Atopic dermatitis prevention in children following maternal probiotic supplementation does not appear to be mediated by breast milk TSLP or TGF-β

Melanie Rae Simpson, Anne Dorthea Bjerkenes Rø, Øystein Grimstad, Roar Johnsen, Ola Storrø, Torbjørn Øien, Melanie Rae Simpson, Anne Dorthea Bjerkenes Rø, Øystein Grimstad, Roar Johnsen, Ola Storrø, Torbjørn Øien

Abstract

Background: The Probiotics in Prevention of Allergy among Children in Trondheim (ProPACT) study, a randomised, placebo controlled trial, demonstrated that maternal supplementation with probiotic milk reduced the incidence of atopic dermatitis (AD) in infancy. The mechanisms behind this effect are incompletely understood and breast milk cytokines have been postulated as possible mediating factors. In this study we aimed to assess whether breast milk TLSP and TGF-β are affected by a maternal probiotic supplementation regime, and their contribution to the preventive effect of this regime on AD in the offspring.

Methods: TSLP and TGF-β isoforms (TGF-β1, TGF-β2 and TGF-β3) were measured using ELISA and multiplex assays, respectively, in breast milk samples collected at 10 days and 3 months postpartum from women participating in the ProPACT trial (n = 259). The natural indirect and direct effects of maternal probiotics on AD, due to changes in breast milk cytokines, were estimated using causal mediation techniques.

Results: Probiotic supplementation tend to lead to high levels of breast milk TSLP at 10 days postpartum (p = 0.062), but this change did not contribute to the prevention of AD according to the mediation analysis. Probiotics had no apparent effect on TSLP at 3 months or TGF-βs at either time points. Thus, these are unlikely to be mediators of the effect of maternal probiotics on AD in offspring.

Conclusions: Whilst maternal probiotic supplementation resulted in higher breast milk concentrations of TLSP at 10 days postpartum, this does not appear to be a mechanism for prevention of AD by maternal probiotics. Trial registration The original trial protocol is registered in ClinicalTrials.gov (identifier NCT00159523).

Figures

Fig. 1
Fig. 1
Flow diagram of participants in the ProPACT study and cytokine analysis of breast milk samples. aThe provided values represent the number of eligible women who had provided at least one breast milk sample. The precise number of samples analysed for each cytokine at each time point varies and is provided in association with the relevant results. bComplete covariates additionally required information on maternal atopy, maternal smoking and the presence of older siblings
Fig. 2
Fig. 2
Breast milk TSLP concentrations at 10 days and 3 months in the probiotic and placebo groups. Proportion of breast milk samples with categorised TSLP concentrations at 10 days and 3 months postpartum in the placebo and probiotic group. Percentages are provided within the bars. Overall, higher concentrations of TSLP were measured significantly more often in samples collected at 10 days postpartum (p < 0.001 from ordinal logistic regression clustered by individual). Also on subgroup analysis, TSLP concentrations were significantly higher at 10 days in both the probiotic group (p < 0.001) and placebo group (p = 0.005)
Fig. 3
Fig. 3
Concentrations of TGF-β1, 2 and 3 at 10 days and 3 months. All three isoforms of TGF-β are found at statistically significantly lower levels at 3 months postpartum compared to 10 days postpartum (p 

Fig. 4

Hypothetical mediation analysis and estimated…

Fig. 4

Hypothetical mediation analysis and estimated natural indirect effect (NIE) and natural direct effect…

Fig. 4
Hypothetical mediation analysis and estimated natural indirect effect (NIE) and natural direct effect (NDE) of maternal probiotic supplementation. The NIE is an estimate of the effect of maternal probiotic ingestion on the development of AD in offspring mediated by increased TSLP levels in breast milk 10 days postpartum. The NDE is an estimate of the effect of maternal probiotic ingestion on the development of AD not mediated through changes in breast milk TSLP concentration 10 days postpartum. This analysis suggests that TSLP does not significantly contribute to, or oppose, the preventative effect of maternal perinatal probiotic supplementation on the development of atopic dermatitis
Fig. 4
Fig. 4
Hypothetical mediation analysis and estimated natural indirect effect (NIE) and natural direct effect (NDE) of maternal probiotic supplementation. The NIE is an estimate of the effect of maternal probiotic ingestion on the development of AD in offspring mediated by increased TSLP levels in breast milk 10 days postpartum. The NDE is an estimate of the effect of maternal probiotic ingestion on the development of AD not mediated through changes in breast milk TSLP concentration 10 days postpartum. This analysis suggests that TSLP does not significantly contribute to, or oppose, the preventative effect of maternal perinatal probiotic supplementation on the development of atopic dermatitis

