Background: Early host-microbe interaction provides important maturational stimuli for the developing immune system. The role of prenatal microbial contact remains elusive. Objectives: Our aim was to investigate whether microbes in placenta or amniotic fluid affect fetal innate immune gene expression during late pregnancy and whether innate immune gene expression profiles in the placenta and the fetal gut may be modulated by dietary supplementation with specific probiotics. Methods: Altogether 43 pregnant women were randomized to receive (1) Bifidobacterium lactis, (2) B. lactis in combination with Lactobacillus rhamnosus GG (LGG) or (3) placebo for 14 days before elective cesarian section at full term in a double-blind clinical trial. Bacteria in amniotic fluid and placenta were detected by quantitative (q)PCR. The expression of Toll-like receptor (TLR)-related genes in the placenta and meconium samples was assessed by qPCR. Gene expression patterns in meconium were interpreted to reflect immune physiology in the fetal gut. Results: The study was completed by 29 mother-infant pairs. Bacterial DNA was detected in all placenta samples. Microbial DNA in amniotic fluid and placenta was associated with changes in TLR-related gene expression in the fetal intestine. Maternal probiotic supplementation significantly modulated the expression of TLR-related genes both in the placenta and in the fetal gut. Conclusions: Microbial contact in utero is associated with changes in fetal intestinal innate immune gene expression profile. Fetal and placental immune physiology may be modulated by maternal dietary intervention using specific probiotics.

Keywords:
Fetal origins, Immunology, Neonatal immune function, Placenta, Probiotics
1.
Mold JE, Michaelsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, Lee TH, Nixon DF, McCune JM: Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 2008;322:1562–1565.
2.
Barker DJ, Bagby SP, Hanson MA: Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2006;2:700–707.
3.
Rautava S, Kalliomäki M, Isolauri E: New therapeutic strategy for combating the increasing burden of allergic disease: probiotics. A nutrition, allergy, mucosal immunology and intestinal microbiota (NAMI) research group report. J Allergy Clin Immunol 2005;116:31–37.
4.
Roduit C, Wohlgensinger J, Frei R, Bitter S, Bieli C, Loeliger S, Buchele G, Riedler J, Dalphin JC, Remes S, Roponen M, Pekkanen J, Kabesch M, Schaub B, von Mutius E, Braun-Fahrländer C, Lauener R: Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis. J Allergy Clin Immunol 2011;127:179–185.
5.
Satokari R, Grönroos T, Laitinen K, Salminen S, Isolauri E: Bifidobacterium and Lactobacillus DNA in the human placenta. Lett Appl Microbiol 2009;48:8–12.
6.
Mshvildadze M, Neu J, Shuster J, Theriaque D, Li N, Mai V: Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. J Pediatr 2010;156:20–25.
7.
Collado MC, Isolauri E, Laitinen K, Salminen S: Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. Am J Clin Nutr 2010;92:1023–1030.
8.
Chapkin RS, Zhao C, Ivanov I, Davidson LA, Goldsby JS, Lupton JR, Mathai RA, Monaco MH, Rai D, Russell WM, Donovan SM, Dougherty ER: Noninvasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells. Am J Physiol Gastrointest Liver Physiol 2010;298:G582–589.
9.
Onderdonk AB, Delaney ML, DuBois AM, Allred EN, Leviton A: Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am J Obstet Gynecol 2008;198:110.e1–e7.
10.
Fichorovna RN, Onderdonk AB, Yamamoto H, Delaney ML, DuBois AM, Allred E, Leviton A: Maternal microbe-specific modulation of inflammatory response in extremely low-gestational-age newborns. MBio 2011;2:e00280–210.
11.
Conrad ML, Ferstl R, Teich R, Brand S, Blumer N, Yildirim AO, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H, Holst O, von Mutius E, Pfefferle PI, Kirschning CJ, Garn H, Renz H: Maternal TLR signalling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 2009;206:2869–2877.
12.
Zhu MJ, Du M, Nathanielsz PW, Ford SP: Maternal obesity up-regulates inflammatory signalling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta 2010;31:387–391.
13.
Luoto R, Laitinen K, Nermes M, Isolauri E: Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br J Nutr 2010;103:792–799.
14.
Luoto R, Kalliomäki M, Laitinen K, Isolauri E: The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int J Obes (Lond) 2010;34:1531–1537.
15.
Rautava S, Walker WA: Commensal bacteria and epithelial cross talk in the developing intestine. Curr Gastroenterol Rep 2007;9:385–392.
16.
Sudo N, Sawamura S, Tanaka K, Alba Y, Kubo C, Koga Y: The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997;159:1739–1745.
17.
Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT: Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010;328:228–231.
18.
Kalliomäki M, Collado MC, Salminen S, Isolauri E: Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 2008;87:534–538.
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2012
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