Maternal prenatal stress, infant microbiota, brain, and behavioral development : The FinnBrain Birth Cohort Study

The gut microbiota and its manipulation have been shown to affect behavior and neurodevelopment in rodents. Likewise, maternal prenatal stress is known to influence offspring health and development as well as gut microbiota composition in rodents and non-human primates. However, how infant fecal microbiota is associated with infant behavioral and brain developmental phenotypes or with exposure to prenatal stress remains largely unknown. The first aim of this dissertation was to explore how infant fecal microbiota associates with temperament, emotional attention, and amygdala volume, all of which may relate to later socioemotional and behavioral development. The second aim was to investigate if maternal prenatal chronic psychological distress and chronic cortisol levels, which are measures of prenatal stress in this study, associate with infant fecal microbiota composition and diversity. The studies were conducted in the prospective, general population-based FinnBrain Birth Cohort Study. First, the results showed that early fecal microbiota composition was associated with temperament traits and attention bias towards fearful faces. Specifically, Bifidobacterium, Stroptococcus, and Atopobium were positively associated with positive emotionality, whereas Bifidobacterium was negatively and Clostridium was positively associated with greater attention bias towards fearful faces. Both temperament and attention bias towards faces showed an interaction by sex regarding fecal microbiota composition. The left amygdala volume as well as negative emotionality and fear reactivity were negatively associated with fecal microbiota diversity. Second, maternal prenatal stress associated with fecal microbiota composition, including increases in abundances of genera within the Proteobacteria phylum and decreases in Lactobacillus abundance. This dissertation argues that infant fecal microbiota associates with later brain and behavioral phenotypes and encourages future longitudinal and mechanistic studies. Likewise, we corroborate some earlier findings regarding maternal prenatal stress and infant fecal microbiota.Äidin raskaudenaikainen stressi, lapsen mikrobisto, käyttäytymisen ja aivojen kehitys Eläintöiden perusteella on ehdotettu, että suolistomikrobisto vaikuttaa aivojen toimintaan ja käyttäytymiseen. Lisäksi jyrsijöillä ja kädellisillä on osoitettu, että äidin raskaudenaikainen stressi vaikuttaa jälkeläisten kasvuun ja terveyteen sekä suolistomikrobiston koostumukseen. Vielä ei kuitenkaan täysin ymmärretä, että liittyykö äidin raskaudenaikainen stressi lapsen suolistomikrobiston koostumukseen tai liittyykö lapsen suolistomirkobiston koostumus varhaiseen käyttäytymiseen tai aivojen kehittymiseen ihmisillä. Tässä väitöskirjassa kartoitettiin FinnBrain-syntymäkohorttitutkimuksessa lapsen varhaisen mikrobiston yhteyksiä temperamenttiin, kasvoihin ja kasvojen ilmeisiin kohdistuvaan kognitiiviseen tarkkaavuuteen sekä mantelitumakkeen kokoon. Lisäksi väitöskirjassa tutkittiin äidin raskauden aikaisen pitkäaikaisten psyykkisten oireiden ja kortisolipitoisuuksien – joita käytettiin raskaudenaikaisen stressin mittareina tässä tutkimuksessa – yhteyksiä lapsen suolistomikrobiston koostumukseen ja monimuotoisuuteen. Lapsen suolistomikrobiston koostumus oli yhteydessä temperamenttiin ja varhaiseen pelokkaisiin kasvoihin kohdistuvaan tarkkaavaisuuteen. Bifidobacterium, Streptococcus, Atopobium bakteerisuvut olivat yhteydessä positiiviseen emotionaalisuuteen, ja toisaalta Clostridium ja Bifidobacterium suvut olivat yhteydessä pelokkaisiin kasvoisiin kohdistuvaan tarkkaavaisuuteen. Sukupuoli vaikutti suolistomikrobiston ja temperamentin sekä lapsen kasvoihin kohdistuvan tarkkaavaisuuden välisiin yhteyksiin. Suolistomikrobiston vähäisempi monimuotoisuus oli yhteydessä suurempaan vasemman mantelitumakkeen kokoon ja voimakkaampaan negatiiviseen emotionaalisuuteen ja pelkoreagoivuuteen. Äidin raskaudenaikaisten stressi oli yhteydessä Proteobakteereihin kuuluvien sukujen ja maitohappobakteerien pitoisuuksiin. Väitöskirjan löydökset tukevat väitettä, että suolistomikrobisto on yhteydessä aivojen kehitykseen ja käyttäytymiseen, mutta löydökset eivät vielä kerro taustalla olevista syy-seuraussuhteesta. Äidin raskaudenaikaisen stressin yhteydet lapsen suolistomikrobistoon vahvistivat jo aiemmin raportoituja löydöksiä

