 132.3, P = 8.4 × 10−34) and were inversely associated with maternal body mass (r = -0.11, t = -2.1, P = 0.032). Conclusions This study provides evidence that infant consumption of miR-375–3p may reduce atopy risk.
Low milk supply (LMS) is associated with early breastfeeding cessation; however, the biological underpinnings in the mammary gland are not understood. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally downregulate gene expression, and we hypothesized the profile of miRNAs secreted into milk reflects lactation performance. Longitudinal changes in milk miRNAs were measured using RNAseq in women with LMS (n = 47) and adequate milk supply (AMS; n = 123). Relationships between milk miRNAs, milk supply, breastfeeding outcomes, and infant weight gain were assessed, and interactions between milk miRNAs, maternal diet, smoking status, and BMI were determined. Women with LMS had lower milk volume (p = 0.003), were more likely to have ceased breast feeding by 24 wks (p = 0.0003) and had infants with a lower mean weight-for-length z-score (p = 0.013). Milk production was significantly associated with milk levels of miR-16-5p (R = −0.14, adj p = 0.044), miR-22-3p (R = 0.13, adj p = 0.044), and let-7g-5p (R = 0.12, adj p = 0.046). Early milk levels of let-7g-5p were significantly higher in mothers with LMS (adj p = 0.0025), displayed an interaction between lactation stage and milk supply (p < 0.001), and were negatively related to fruit intake (p = 0.015). Putative targets of let-7g-5p include genes important to hormone signaling, RNA regulation, ion transport, and the extracellular matrix, and down-regulation of two targets (PRLR and IGF2BP1/IMP1) was confirmed in mammary cells overexpressing let-7g-5p in vitro. Our data provide evidence that milk-derived miRNAs reflect lactation performance in women and warrant further investigation to assess their utility for predicting LMS risk and early breastfeeding cessation.
Food reactions (FR) are multifactorial and impacted by medical, demographic, environmental, and immunologic factors. We hypothesized that multi-omic analyses of host-microbial factors in saliva would enhance our understanding of FR development. This longitudinal cohort study included 164 infants followed from birth through two years. The infants were identified as FR (n = 34) or non-FR (n = 130) using the Infant Feeding Practice II survey and medical record confirmation. Saliva was collected at six months for the multi-omic assessment of cytokines, mRNAs, microRNAs, and the microbiome/virome. The levels of one miRNA (miR-203b-3p, adj. p = 0.043, V = 2913) and one viral phage (Proteus virus PM135, adj. p = 0.027, V = 2955) were lower among infants that developed FRs. The levels of one bacterial phylum (Cyanobacteria, adj. p = 0.048, V = 1515) were higher among infants that developed FR. Logistical regression models revealed that the addition of multi-omic features (miR-203b-3p, Cyanobacteria, and Proteus virus PM135) improved predictiveness for future FRs in infants (p = 0.005, X2 = 12.9), predicting FRs with 72% accuracy (AUC = 0.81, sensitivity = 72%, specificity = 72%). The multi-omic analysis of saliva may enhance the accurate identification of infants at risk of FRs and provide insights into the host/microbiome interactions that predispose certain infants to FRs.
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