Maternal prenatal stress is associated with the infant intestinal microbiota
Introduction
Although the underlying mechanisms remain unclear, an increasing number of studies link maternal prenatal stress to infant physical development and health, and psychological functioning and behavior. Stress during pregnancy predisposes to premature birth and low birth weight (Mulder et al., 2002, Beydoun and Saftlas, 2008), eczema (Sausenthaler et al., 2009), asthma (Cookson et al., 2009), and respiratory, general and skin illnesses (Beijers et al., 2010). Regarding psychological functioning and behavior, children of prenatally stressed mothers often show more impulsivity, anxiety problems, ADHD symptoms, and worse cognitive and psychomotor development (Beydoun and Saftlas, 2008). Recently, the development of the infant gut microbiota has been put forward as a possible factor underlying the links between maternal prenatal stress and infant development (Beijers et al., 2014). Rhesus monkey infants whose mothers had experienced stress during late pregnancy, in the form of repeated exposure to an acoustic startle, had lower levels of Bifidobacteria and Lactobacilli and more diarrheic symptoms than the infants of non-stressed mothers (Bailey et al., 2004). Also, in adult mice a social stressor (i.e., social disruption) provoked a decrease in the relative abundance of the genus Bacteroides together with an increase in the relative abundance of the genus Clostridium (Bailey et al., 2011). The goal of the present study is to investigate the relation between maternal prenatal stress (i.e., reported stress and cortisol concentrations) and the development of infant intestinal microbiota and health in the first 110 days of life in humans.
The intestinal microbiota are known to play an important role in the maturation of an infant's gastro-intestinal tract, immunity, metabolism, as well as the hypothalamic-pituitary-adrenal system (Sudo et al., 2004, Dimmitt et al., 2010, Bäckhed, 2011). An aberrant acquisition of intestinal bacteria or a reduced complexity of the microbiota may delay immune maturation or alter the development of the immune system and stress responses (Sudo et al., 2004, Adlerberth and Wold, 2009, Sekirov et al., 2010). Bacterial colonization of the infant gut is thought to begin in utero (Gosalbes et al., 2013), and to accelerate dramatically during and after delivery, and during the first months of life (Palmer et al., 2007, Fallani et al., 2010). Microbes from the mother and, to a lesser extent, of the environment are thought to be the first colonizers of the infant's gut (Tannock et al., 1990, Gosalbes et al., 2013). After the initial establishment of the intestinal microbiota during the first year of life, the microbiota begins to stabilize to a unique individual composition, continuing to develop gradually throughout childhood and adolescence. To what extent the early colonization dictates later development and finally the stable adult composition, is currently unknown. Due to the intimate interaction between the developing intestinal microbiota and the immune system, the early-life development of the intestinal microbiota may have long-lasting consequences (Bäckhed, 2011).
Distortions in the intestinal microbiota are associated with a wide range of diseases, including the risk of diarrheal illness, food allergy, inflammatory diseases (atopic diseases and inflammatory bowel disease), irritable bowel syndrome, obesity, and diabetes (Sekirov et al., 2010). Furthermore, as is the case with irritable bowel syndrome, gut-related diseases can develop or worsen during stressful periods (O’Mahony et al., 2009, De Palma et al., 2014). This may be due to the bidirectional communication between the central nervous system (CNS) and the gut (brain-gut axis; Dinan and Cryan, 2012), where both the autonomic nervous system (ANS) and the hypothalamic pituitary adrenal (HPA) axis play important roles (Rhee et al., 2009). When the HPA axis is activated in reaction to stress, cortisol is produced as an end product. In rats, experimentally increased cortisone levels in pregnant females resulted in lower levels of total bacteria and gram negatives in the intestine of the pups (Schiffrin et al., 1993). This suggests that cortisone may influence the maternal microbiota, and thereby the transmission of bacteria to offspring. In humans it is as yet unknown if maternal prenatal psychological stress and cortisol concentrations are related to the infant gut microbiota.
The goal of the present human study is to prospectively investigate the relation between maternal prenatal stress and the development of infant intestinal microbiota and health in the first 110 days of life. A limitation of the Rhesus monkey study of Bailey et al. (2004) is that the intestinal microbiota analyses were carried out with traditional culturing approaches and were not able to show the more complex microbiota signatures. The present study avoids this limitation by using a high-throughput phylogenetic microarray (Rajilic-Stojanovic et al., 2009).
Section snippets
Participants and procedure
This project is part of an ongoing longitudinal study in which 192 children are followed from the third trimester of pregnancy on. Infants were healthy, born at full term (≥37 weeks) and had a 5-min APGAR score ≥7. Inclusion criteria were an uncomplicated, singleton pregnancy, clear understanding of the Dutch language, no drug use and no current physical health problems (see Beijers et al., 2010 or Tollenaar et al., 2011 for more details). All mothers gave written informed consent, and the
Correlations between prenatal stress and anxiety variables
None of the reported stress and anxiety variables was significantly correlated with the cortisol variables, indicating that cortisol and reported stress represent independent measures of stress. The questionnaire-based stress variables were weakly to moderately correlated (r ranging from 0.22 to 0.74), and the cortisol concentrations measured at different times of day were weakly to strongly correlated with each other (r ranging from 0.15 to 0.87).
Comparison of the different stress indicators
Based on the number of significantly associated
Maternal prenatal stress is associated with altered infant microbiota
We characterized the temporal dynamics of the human infant microbiota during the early stage of succession, using a phylogenetic microarray covering the majority of intestinal bacteria, in a cohort of 56 healthy, vaginally born infants, with varying exposure to maternal prenatal stress. Both maternal reported stress and salivary cortisol concentrations during late pregnancy were associated with dramatic shifts in the infant microbiota, which persisted until the end of the follow-up period at 16
Conclusion
In conclusion, maternal prenatal stress, based on questionnaires or on elevated basal cortisol concentrations, or on both, was strongly and persistently associated with the infants’ microbiota composition and colonization pattern. Furthermore, the altered colonization pattern appeared to predispose the infants to gastrointestinal symptoms and allergic reactions. This is the first study to show a link between maternal prenatal stress, and the infant intestinal microbiota in humans. These results
Role of the funding source
Research was funded by the Netherlands Organization for Scientific Research (NWO, Spinoza and Gravity (SIAM): WMdV/VIDI grant number 452-04-320: CdW), the Academy of Finland (grant number 141130 to WMdV), the Doctoral Program in Biomedicine, University of Helsinki (KK) and the Graduate school Behavioural Science Institute (grant number: 022.002.011: MACZ). The funding sources had no further role in study design, collection, analysis and interpretation of the data, in the writing of the report,
Conflict of interest statement
None declared.
Acknowledgements
The authors would like to thank the participants of the study.
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Note: Maartje A.C. Zijlmans and Katri Korpela: both first author.