Improved feeding tolerance and growth are linked to increased gut microbial community diversity in very-low-birth-weight infants fed mother's own milk compared with donor breast milk

Steven L Ford, Pablo Lohmann, Geoffrey A Preidis, Pamela S Gordon, Andrea O'Donnell, Joseph Hagan, Alamelu Venkatachalam, Miriam Balderas, Ruth Ann Luna, Amy B Hair, Steven L Ford, Pablo Lohmann, Geoffrey A Preidis, Pamela S Gordon, Andrea O'Donnell, Joseph Hagan, Alamelu Venkatachalam, Miriam Balderas, Ruth Ann Luna, Amy B Hair

Abstract

Background: Mother's own milk (MOM) is protective against gut microbiota alterations associated with necrotizing enterocolitis (NEC) and feeding intolerance among preterm infants. It is unclear whether this benefit is preserved with donor milk (DM) feeding.

Objective: We aimed to compare microbiota development, growth, and feeding tolerance in very-low-birth-weight (VLBW) infants fed an exclusively human milk diet of primarily MOM or DM.

Methods: One hundred and twenty-five VLBW infants born at Texas Children's Hospital were enrolled and grouped into cohorts based on percentage of MOM and DM in enteral feeds. Feeds were fortified with DM-derived fortifier per unit protocol. Weekly stool samples were collected for 6 wk for microbiota analysis [16S ribosomal RNA (rRNA) sequencing]. A research nurse obtained weekly anthropometrics. Clinical outcomes were compared via Wilcoxon's rank-sum test and Fisher's exact test, as well as multivariate analysis.

Results: The DM cohort (n = 43) received on average 14% mothers' milk compared with 91% for the MOM cohort (n = 74). Diversity of gut microbiota across all time points (n = 546) combined was increased in MOM infants (P < 0.001). By 4 and 6 wk of life, microbiota in MOM infants contained increased abundance of Bifidobacterium (P = 0.02) and Bacteroides (P = 0.04), whereas DM-fed infants had increased abundance of Staphylococcus (P = 0.02). MOM-fed infants experienced a 60% reduction in feeding intolerance (P = 0.03 by multivariate analysis) compared with DM-fed infants. MOM-fed infants had greater weight gain than DM-fed infants.

Conclusions: Compared with DM-fed infants, MOM-fed infants have increased gut microbial community diversity at the phylum and genus levels by 4 and 6 wk of life, as well as better feeding tolerance. MOM-fed infants had superior growth. The incidence of NEC and other gastrointestinal morbidity is low among VLBW infants fed an exclusively human milk diet including DM-derived fortifier. This trial was registered at clinicaltrials.gov as NCT02573779.

Keywords: breast milk; donor milk; feeding intolerance; growth; microbiota; neonate; premature infant; very low birth weight.

Copyright © American Society for Nutrition 2019.