Interactions between cortisol and lipids in human milk

Background Human breast milk is one of the key early postnatal biological exposures for the developing child. It includes bioactive compounds, such as cortisol and fatty acids, which may be linked via the mother's lipid metabolism. Methods This study investigated the associations between cortisol and lipids in human milk at the infant age of 2.5 months. Human milk cortisol concentrations were measured using luminescence immunoassay, and two groups of milks (n = 50 each) were formed based on either high (> 10 nmol/L) or low (Results The percentage of phospholipid-rich lipids of total lipids was 33.08% +/- 1.33%. In triacylglycerol-rich lipids, high cortisol level in milk was associated with higher lauric (12:0, mass % and mg/mL), myristic (14:0, mass % and mg/mL), eicosenoic (20:1n - 9, mass %), docosenoic (22:1n - 9, mass %, and mg/mL) acids, and to lower palmitic acid (16:0, mass %) compared with low cortisol levels in milk. In phospholipid-rich lipids, high cortisol level was associated with higher myristic (14:0, mass %) and docosenoic (22:1n - 9, mass %) acids. After adjusting for pre-pregnancy BMI and sampling time by linear regression, the milk cortisol remained a significant predictor for lauric and myristic acids in triacylglycerol-rich lipids, and myristic and docosenoic acid in phospholipid-rich lipids (beta = 0.23 to 0.38 andp Conclusions This study revealed certain significant associations between milk cortisol and the fatty acid composition of human milk, indicating that cortisol might be one of the factors affecting the origin of the lipids in human milk.</div

Gut microbiota composition is associated with temperament traits in infants

Background: One of the key behavioral phenotypes in infancy are different temperament traits, and certain early life temperament traits have been shown to precede later mental health problems. Differences in the gut microbiota composition (GMC) have been suggested to link with neurodevelopment. For example, toddler temperament traits have been found to associate with differences in GMC; however, studies in infants are lacking although infancy is a rapid period of neurodevelopment as well as GM development. Thus, we aimed to investigate association between infant GMC and temperament. Methods: The study population (n = 301, 53% boys) was drawn from the FinnBrain Birth Cohort Study. Stool samples were collected from the 2.5-month-old infants and sequenced with 16S Illumina MiSeq platform. GMC taxonomic composition (at Genus and OTU level), observed sample clusters, diversity and richness were investigated in relation to the maternal reports of Infant Behavior Questionnaire -Revised (IBQ-R) at the age of 6 months. Results: Three sample clusters (Bifidobacterium/Enterobacteriaceae, Bacteroides, V. Dispar) based on GMC were identified, of which Bifidobacterium/Enterobacteriaceae–cluster presented with higher scores on the IBQ-R main dimension regulation and its subscale duration of orienting compared to Bacteroides-cluster. The clusters associated with temperament in a sex-dependent manner. The IBQ-R main dimension surgency (positive emotionality) was associated positively both with genus Bifidobacterium and Streptococcus. Alpha diversity had a negative association with negative emotionality and fear reactivity. Conclusion This is the first study demonstrating associations, but not causal connections, between GMC and temperament in young infants in a prospective design

Human milk cortisol concentration predicts experimentally induced infant fear reactivity: moderation by infant sex

Little consideration has been given to the possibility of human infant development being shaped via lactocrine programming, and by breast milk cortisol levels specifically. Despite animal models indicating that glucocorticoid (GC) exposure via lactation might modify brain development and behavior, only one study has reported that milk cortisol levels were positively associated with infant negative affectivity, especially fearfulness and sadness—early emerging risk factors for internalizing difficulties such as anxiety. The aim of the current study was to investigate whether human milk cortisol is associated with mother-reported fearfulness and experimentally induced infant fear reactivity. Mother-infant dyads (n = 65) enrolled in the FinnBrain Cohort Study participated. Breast milk samples were obtained 2.5 months postpartum, and milk cortisol concentrations were ascertained using validated luminescence immunoassay methodology. Infant fear reactivity was assessed using maternal reports 6 months postpartum and in a laboratory 8 months postpartum. There was a significant interaction between infant sex and milk cortisol such that higher milk cortisol was related to higher infant fear reactivity in a laboratory setting in girls (β = 0.36, p = .04) but not in boys (β = −0.15, p = .40). Milk cortisol was not associated with mother-reported infant fearfulness. Results suggest that higher human milk cortisol concentrations are associated with elevated experimentally induced fear in infancy. Findings support lactocrine programming, and suggest that mothers may “communicate” vital information about stressful environments via cortisol contained in breast milk, shaping girls’ early emotional reactivity.</p

