Breastmilk as Epigenetic Medium NPO Conference, Portland Oct 2018 - PowerPoint PPT Presentation

Breastmilk as Epigenetic Medium NPO Conference, Portland Oct 2018 Sylvia Metzger

Objectives 1. Introduce the concept of epigenetics 2. Discuss epigenetic effects of breastmilk and lactation programming on infant health outcomes 3. Compare and contrast modes of feeding and its impact on microbiome and infant health outcomes 4. Discuss common breastfeeding challenges and strategies to support mother-baby breastfeeding dyads in clinical practice .

Baby’s menu impacts DNA Globally, only 38% of infants are exclusively breastfed US: only 13-14% are exclusively breastfed for 6 months Nutritional epigenetics – the diet changes the gene expression • modulates gene expression – turns genes on/off • later effects on health. Verduci et al. ( 2014). Epigenetic effects of human breast milk . Nutrients, 6 : 1711-1724 .

Epigenetics Modification of gene expression without changes in DNA (the genetic code itself) .

Basic epigenetic mechanisms 1. DNA methylation 2. Histone modification 3. miRNA https://en.wikipedia.org/wiki/File:Epigenetic_mechanisms.jpg .

1. DNA methylation – genome guardian • A chemical cap (CH3-) binds to or near a gene • Gene is silenced or turned off e.g. Breastfeeding – baby LEPTIN “ I am full” The longer she BF, the less chance that the gene will be methylated (silenced), which sends signals of satiety Obermann-Borst, S.A. et al (2013). Duration of breastfeeding and gender are associated with methylation of the LEPTIN gene in very young children . Pediatric Research, 74(3 ):344-349. .

2. Histone modification- access to info • DNA hugged tightly: the info CANNOT be “read”  NO PROTEIN • Histones “loosen”, information is ACCESSED & “READ” - PROTEIN is made e.g. DM Type 1 : Altered histone methylation induced by hyperglycemia Picascia et al. (2015). Epigenetic control of autoimmune diseases: from bench to bedside. Clinical Immunology, 157(1):1-15. .

3. miRNAs – key regulators in maternal-fetal crosstalk Do not code, but regulate gene expression • Key in fetal metabolic & immune programming • Promote infant’s growth • Deficient in infant formula • Most human and bovine milk miRNAs sequences are miRNA identical • Raw farm milk (miRNA-148s)- atopy preventive effect • Persistent consumption of pasteurized milk – increased risk of obesity and hyperphagia Melnik , B.C., & Schmitz, G. (2017). MicroRNAs: Milk’s epigenetic regulators. Best Practice & Research Clinical Endocrinology & Metabolism, 31:427-442 . .

Breast Milk Microbiota • Modulates the immunologic development via personalied microbial and immune factors • Breastfed baby ingests up to 800,000 bacteria daily (BM 1,000 CFUs/ml) • Seeding the infant’s gut: transfer from breastmilk to baby • Different composition in formula fed infants • Maternal health also alters milk microbiota (delivery mode, stress etc) • Better Th1 responses in breastfed infants compared to formula Le Doare, K.L., Holder, B., Bassett, A, & Pannaraj, P.S. (2018). Mothers’s Milk : A purposeful contribution to the development of the infant microbiota and immunity. Frontiers in Immunology,9(361 ):1-10. . Pannaraj, P.S., Rollie, A. & Bailey, A. (2017). Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatrics, 17(7 ):647-654.

Be Benefits nefits fo for r BA BABY BY Condition % Lower risk Breastfeeding comment Otitis media 23% Any BF compared to formula 50% >3 or 6 mon of EBF (exclusive) Recurrent OM 77% > 6 mon EBF compared to 4-6 BF Upper respiratory tract infection (serious 63% >6 mon (EBF) colds, ear and throat infections) Lower respiratory tract infection – risk of 72% >4 mon EBF hospitalization in 1 st yr of life 77% > 6 mon EBF compared to BF 4-6 mon Asthma 40% >3 mon (if atopic family history) 26% >3 mon (if no atopic family history) RSV bronchiolitis – severity (duration of 74% > 4 mon EBF hospitalization / O2 requirements) NEC (1 case could be prevented if 10 babies 77% NICU, preterm – exclusive human milk EBF) Atopic dermatitis 27% > 3 mon (EBF negative family history) 42% > 3mon (EBF positive family history) American Academy of Pediatrics (2012). Breastfeeding and the Use of Human Milk, 129(3)”827 -841 . http://pediatrics.aappublications.org/content/129/3/e827/T2.expansion.html