References

    1. Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach JF, La Vecchia C. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology. 2012;23(3):402–414. doi: 10.1097/EDE.0b013e31824d5da2.
    1. Panduru M, Panduru NM, Salavastru CM, Tiplica GS. Probiotics and primary prevention of atopic dermatitis: a meta-analysis of randomized controlled studies. J Eur Acad Dermatol Venereol JEADV. 2015;29(2):232–242. doi: 10.1111/jdv.12496.
    1. Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163(3):616–623. doi: 10.1111/j.1365-2133.2010.09889.x.
    1. Dotterud CK, Avershina E, Sekelja M, Simpson MR, Rudi K, Storrø O, Johnsen R, Øien T. Does maternal perinatal probiotic supplementation alter the intestinal microbiota of mother and child. J Pediat Gastroent Nutr. 2015;61(2):200–2007. doi: 10.1097/MPG.0000000000000781.
    1. Hosea Blewett HJ, Cicalo MC, Holland CD, Field CJ. Chapter 2—The immunological components of human milk. In: Steve LT, editor. Advances in food and nutrition research. Cambridge: Academic Press; 2008. pp. 45–80.
    1. Ziegler SF. Thymic stromal lymphopoietin and allergic disease. J Allergy Clin Immunol. 2012;130(4):845–852. doi: 10.1016/j.jaci.2012.07.010.
    1. Gao P-S, Rafaels NM, Mu D, Hand T, Murray T, Boguniewicz M, Hata T, Schneider L, Hanifin JM, Gallo RL, et al. Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum. J Allergy Clin Immunol. 2010;125(6):1403.e1404–1407.e1404. doi: 10.1016/j.jaci.2010.03.016.
    1. Kim J, Kim BE, Lee J, Han Y, Jun H-Y, Kim H, Choi J, Leung DYM, Ahn K. Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol. 2016;137(4):1282.e1284–1285.e1284. doi: 10.1016/j.jaci.2015.12.1306.
    1. Tatsuno K, Fujiyama T, Yamaguchi H, Waki M, Tokura Y. TSLP directly interacts with skin-homing Th2 cells highly expressing its receptor to enhance IL-4 production in atopic dermatitis. J Invest Dermatol. 2015;135(12):3017–3024. doi: 10.1038/jid.2015.318.
    1. Schwartz C, Eberle JU, Hoyler T, Diefenbach A, Lechmann M, Voehringer D. Opposing functions of TSLP-responsive basophils and dendritic cells in a mouse model of atopic dermatitis. J Allergy Clin Immunol. 2016. doi:10.1016/j.jaci.2016.04.031.
    1. Macfarlane TV, Seager AL, Moller M, Morgan G, Thornton CA. Thymic stromal lymphopoietin is present in human breast milk. Pediatr Allergy Immunol. 2010;21(2 Pt 2):e454–e456. doi: 10.1111/j.1399-3038.2009.00916.x.
    1. Nakao A. The role and potential use of oral transforming growth factor-beta in the prevention of infant allergy. Clin Exp Allergy. 2010;40(5):725–730.
    1. Oddy WH, Rosales F. A systematic review of the importance of milk TGF-beta on immunological outcomes in the infant and young child. Pediatr Allergy Immunol. 2010;21(1 Pt 1):47–59. doi: 10.1111/j.1399-3038.2009.00913.x.
    1. Bottcher MF, Abrahamsson TR, Fredriksson M, Jakobsson T, Bjorksten B. Low breast milk TGF-beta2 is induced by Lactobacillus reuteri supplementation and associates with reduced risk of sensitization during infancy. Pediatr Allergy Immunol. 2008;19(6):497–504. doi: 10.1111/j.1399-3038.2007.00687.x.
    1. Kuitunen M, Kukkonen AK, Savilahti E. Impact of maternal allergy and use of probiotics during pregnancy on breast milk cytokines and food antibodies and development of allergy in children until 5 years. Int Arch Allergy Immunol. 2012;159(2):162–170. doi: 10.1159/000336157.
    1. Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol. 2002;109(1):119–121. doi: 10.1067/mai.2002.120273.
    1. Huurre A, Laitinen K, Rautava S, Korkeamaki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebo-controlled study. Clin Exp Allergy. 2008;38(8):1342–1348. doi: 10.1111/j.1365-2222.2008.03008.x.
    1. Prescott SL, Wickens K, Westcott L, Jung W, Currie H, Black PN, Stanley TV, Mitchell EA, Fitzharris P, Siebers R, et al. Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon-gamma and breast milk transforming growth factor-beta and immunoglobin A detection. Clin Exp Allergy. 2008;38(10):1606–1614. doi: 10.1111/j.1365-2222.2008.03061.x.
    1. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, Bingham EA, Finlay AY, Pembroke AC, Graham-Brown RA, et al. The U.K. working party’s diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383–396. doi: 10.1111/j.1365-2133.1994.tb08530.x.
    1. Simpson MR, Dotterud CK, Storrø O, Johnsen R, Øien T. Perinatal probiotic supplementaion in the prevention of allergy related disease: 6 year follow up of a randomised controlled trial. BMC Dermatol. 2015;15:13. doi: 10.1186/s12895-015-0030-1.
    1. Valeri L, Vanderweele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18(2):137–150. doi: 10.1037/a0031034.
    1. VanderWeele T. Explanation in causal inference: methods for mediation and interaction. Oxford: Oxford University Press; 2015.
    1. Liu H, Emsley R, Dunn G, VanderWeele T, Valeri L: PARAMED: Stata module to perform causal mediation analysis using parametric regression models. The Stata Journal 2014, Technical paper in preparation:Installation instructions for program code and help file available from: .
    1. Vickery BP, Scurlock AM, Jones SM, Burks AW. Mechanisms of immune tolerance relevant to food allergy. J Allergy Clin Immunol. 2011;127(3):576–584. doi: 10.1016/j.jaci.2010.12.1116.
    1. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostatis. Nat Rev Immunol. 2014;24(3):141–153. doi: 10.1038/nri3608.
    1. Ramirez-Santana C, Perez-Cano FJ, Audi C, Castell M, Moretones MG, Lopez-Sabater MC, Castellote C, Franch A. Effects of cooling and freezing storage on the stability of bioactive factors in human colostrum. J Dairy Sci. 2012;95(5):2319–2325. doi: 10.3168/jds.2011-5066.
    1. Pontes GN, Cardoso EC, Carneiro-Sampaio MMS, Markus RP. Pineal melatonin and the innate immune response: the TNF-alpha increase after cesarean section suppresses nocturnal melatonin production. J Pineal Res. 2007;43(4):365–371. doi: 10.1111/j.1600-079X.2007.00487.x.
    1. Saarela T, Kokkonen J, Koivisto M. Macronutrient and energy contents of human milk fractions during the first six months of lactation. Acta Paediatrica (Oslo, Norway: 1992) 2005;94(9):1176–1181. doi: 10.1080/08035250510036499.
    1. Filteau SM, Lietz G, Mulokozi G, Bilotta S, Henry CJK, Tomkins AM. Milk cytokines and subclinical breast inflammation in Tanzanian women: effects of dietary red palm oil or sunflower oil supplementation. Immunology. 1999;97(4):595–600. doi: 10.1046/j.1365-2567.1999.00834.x.
    1. Namachivayam K, Blanco CL, Frost BL, Reeves AA, Jagadeeswaran R, Mohankumar K, Safarulla A, Mandal P, Garzon SA, Raj JU, et al. Preterm human milk contains a large pool of latent TGF-beta, which can be activated by exogenous neuraminidase. Am J Physiol Gastrointest Liver Physiol. 2013;304(12):G1055–G1065. doi: 10.1152/ajpgi.00039.2013.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe