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Figure.  Probiotics and Human Milk Oligosaccharide Levels
Probiotics and Human Milk Oligosaccharide Levels

A, Human milk oligosaccharide levels in mothers who received a mixture of probiotics or placebos. Boxplots show median and quartiles of concentrations of each of the human milk oligosaccharides and the P value of the t test comparing log-transformed concentrations of the 2 groups. Human milk oligosaccharides that were found in a significantly lower concentration in the milk of mothers receiving the probiotic are difucosyllacto-N-hexaose, lacto-N-tetraose, lacto-N-fucopentaose I, and 6′-sialyllactose (marked with orange); those found in higher concentrations are 3-fucosyllactose and 3′-sialyllactose (marked with blue). B, Biosynthetic associations of human milk oligosaccharides are shown with probiotic-induced decreases and increases as indicated in part A.

1.
Lewis  ZT, Totten  SM, Smilowitz  JT,  et al.  Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants.  Microbiome. 2015;3:13. doi:10.1186/s40168-015-0071-zPubMedGoogle ScholarCrossref
2.
Sprenger  N, Odenwald  H, Kukkonen  AK, Kuitunen  M, Savilahti  E, Kunz  C.  FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk.  Eur J Nutr. 2017;56(3):1293-1301. doi:10.1007/s00394-016-1180-6PubMedGoogle ScholarCrossref
3.
Seppo  AE, Autran  CA, Bode  L, Järvinen  KM.  Human milk oligosaccharides and development of cow’s milk allergy in infants.  J Allergy Clin Immunol. 2017;139(2):708-711.e5. doi:10.1016/j.jaci.2016.08.031PubMedGoogle ScholarCrossref
4.
Thurl  S, Munzert  M, Henker  J,  et al.  Variation of human milk oligosaccharides in relation to milk groups and lactational periods.  Br J Nutr. 2010;104(9):1261-1271. doi:10.1017/S0007114510002072PubMedGoogle ScholarCrossref
5.
Kukkonen  K, Savilahti  E, Haahtela  T,  et al.  Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.  J Allergy Clin Immunol. 2007;119(1):192-198. doi:10.1016/j.jaci.2006.09.009PubMedGoogle ScholarCrossref
6.
Kuitunen  M, Kukkonen  K, Juntunen-Backman  K,  et al.  Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.  J Allergy Clin Immunol. 2009;123(2):335-341. doi:10.1016/j.jaci.2008.11.019PubMedGoogle ScholarCrossref
Research Letter
January 22, 2019

Association of Maternal Probiotic Supplementation With Human Milk Oligosaccharide Composition

Author Affiliations
  • 1Department of Pediatrics, Division of Pediatric Allergy and Immunology, University of Rochester Medical Center, Rochester, New York
  • 2Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland
  • 3Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland
  • 4Department of Pediatrics, Division of Neonatology, Division of Gastroenterology and Nutrition, University of California, San Diego
  • 5Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence, University of California, San Diego
JAMA Pediatr. 2019;173(3):286-288. doi:10.1001/jamapediatrics.2018.4835

Human milk oligosaccharides (HMOs) are complex glycans and the third-largest solid component in human milk. They are typically nondigestible by humans but are a major substrate for infants’ gut microbiota and affect the maturation of the intestinal mucosal immune system. All HMOs are extensions of lactose generated by the action of a series of glycosyltransferases. Depending on the mother’s Secretor and Lewis blood groups, the fucosyltransferases FUT2 (the Secretor gene) and/or FUT3 (the Lewis gene) are available for the synthesis of HMOs. The resulting heterogeneity implies that some breastfed infants are not being exposed to certain structures, which may affect their microbiome composition and thereby disease risk for illnesses in which gut microbiome plays a role. Infants fed by mothers who lack a Secretor gene and therefore lack a functional FUT2 enzyme and all α-1-2-fucosylated oligosaccharides have delayed development of bifidobacteria-laden microbiota.1 Also, if these infants are born via cesarean delivery, they have a higher risk to manifest IgE-associated eczema.2 We recently showed that certain HMOs are associated with protection against cow-milk allergy in infants.3 Besides genetic differences that are responsible for differences in HMO profiles, HMO abundance changes throughout lactation.4 However, no other factors have been associated with variation in HMO abundances. This study sought to assess the association of maternal probiotic supplementation with HMO concentrations.

Methods

We used stored frozen colostrum samples from a previously published large, double-blind, placebo-controlled randomized clinical trial5,6 of probiotic supplementation study of 1223 pregnant mothers from Helsinki, Finland, carrying fetuses at hereditary risk for allergy (ie, the offspring had 1 or both parents with physician-diagnosed allergic rhinitis, eczema, and/or asthma). The children born to these mothers were followed up for 10 years for the development of allergic disease. In the probiotic group, mothers took twice-daily doses of Lactobacillus rhamnosus GG, Lactobacillus rhamnosus LC705, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii subspecies shermanii JS in capsules from 36 weeks’ gestation until the birth of the infant. Mature milk samples were available for more than 500 mothers; we randomly selected 81 colostrum samples (stored frozen at −62.2°C), with 30 samples from the placebo group and 51 from the probiotic group. There was an equal distribution of tobacco-smoking mothers and mothers with a history of atopic disease between the 2 groups. The concentrations of 19 HMOs were determined using high-performance liquid chromatography after 2-aminobenzamide labeling.3 Raffinose was added to milk samples as an internal standard to allow for absolute quantification. Freezing does not affect HMO levels, which are very stable in full-term milk from day to day and diurnally.4

The study was approved by the institutional review board of the Hospital for Children and Adolescents, Helsinki University Central Hospital, Finland. All mothers signed a written informed consent form.