Condition % Lower risk Breastfeeding comment Gastroenteritis (effect lasts for 2 m after BF is stopped) 64% Any BF SIDS 36% Any BF > 1 mon Inflammatory bowel disease (intestinal colonization is different in BF 31 % Any BF babies) Obesity 24% Any BF Celiac disease (if BF when exposed to gluten) 52% > 2mo Type 1 DM 30% >3 mon EBF Type 2 DM 40% Any BF Leukemia (ALL) 20% > 6 mon Leukemia (AML) 15% > 6 mon American Academy of Pediatrics (2012). Breastfeeding and the Use of Human Milk, 129(3)”827 -841 . http://pediatrics.aappublications.org/content/129/3/e827/T2.expansion.html

Autoimmunity • Diabetes Type I – by 30% if exclusively BF at least 3 months • Celiac disease – by 52% in infants breastfed when exposed to gluten • Rheumatoid arthritis (cumulative BF > 12 m, RR 0.8, if > 24 m, RR 0.5) • Childhood inflammatory bowel disease – by 31% (Crohn’s , Ulcerative colitis) American Academy of Pediatrics (2012). Breastfeeding and the Use of Human Milk. Pediatrics 129(3 ): e827-e841 . Lund-Blix et al. (2017). Infant feeding and risk of type 1 diabetes in two large Scandinavian Birth Cohorts. Diabetes Care, 40(7 ): 921-927

Maternal Benefits Decreased risk of • Breast , ovarian, & endometrial cancer • Obesity • Diabetes mellitus II • Hyperlipidemia • Hypertension • Myocardial infarction • Rheumatoid arthritis • Decreased postpartum blood loss • Postpartum depression Schwarz, E.B., & Nothnagle, M. (2015). The Maternal Health Benefits of Breastfeeding. Am Fam Physician, 91 (9):604-4 . American Academy of Pediatrics (2012). Breastfeeding and the Use of Human Milk, 129(3):827-841 http://pediatrics.aappublications.org/content/129/3/e827/T

Lactation as critical window of opportunity • The First 1000 days – breastmilk as a significant early life programming medium Cunha, A.J., Leite , A.J., & Almeida, I.S. (2015). The pediatrician’s role in the first thousand days of the child: the pursuit of healthy nutr ition and development. J Pediatri (Rio J), 91(6 Suppl 1): S44-51 .

Lactational programming .

1. IMMUNE programming miRNA • miRNAs in breastmilk – key players in immunity • Milk – body fluid richest in miRNA • More in colostrum > mature milk • Modify gene expression of distant cells • ~60% of all human genes • Decrease inflammation ( ↓ NEC) • This mom-baby signaling is absent in formula Alsaweed, M., Hartmann, P.E., Geddes, D.T., & Kakulas, F. (2015). MicroRNAs in Breastmilk and the Lactating Breast: potential immunoprotectors and developmental regulators for the infant and the mother. International Journal of Environmental Research and Public Health, 12(11 ):13981-14020. . Melnik , B.C., & Schmitz. G. (2017). MicroRNAs: Milk’s epigenetic regulators. Best Practice and Research. Clinical Endocrinology and Metabolism, 31(4 ):427-442.

Breastfeeding & Childhood Asthma Canadian longitudinal birth cohort (N=3296) • Mode of feeding ~ asthma diagnosis at 3 yrs Results • Modes of infant feeding are associated with asthma development • Direct BF (most protective) > expressed breastmilk> formula • Bottled fed with BM or formula – increased risk of coughing/wheezing episodes by 1 yr compared to babies directly BF Klopp et al. (201 7). Modes of Infant Feeding and the Risk of Childhood Asthma: A Prospective Birth Cohort Study. The Journal of Pediatrics, 190:192-199 . .

2. METABOLIC programming • Lactation period- a critical window of susceptibility to insults due to continued organ differentiation and growth • Transient insults can have lasting effects • Metabolic tissues – sensitive to developmental stressors • Increased risk of Obesity, insulin resistance, abnormal glucose levels, DM in offspring Ellsworth, L., Harman, E., Padmanabhan, V., & Gregg, B. (2018). Lactational programming of glucose homeostasis: a window of opportunity. Reproduction, 156(2):R23-R42 .

Breastmilk ↓ the risk of pediatric obesity Authors propose that: • Early nutrition influences the baby epigenome via microbial metabolites • ↑ adult obesity • The type of feeding • Affects the composition of the early gut microbiota • Formula feeding • different metabolites impact the epigenome of intestinal cells, hepatocytes, and adipocytes- predisposes to obesity Mischke & Pl ösch ( 2013). More than just a gut instinct- the potential interplay between a baby’s nutrition, its gut microbiome, and the epigenome. American Journal of Physiology. Regulatory, Integrative, and Comparative Physiology, 304(12):R1065-9 . .