Human milk metabolome is associated with symptoms of maternal psychological distress and milk cortisol

The composition of human milk is subject to considerable variation, but the effects of maternal stress are largely unknown. We studied differences in human milk metabolome between Finnish mothers (n = 120, secretors) with symptoms of prenatal symptoms of psychological distress and milk cortisol concentrations. Human milk samples acquired at 2.5 months postpartum were analyzed using targeted 1H NMR metabolomics. Self-reported scores for depression (EPDS), overall anxiety (SCL-90), and pregnancy-related anxiety (PRAQ) were used to evaluate psychological distress. Prenatal psychological distress was positively associated with concentrations of short-chain fatty acids, caprate, and hypoxanthine (q q < 0.05). Changes in the human milk metabolome were shown to be associated with maternal psychological distress and concentration of milk cortisol in a dissimilarly, suggesting alterations in bacterial and energy metabolism of the mother, respectively.</p

Gut microbiota composition is associated with temperament traits in infants

BackgroundOne of the key behavioral phenotypes in infancy are different temperament traits, and certain early life temperament traits have been shown to precede later mental health problems. Differences in the gut microbiota composition (GMC) have been suggested to link with neurodevelopment. For example, toddler temperament traits have been found to associate with differences in GMC; however, studies in infants are lacking although infancy is a rapid period of neurodevelopment as well as GM development. Thus, we aimed to investigate association between infant GMC and temperament.MethodsThe study population (n=301, 53% boys) was drawn from the FinnBrain Birth Cohort Study. Stool samples were collected from the 2.5-month-old infants and sequenced with 16S Illumina MiSeq platform. GMC taxonomic composition (at Genus and OTU level), observed sample clusters, diversity and richness were investigated in relation to the maternal reports of Infant Behavior Questionnaire -Revised (IBQ-R) at the age of 6 months. ResultsThree sample clusters (Bifidobacterium/Enterobacteriaceae, Bacteroides, V. Dispar) based on GMC were identified, of which Bifidobacterium/Enterobacteriaceae–cluster presented with higher scores on the IBQ-R main dimension regulation and its subscale duration of orienting compared to Bacteroides-cluster. The clusters associated with temperament in a sex-dependent manner. The IBQ-R main dimension surgency (positive emotionality) was associated positively both with genus Bifidobacterium and Streptococcus. Alpha diversity had a negative association with negative emotionality and fear reactivity.ConclusionThis is the first study demonstrating associations, but not causal connections, between GMC and temperament in young infants in a prospective design. </p

Human milk: From complex tailored nutrition to bioactive impact on child cognition and behavior

Human milk is a highly complex liquid food tailor-made to match an infant's needs. Beyond documented positive effects of breastfeeding on infant and maternal health, there is increasing evidence that milk constituents also impact child neurodevelopment. Non-nutrient milk bioactives would contribute to the (long-term) development of child cognition and behavior, a process termed 'Lactocrine Programming'. In this review we discuss the current state of the field on human milk composition and its links with child cognitive and behavioral development. To promote state-of-the-art methodologies and designs that facilitate data pooling and meta-analytic endeavors, we present detailed recommendations and best practices for future studies. Finally, we determine important scientific gaps that need to be filled to advance the field, and discuss innovative directions for future research. Unveiling the mechanisms underlying the links between human milk and child cognition and behavior will deepen our understanding of the broad functions of this complex liquid food, as well as provide necessary information for designing future interventions

Human milk: From complex tailored nutrition to bioactive impact on child cognition and behavior

Human milk is a highly complex liquid food tailor-made to match an infant's needs. Beyond documented positive effects of breastfeeding on infant and maternal health, there is increasing evidence that milk constituents also impact child neurodevelopment. Non-nutrient milk bioactives would contribute to the (long-term) development of child cognition and behavior, a process termed 'Lactocrine Programming'. In this review we discuss the current state of the field on human milk composition and its links with child cognitive and behavioral development. To promote state-of-the-art methodologies and designs that facilitate data pooling and meta-analytic endeavors, we present detailed recommendations and best practices for future studies. Finally, we determine important scientific gaps that need to be filled to advance the field, and discuss innovative directions for future research. Unveiling the mechanisms underlying the links between human milk and child cognition and behavior will deepen our understanding of the broad functions of this complex liquid food, as well as provide necessary information for designing future interventions.All authors participated in the four-day hybrid meeting on ‘Lactational Programming: joining forces to optimize research on how maternal milk composition influences child cognition and behavior’ (Zeist, the Netherlands, 16-19 November 2020), which was financed by an Early Career Partnership 2020 Grant of the Royal Netherlands Academy of Arts and Sciences (awarded to Beijers). Funding sources for individual authors: Netherlands Organization for Scientific Research VICI grant (016.Vici.185.038-to de Weerth), The National Center for Advancing Translational Sciences Clinical Science and Translational Award (UL1TR001863-to Dettmer), NWO Food Cognition and Behaviour (057-14-003-to Korosi), Turku University Foundation, Maire Taponen Foundation and Finnish Psychiatry Foundation (-to Aatsinki), Polish National Science Centre OPUS grant (2015/17/B/NZ8/02436 -to Ziomkiewicz), Canadian Research Chair in Human Nutrition and Metabolism and funding from Natural Science and Engineering Council of Canada NSERC (RGPIN-2017-04746-to Field), The USDA National Institute of Food and Agriculture Hatch Project (1021411-to Slupsky), USDA NRI (2007-35203-18098 and 2013-67016-20523-to Bartol), Spanish Ministry of Science and Innovation grant (PID2019-105606RB-I00-to Rodríguez), UC San Diego Chair of Collaborative Human Milk Research, endowed by the Family Larsson-Rosenquist Foundation, Switzerland (-to Bode), Wellcome Trust (220225/Z/20/Z-to Moore), Tier 2 Canada Research Chair and Fellow in the CIFAR Humans and the Microbiome Program, Canadian Institutes of Health Research (CIHR), Research Manitoba, the Canada Foundation for Innovation, the Bill and Melinda Gates Foundation, the Manitoba Children’s Hospital Foundation, Prolacta Biosciences, Mitacs, CIFAR, and the Garfield G. Weston Foundation (-to Azad), CIHR Vanier Canada Graduate Scholarship (-to Turner), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC starting grant, no. 639226-to Collado), Netherlands Organization for Scientific Research VENI grant (016.195.197-to Beijers).Peer reviewe

Associations between maternal socioeconomic, psychosocial and seasonal factors, infant characteristics and human milk cortisol concentrations

Published online: 04 January 2021Objectives: Glucocorticoids are one component of human milk (HM) potentially affecting offspring development. Previous studies have identified various maternal, obstetric and socioeconomic characteristics that are associated with HM cortisol concentration but the literature is still scarce concerning these determinants in human populations. We aimed to identify which factors are linked with HM cortisol concentration at 2 months postpartum. Methods: We analyzed data from 340 lactating Finnish mothers using ordinary least squares regression with log-transformed HM cortisol concentration as the dependent variable. Potential predictors included obstetric and maternal factors (maternal age, parity status, delivery mode, gestational age, pre-pregnancy obesity, and smoking in pregnancy), socioeconomic status (education and socioeconomic class), subjective economic well-being, maternal psychosocial factors (postpartum depression and anxiety symptoms), infant sex and age, and HM sample characteristics (time of the day and season of the year at sample collection). Results: The strongest and most robust predictors were season of the year of sample collection and parity status. HM cortisol concentration was significantly higher for primiparas than multiparas. HM samples collected in summer showed significantly higher cortisol concentrations than those collected in winter, spring or autumn. Conclusions: The findings suggest that parity and season of the year at sample collection may be important factors to control for when examining HM cortisol. The strongest and most robust associations were related to maternal and sample characteristics and not to socioeconomic and psychosocial distress. This may be related to the fact that the study was conducted in a low-risk population