Statistical analysis was carried out using R software version 3.5.0 (R Foundation for Statistical Computing), and 2-sided P values less than .05 were considered significant in all comparisons. Data collection occurred from November 2000 to March 2003, and data analysis from March 2018 to June 2018.

Results

The concentrations of 3-fucosyllactose (Figure, A) were significantly higher in colostrum from the mothers in the probiotic supplementation group (mean [SD], 413 [164] μmol/mL) compared with those in the nonsupplemented group (mean [SD], 312 [232] μmol/mL; P = .008). Likewise, 3′-sialyllactose was higher in colostrum from the probiotic supplementation group (mean [SD], 833 [679] μmol/mL) than in control participants (mean [SD], 516 [378] μmol/mL; P = .006).

However, mean [SD] levels of HMOs were lower in colostrum from mothers who received probiotic supplementation than in the control group; this was found in difucosyllacto-N-hexaose (probiotic group, 62.0 [43.4] μmol/mL; control group, 93.7 [47.7] μmol/mL; P = .005), lacto-N-tetraose (probiotic group, 509 [339] μmol/mL; control group, 861 [563] μmol/mL; P = .01), lacto-N-fucopentaose I (probiotic group, 2000 [585] μmol/mL; control group, 2450 [836] μmol/mL; P = .03), and 6′-sialyllactose (probiotic group, 472 [159] μmol/mL; control group, 567 [179] μmol/mL; P = .03). These changes are consistent with a change in select pathways in overall HMO biosynthetic machinery (Figure, B).

Conclusions

Although HMO composition is largely genetically determined, maternal probiotic supplementation during late stages of pregnancy may change the HMO composition in human milk. It is unknown whether the change is specific to the probiotics used in this study, and findings need to be confirmed by other studies. In this case, we hypothesize a shift from 6′-sialylation to 3′-sialylation and toward type-2 core structures in HMOs. Maternal diet, medications, and microbiome may be important factors modulating a mother’s colostrum HMO levels that should be considered when assessing biological effects suspected to be mediated by HMO levels. Ultimately, modifying mothers’ milk HMO composition may open new avenues for disease modification in infants who are breastfed.

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Article Information

Accepted for Publication: September 29, 2018.

Corresponding Author: Antti E. Seppo, PhD, Department of Pediatrics, Division of Pediatric Allergy and Immunology, University of Rochester Medical Center, 601 Elmwood Ave, PO Box 611, Rochester, NY 14642 (antti_seppo@urmc.rochester.edu).

Published Online: January 22, 2019. doi:10.1001/jamapediatrics.2018.4835

Author Contributions: Dr Seppo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kukkonen, Savilahti, Järvinen.

Acquisition, analysis, or interpretation of data: Seppo, Kukkonen, Kuitunen, Savilahti, Yonemitsu, Bode, Järvinen.

Drafting of the manuscript: Järvinen, Seppo.

Critical revision of the manuscript for important intellectual content: Kukkonen, Kuitunen, Savilahti, Yonemitsu, Bode, Järvinen.

Obtained funding: Savilahti, Järvinen.

Administrative, technical, or material support: Kuitunen, Savilahti, Bode, Järvinen.

Supervision: Savilahti, Bode, Järvinen.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the National Institute of Allergy and Infectious Diseases (grant R03 AI122126; Dr Järvinen).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

References
1.
Lewis  ZT, Totten  SM, Smilowitz  JT,  et al.  Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants.  Microbiome. 2015;3:13. doi:10.1186/s40168-015-0071-zPubMedGoogle ScholarCrossref
2.
Sprenger  N, Odenwald  H, Kukkonen  AK, Kuitunen  M, Savilahti  E, Kunz  C.  FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk.  Eur J Nutr. 2017;56(3):1293-1301. doi:10.1007/s00394-016-1180-6PubMedGoogle ScholarCrossref
3.
Seppo  AE, Autran  CA, Bode  L, Järvinen  KM.  Human milk oligosaccharides and development of cow’s milk allergy in infants.  J Allergy Clin Immunol. 2017;139(2):708-711.e5. doi:10.1016/j.jaci.2016.08.031PubMedGoogle ScholarCrossref
4.
Thurl  S, Munzert  M, Henker  J,  et al.  Variation of human milk oligosaccharides in relation to milk groups and lactational periods.  Br J Nutr. 2010;104(9):1261-1271. doi:10.1017/S0007114510002072PubMedGoogle ScholarCrossref
5.
Kukkonen  K, Savilahti  E, Haahtela  T,  et al.  Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.  J Allergy Clin Immunol. 2007;119(1):192-198. doi:10.1016/j.jaci.2006.09.009PubMedGoogle ScholarCrossref
6.
Kuitunen  M, Kukkonen  K, Juntunen-Backman  K,  et al.  Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.  J Allergy Clin Immunol. 2009;123(2):335-341. doi:10.1016/j.jaci.2008.11.019PubMedGoogle ScholarCrossref
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