Figures

FIGURE 1
FIGURE 1
α-Diversity comparisons of gut microbiota from DM and MOM infants by age and antibiotic exposure. Using mixed-effects linear models for data analysis to look across all time points (n = 156 for MOM samples and n = 93 for DM samples), (A) observed OTU richness was significantly higher in the MOM group (slope = 9.4, SE = 3.6, P = 0.013), but (B) the SDI was not significantly different (slope = 0.22, SE = 0.14, P = 0.126). (C) For infants who received empiric antibiotics (≤48 h after birth) observed OTU richness was significantly higher in the MOM group (slope = 10.5, SE = 4.1, P = 0.028), but there was not a significant difference among infants who did not receive antibiotics (slope = 5.1, SE = 7.5, P = 0.497). (D) Among infants who received empiric antibiotics, the SDI tended to be higher for the MOM group (slope = 0.31, SE = 0.15, P = 0.068), but there was not a significant difference for MOM compared with DM among infants who did not receive antibiotics (slope = −0.12, SE = 0.29, P = 0.689). DM, donor human milk; MOM, mother's own milk; OTU, operational taxonomic unit; SDI, Shannon Diversity Index.
FIGURE 2
FIGURE 2
β-Diversity among gut microbial communities from DM compared with MOM infants over time. (A) Bray-Curtis PCoA ordination of stool samples obtained at 1, 2, 4, and 6 wk of life from DM-fed infants. Samples obtained during the first week of life are shown in red, second week in blue, fourth week in gray, and sixth week in orange. No obvious clustering was apparent within samples obtained from DM-fed infants (n = 43). (B) Bray-Curtis PCoA ordination of samples obtained from MOM-fed infants. Results revealed a pattern of development with stool samples obtained during the first week of life clustering separately from those obtained during the second week of life, followed by separate clustering of samples obtained in the third or fourth weeks of life, suggesting a developmental pattern among fecal microbial communities in MOM-fed infants (n = 74). (C) When comparing longitudinal changes across samples from all study subjects, increasing relative abundance of Proteobacteria was observed. There were no significant differences observed at the phylum level during the first 2 wk of life. By week 4, microbiota from the MOM cohort had significantly higher abundance of Actinobacteria (P = 0.032) and decreased abundance of Firmicutes (P = 0.011). (D) By week 4, microbiota from the MOM cohort had significantly increased abundance of Bacteroides (P = 0.046), Bifidobacterium (P = 0.026), and Enterococcus (P < 0.001) in comparison to the DM cohort. DM infants had significantly higher abundance of Staphylococcus (P = 0.014). DM, donor human milk; MOM, mother's own milk; PCoA, principal coordinates analysis.
FIGURE 3
FIGURE 3
Impact of early-life antibiotics on composition of the gut microbiota from DM and MOM infants at the genus level. (A) Relative abundance of genera during the first week of life separated by diet and timing by which antibiotic-exposed infants’ stool samples were obtained (before, during, or after exposure to antibiotics). No stool samples in week 1 were obtained before the initiation of antibiotics. Sample sizes are small for this group because most premature infants did not have a stool sample of sufficient quantity during the first week of life. (B) Relative abundance of genera during the second week of life separated by diet and timing by which antibiotic-exposed infants’ stool samples were obtained (before, during, or after antibiotics). One infant receiving DM had a stool sample obtained in week 2 before initiation of antibiotics, and this patient's microbiota composition was similar to those obtained in week 2 from the 7 infants receiving DM who never received antibiotics. DM, donor human milk; MOM, mother's own milk.

References

    1. Schanler RJ. Outcomes of human milk-fed premature infants. Semin Perinatol. 2011;35(1):29–33.
    1. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U, Chan GM, Blanco CL, Abrams S, Cotten CM et al. .. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010;156(4):562–7..e1.
    1. Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, Dudell G, Rechtman DJ, Lee ML, Lucas A et al. .. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013;163(6):1592–5.
    1. Abrams SA, Schanler RJ, Lee ML, Rechtman DJ. Greater mortality and morbidity in extremely preterm infants fed a diet containing cow milk protein products. Breastfeed Med. 2014;9(6):281–5.
    1. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103(6pt 1):1150–7.
    1. Sisk PM, Lovelady CA, Gruber KJ, Dillard RG, O'Shea TM. Human milk consumption and full enteral feeding among infants who weigh < 1250 grams. Pediatrics. 2008;121(6):e1528–33.
    1. American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129(3):e827–41.
    1. Schanler RJ. Mother's own milk, donor human milk, and preterm formulas in the feeding of extremely premature infants. J Pediatr Gastroenterol Nutr. 2007;45(Suppl 3):S175–7.
    1. Dewey KG, Heinig MJ, Nommsen-Rivers LA. Differences in morbidity between breast-fed and formula-fed infants. J Pediatr. 1995;126(5):696–702.
    1. Le Huërou-Luron I, Blat S, Boudry G. Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects. Nutr Res Rev. 2010;23(1):23–36.
    1. Duijts L, Ramadhani MK, Moll HA. Breastfeeding protects against infectious diseases during infancy in industrialized countries. A systematic review. Matern Child Nutr. 2009;5(3):199–210.
    1. ESPGHAN Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 2013;57(4):535–42.
    1. Bertino E, Giuliani F, Baricco M, Di Nicola P, Peila C, Vassia C, Chiale F, Pirra A, Cresi F, Marrtano C et al. .. Benefits of donor milk in the feeding of preterm infants. Early Human Dev. 2013;89:S3–S6.
    1. Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2014;(4):CD002971.
    1. Gregory KE, Samuel BS, Houghteling P, Shan G, Ausubel FM, Sadreyev RI, Walker WA. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome. 2016;4(1):68.
    1. Cong X, Judge M, Xu W, Diallo A, Janton S, Brownell EA, Maas K, Graf J. Influence of feeding type on gut microbiome development in hospitalized preterm infants. Nurs Res. 2017;66(2):123–33.
    1. Parra-Lorca A, Gormaz M, Alcantara C, Cernada M, Nunez-Ramiro A, Vento M, Collado MC. Preterm gut microbiome depending on feeding type: significance of donor human milk. Front Microbiol. 2018;9:1376.
    1. Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 2009;3(8):944–54.
    1. Mai V, Young CM, Ukhanova M, Warng X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M et al. .. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One. 2011;6(6):e20647.
    1. Warner BB, Deych E, Zhou Y, Hall-Moore C, Weinstock GM, Sodergren E, Shaikh N, Hoffmann JA, Linneman LA, Hamvas A et al. .. Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. Lancet. 2016;387(10031):1928–36.
    1. Pammi M, Crope J, Tarr PI, Warner BB, Morrow AL, Mai V, Gregory KE, Kroll JS, McMurtry V, Ferris MJ et al. .. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome. 2017;5(1):31.
    1. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics. 2005;116(2):400–6.
    1. Montjaux-Régis N, Cristini C, Arnaud C, Glorieux I, Vanpee M, Casper C. Improved growth of preterm infants receiving mother's own raw milk compared with pasteurized donor milk. Acta Paediatr. 2011;100(12):1548–54.
    1. García-Lara NR, Vieco DE, De la Cruz-Bértolo J, Lora-Pablos D, Velasco NU, Pallás-Alonso CR. Effect of Holder pasteurization and frozen storage on macronutrients and energy content of breast milk. J Pediatr Gastroenterol Nutr. 2013;57(3):377–82.
    1. Marx C, Bridge R, Wolf AK, Rich W, Kim JH, Bode L. Human milk oligosaccharide composition differs between DM and mother's own milk. J Hum Lact. 2014;30(1):54–61.
    1. Evans TJ, Ryley HC, Neale LM, Dodge JA, Lewarne VM. Effect of storage and heat on antimicrobial proteins in human milk. Arch Dis Child. 1978;53(3):239–41.
    1. Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, Welling GW. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr. 2000;30(1):61–7.
