Samuli Rautava

Microbial contact during pregnancy, intestinal colonization and human disease.

Interaction with colonizing intestinal bacteria is essential for healthy intestinal and immunological development in infancy. Advances in understanding early host–microbe interactions indicate that this early microbial programming begins in utero and is substantially modulated by mode of birth, perinatal antibiotics and breastfeeding. Furthermore, it has become evident that this stepwise microbial colonization process, as well as immune and metabolic programming by the microbiota, might have a long-lasting influence on the risk of not only gastrointestinal disease, but also allergic, autoimmune and metabolic disease, in later life. Modulating early host–microbe interaction by maternal probiotic intervention during pregnancy and breastfeeding offers a promising novel tool to reduce the risk of disease. In this Review, we describe the current body of knowledge regarding perinatal microbial contact, initial intestinal colonization and its association with human disease, as well as means of modulating early host–microbe interaction to reduce the risk of disease in the child.

Mode of Delivery – Effects on Gut Microbiota and Humoral Immunity

Background: The rate of caesarean deliveries has increased 10-fold worldwide during the past decades. Objective: To evaluate differences in the establishment of gut microbiota in infants born by vaginal or caesarean delivery and its impact on mucosal immunity. Methods: Altogether, 165 consecutive children, prospectively followed from birth at our clinic in Turku, Finland, were gathered; 141 (85%) were born by vaginal delivery and 24 (15%) by caesarean section. Blood was drawn at physician visits for indirect evaluation of mucosal immunity by ELISPOT assay. Faecal samples were obtained for determination of the gut microbiota by fluorescence in situ hybridization of bacterial cells. Results: Infants delivered by caesarean section harboured fewer bifidobacteria at an early age and were shown to mount a stronger humoral immune response. At 1 month of age, the total gut bacterial cell counts per 1 g faeces were higher in vaginally delivered infants (9.9 × 109, 95% CI 7.9 × 109–1.2 × 1010) as compared to caesarean section delivered (3.1 × 109, 95% CI 1.1 × 109–8.6 × 109) (p = 0.001). This distinction was mainly due to the greater number of bifidobacteria in vaginally delivered infants (1.9 × 109, 95% CI 6.3 × 108–5.6 × 109 vs. 1.5 × 106, 95% CI 4.1 × 102–5.7 × 109, respectively) (p = 0.001). During the first year of life, the total number of IgA-, IgG- and IgM-secreting cells was lower (p = 0.03, p = 0.02, p = 0.11, respectively) in infants born by vaginal delivery than in those born by caesarean section, possibly reflecting excessive antigen exposure across the vulnerable gut barrier. Conclusions: Our findings demonstrate that the mode of delivery may have, possibly via gut microbiota development, significant effects on immunological functions in the infant (http://www.clinicaltrials.gov/ct/gui/show/NCT00167700).

Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid

Interaction with intestinal microbes in infancy has a profound impact on health and disease in later life through programming of immune and metabolic pathways. We collected maternal faeces, placenta, amniotic fluid, colostrum, meconium and infant faeces samples from 15 mother-infant pairs in an effort to rigorously investigate prenatal and neonatal microbial transfer and gut colonisation. To ensure sterile sampling, only deliveries at full term by elective caesarean section were studied. Microbiota composition and activity assessment by conventional bacterial culture, 16S rRNA gene pyrosequencing, quantitative PCR, and denaturing gradient gel electrophoresis revealed that the placenta and amniotic fluid harbour a distinct microbiota characterised by low richness, low diversity and the predominance of Proteobacteria. Shared features between the microbiota detected in the placenta and amniotic fluid and in infant meconium suggest microbial transfer at the foeto-maternal interface. At the age of 3–4 days, the infant gut microbiota composition begins to resemble that detected in colostrum. Based on these data, we propose that the stepwise microbial gut colonisation process may be initiated already prenatally by a distinct microbiota in the placenta and amniotic fluid. The link between the mother and the offspring is continued after birth by microbes present in breast milk.

The Hygiene Hypothesis of Atopic Disease—an Extended Version

The hygiene hypothesis of atopic disease suggests that environmental changes in the industrialized world have lead to reduced microbial contact at an early age and thus resulted in the growing epidemic of atopic eczema, allergic rhinoconjunctivitis, and asthma. The epidemiological findings have been combined with the Th1/Th2 paradigm of immune responsiveness to provide a coherent theory. Recent advances in epidemiology and immunology demonstrate, however, that the hygiene hypothesis may need to be extended in three respects. First, the importance of infections in causing immune deviance may be outweighed by other sources of microbial stimulation, perhaps most importantly by the indigenous intestinal microbiota. Second, immunomodulatory and suppressive immune responses complement the Th1/Th2 paradigm. Third, in addition to protection against atopy, protection against infectious, inflammatory, and autoimmune diseases may also depend upon healthy host-microbe interactions implicated in the hygiene hypothesis.

Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double‐blind placebo‐controlled study

Background The effects of breastfeeding and probiotics on infant sensitization still remain discrepant.

Specific probiotics in enhancing maturation of IgA responses in formula-fed infants

The first months of life represent a critical period for the maturation of the infants immune system and, thus, a window of opportunity for measures to reduce the risk of disease. We hypothesized that specific probiotics might promote mucosal immunologic maturation in formula-fed infants. The numbers of cows milk–specific and total IgA-secreting cells were measured at 3, 7, and 12 mo of age in a double-blind placebo-controlled study of 72 infants with early artificial feeding. The infants consumed infant formula supplemented with specific probiotics (Lactobacillus GG and Bifidobacterium lactis Bb-12) or placebo during the first year of life. Further analyses of the serum concentrations of the IgA-inducing cytokine TGF-β2 and the soluble innate microbial receptor sCD14 were conducted. The numbers of cows milk–specific IgA secreting cells were significantly higher in infants receiving probiotics compared with those receiving placebo (p = 0.045, ANOVA for repeated measures). At 12 mo of age, the serum concentrations of sCD14 were 1479 pg/mL [95% confidence interval (CI) 1373–1592] in infants receiving probiotics and 1291 pg/mL (95% CI 1152–1445) in infants receiving placebo (p = 0.046). Administration of the probiotics Lactobacillus GG and Bifidobacterium lactis Bb-12 at the time of introduction of cows milk in the infants diet results in cows milk–specific IgA antibody responsiveness that may be the result of increased production of sCD14.

Specific probiotics in reducing the risk of acute infections in infancy – a randomised, double-blind, placebo-controlled study

A randomised, double-blind, placebo-controlled study was conducted to determine whether probiotics might be effective in reducing the risk of infections in infancy. Infants requiring formula before the age of 2 months were recruited from community well-baby clinics. Infant formula supplemented with the probiotics Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb-12 or placebo was administered daily until the age of 12 months. Incidence of early infections (before the age of 7 months) and incidence of recurrent (three or more) infections during the first year of life were recorded as the main outcome measures of the study. During the first 7 months of life, seven out of thirty-two (22 %) infants receiving probiotics and twenty out of forty (50 %) infants receiving placebo experienced acute otitis media (risk ratio (RR) 0.44 (95 % CI 0.21, 0.90); P = 0.014) and antibiotics were prescribed for ten out of thirty-two (31 %) infants receiving probiotics and twenty-four out of forty (60 %) infants receiving placebo (RR 0.52 (95 % CI 0.29, 0.92); P = 0.015). During the first year of life, nine out of thirty-two (28 %) infants receiving probiotics and twenty-two out of forty (55 %) infants receiving placebo encountered recurrent respiratory infections (RR 0.51 (95 % CI 0.27, 0.95); P = 0.022). These data suggest that probiotics may offer a safe means of reducing the risk of early acute otitis media and antibiotic use and the risk of recurrent respiratory infections during the first year of life. Further clinical trials are warranted.

Probiotics Modulate Host-Microbe Interaction in the Placenta and Fetal Gut: A Randomized, Double-Blind, Placebo-Controlled Trial

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.

Role of probiotics in food hypersensitivity.

The definition of probiotics has evolved concomitant with a resurgence of research interest in host-microbe crosstalk. The original definition stated that the live active culture beneficially affects the host by improving its intestinal microbial balance, while current conceptions are based on target- and site- specific effects of clearly defined strains. The establishment of normal microbiota in the intestine represents a key process whereby the intestinal milieu is kept disease-free as it performs its dual function: mounting an inflammatory response to pathogens and maintaining hyporesponsiveness to innocuous antigens. Probiotic therapy is based on this concept of a healthy well-balanced gut microbiota. The probiotic performance of strains differs, however. Different bacteria have clearly defined adherence sites and immunological effects and divergent effects in the healthy versus inflamed mucosa. Hence, notwithstanding recent demonstrations of the important immunoregulatory potential of the healthy well-balanced gut microbiota, current probiotic research is directed towards identification of specific strains with anti-allergenic potential.

Academy of Breastfeeding Medicine Founder's Lecture 2008: Breastfeeding—An Extrauterine Link Between Mother and Child

In addition to a near-optimal combination of nutrients for the growing infant, breastmilk contains a wide array of bioactive molecules that are known to protect the infant against infectious disease and modulate the composition of the indigenous intestinal microbiota. A growing number of factors that modulate the infants immunophysiology have also been identified in breastmilk. We suggest that this early immunomodulation via breastmilk is vital for infant health and may explain the epidemiological data indicating that breastmilk reduces the risk of immunoinflammatory conditions in infancy and also later in life. The body of scientific data regarding the role of transforming growth factor-beta in breastmilk in enhancing healthy immune maturation and reducing the risk of disease is reviewed in this article.