    1. Hanson LA, Korotkova M, Telemo E. Breast-feeding, infant formulas, and the immune system. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):59–63.
    1. Ward RE, Nirñonuevo M, Mills DA, Lerbrilla CB, German JB. In vitro fermentation of breast milk oligosaccharides by Bifidobacterium infantis and Lactobacillus gasseri. Appl Environ Microbiol. 2006;72(6):4497–9.
    1. Björkström MV, Hall L, Söderlund S, Håkansson EG, Håkansson S, Domellöf M. Intestinal flora in very low-birth weight infants. Acta Paediatr. 2009;98(11):1762–7.
    1. Hair A, Hawthorne K, Chetta K, Abrams S. Human milk feeding supports adequate growth in infants < 1250 grams birth weight. BMC Research Notes. 2013;6:459.
    1. Eunice Kennedy Shriver National Institute of Child Health and Human Development. NICHD Neonatal Research Network (NRN): extremely preterm birth outcome data[Internet]. National Institutes of Health; [cited 25 Sep, 2018]. Available from: .
    1. Kourosh A, Luna RA, Balderas M, Nance C, Anagnostou A, Devaraj S, Davis CM. Fecal microbiome signatures are different in food-allergic children compared to siblings and healthy children. Pediatric Allergy Immunol. 2018;29(5):545–54.
    1. Hildebrand F, Tadeo R, Voigt AY, Bork P, Raes J. LotuS: an efficient and user-friendly OTU processing pipeline. Microbiome. 2014;2(1):30.
    1. Edgar RC. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods. 2013;10(10):996–8.
    1. Yilmaz P. The SILVA and “All-species Living Tree Project (LTP)” taxonomic frameworks. Nucleic Acids Res. 2014;42:D643–8.
    1. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Peña AG, Goodrich JK, Gordon JI et al. .. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–6.
    1. Zakrzewski M, Proietti C, Ellis J, Hasan S, Brion MJ, Berger B, Krause L. Calypso: a user-friendly web-server for mining and visualizing microbiome-environment interactions. Bioinformatics. 2017;33(5):782–3.
    1. Walsh M, Kliegman R. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179–201.
    1. Hair AB, Peluso AM, Hawthorne KM, Perez J, Smith DP, Khan JY, O'Donnell A, Powers RJ, Lee ML, Abrams SA. Beyond necrotizing enterocolitis prevention: improving outcomes with an exclusive human milk-based diet. Breastfeed Med. 2016;11(2):70–4.
    1. Palmer C, Bik EM, DiGriulio DB, Relman DA, Brown PO. Development of the human intestinal microbiota. PLoS Biol. 2007;5(7):e177.
    1. La Rosa PS, Warner BB, Zhou Y, Weinstock GM, Sodergren E, Hall-Moore CM, Stevens HJ, Bennett WE Jr, Shaikh N, Linneman LA et al. .. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci U S A. 2014;111(34):12522–7.
    1. Zhou Y, Shan G, Sodergren E, Weinstock G, Walker WA, Gregory KE. Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS One. 2015;10(3):e0118632.
    1. Chu DM, Ma J, Prince AL, Antony KM, Seferovic MD, Aagaard KM. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med. 2017;23(3):314–26.
    1. Clarke SF, Murphy EF, Nilaweera K, Ross PR, Shanahan F, O'Toole PW, Cotter PD. The gut microbiota and its relationship to diet and obesity. Gut Microbes. 2012;3(3):186–202.
    1. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102(31):11070–5.
    1. Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and methanogens in anorexic patients. PLoS One. 2009;4:e7125.
    1. Gewolb IH, Schwalbe RS, Taciak VL, Harrison TS, Panigrahi P. Stool microflora in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1999;80(3):F167–73.
    1. Magne F, Abély M, Boyer F, Morville P, Pochart P, Suau A. Low species diversity and high interindividual variability in faeces of preterm infants as revealed by sequences of 16S rRNA genes and PCR-temporal temperature gradient gel electrophoresis profiles. FEMS Microbiol Ecol. 2006;57(1):128–38.
    1. Drell T, Lutsar I, Stšepetova J, Parm U, Metsvaht T, Ilmoja ML, Simm J, Sepp E. The development of gut microbiota in critically ill extremely low birth weight infants assessed with 16S rRNA gene based sequencing. Gut Microbes. 2014;5(3):304–12.
    1. Patel AL, Mutlu EA, Sun Y, Koenig L, Green S, Jakubowicz A, Mryan J, Engen P, Fogg L, Chen AL et al. .. Longitudinal survey of microbiota in hospitalized preterm very-low-birth-weight infants. J Pediatr Gastroenterol Nutr. 2016;62(2):292–303.
    1. Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14(5):273–87.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe