Infant Gut Microbiome Associated With Cognitive Development

doi:10.1016/j.biopsych.2017.06.021

Biological Psychiatry

Volume 83, Issue 2, 15 January 2018, Pages 148-159

https://doi.org/10.1016/j.biopsych.2017.06.021 Get rights and content

Abstract

Background

Studies in rodents provide compelling evidence that microorganisms inhabiting the gut influence neurodevelopment. In particular, experimental manipulations that alter intestinal microbiota impact exploratory and communicative behaviors and cognitive performance. In humans, the first years of life are a dynamic time in gut colonization and brain development, but little is known about the relationship between these two processes.

Methods

We tested whether microbial composition at 1 year of age is associated with cognitive outcomes using the Mullen Scales of Early Learning and with global and regional brain volumes using structural magnetic resonance imaging at 1 and 2 years of age. Fecal samples were collected from 89 typically developing 1-year-olds. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa.

Results

Cluster analysis identified 3 groups of infants defined by their bacterial composition. Mullen scores at 2 years of age differed significantly between clusters. In addition, higher alpha diversity was associated with lower scores on the overall composite score, visual reception scale, and expressive language scale at 2 years of age. Exploratory analyses of neuroimaging data suggest the gut microbiome has minimal effects on regional brain volumes at 1 and 2 years of age.

Conclusions

This is the first study to demonstrate associations between the gut microbiota and cognition in human infants. As such, it represents an essential first step in translating animal data into the clinic.

Section snippets

Study Population

We recruited 89 1-year-old infants (twins and singletons) from two prospective longitudinal studies of early brain development at the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 30, 31, 35, 36. Exclusion criteria for the parent studies included fetal ultrasound abnormalities and major medical illness of the mother. Informed written consent was obtained from the parent/legal guardian of each subject. This study was approved by the Institutional Review Board of the

Infant Microbiota Cluster Into Three Groups

There was modest support for clustering subjects into three groups based on average silhouette width and Calinksi–Harabasz scoring (Figure 1A). The Jensen–Shannon distance metric scored highest for three groups and was used for subsequent analyses. Clusters differed in the abundance of many genera (Table S1 in Supplement 1), with cluster 1 (C1) characterized by a relatively high abundance of Faecalibacterium, cluster 2 (C2) by a relatively high abundance of Bacteroides, and cluster 3 (C3) by a

Discussion

There is increasing agreement from preclinical work that the gut microbiota influences brain development during a critical period in early life, resulting in long-term changes in behavior. This is the first study to show that variation in the human gut microbiome is associated with cognition in a cohort of typically developing infants during the hypothesized period of sensitivity. This study does not attempt to address a causative role in the observed relationships but is an important

Acknowledgments and Disclosures

This study was supported by National Institute of Health Grant Nos. T32 NS007432 (to ALC), P30 DK34987 (to MAA-P), R01 HD053000 (to JHG), U01 MH070890 (to JHG), R33 MH104330 (to RCK), and the Foundation of Hope for Research and Treatment of Mental Illness (to XG, JHG, RCK).

JHG, XG, ALT, and RCK conceptualized this study. Statistical analysis was done by KX, MA, and MAA. Image analysis was done by MAS. Behavior analysis was done by BDG. Microbiome analysis was done by MAA. Data curation was done

References (59)

T.R. Sampson et al.
Control of brain development, function, and behavior by the microbiome
Cell Host Microbe
(2015)
E.Y. Hsiao et al.
Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders
Cell
(2013)
E.E. Fröhlich et al.
Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication
Brain Behav Immun
(2016)
H.M. Savignac et al.
Bifidobacteria modulate cognitive processes in an anxious mouse strain
Behav Brain Res
(2015)
L. Desbonnet et al.
The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat
J Psychiatr Res
(2008)
S.M. Finegold et al.
Pyrosequencing study of fecal microflora of autistic and control children
Anaerobe
(2010)
L. Wang et al.
Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder
Mol Autism
(2013)
A. Tomova et al.
Gastrointestinal microbiota in children with autism in Slovakia
Physiol Behav
(2015)
H. Jiang et al.
Altered fecal microbiota composition in patients with major depressive disorder
Brain Behav Immun
(2015)
L.M. Christian et al.
Gut microbiome composition is associated with temperament during early childhood
Brain Behav Immun
(2015)

J.K. Goodrich et al.

Genetic determinants of the gut microbiome in UK twins correspondence

Cell Host Microbe

(2016)

A.D.D. Kostic et al.

The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes

Cell Host Microbe

(2015)

P.A. Yushkevich et al.

User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability

Neuroimage

(2006)

F. Bäckhed et al.

Dynamics and stabilization of the human gut microbiome during the first year of life

Cell Host Microbe

(2015)

D. Knights et al.

Rethinking enterotypes

Cell Host Microbe

(2014)

J.F. Cryan et al.

Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour

Nat Rev Neurosci

(2012)

G. De Palma et al.

Microbiota and host determinants of behavioural phenotype in maternally separated mice

Nat Commun

(2015)

R. Diaz Heijtz et al.

Normal gut microbiota modulates brain development and behavior

PNAS

(2011)

P. Zheng et al.

Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism

Mol Psychiatry

(2016)

K.A.M. Neufeld et al.

Effects of intestinal microbiota on anxiety-like behavior

Commun Integr Biol

(2011)

G. Clarke et al.

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner

Mol Psychiatry

(2012)

K.M. Neufeld et al.

Reduced anxiety-like behavior and central neurochemical change in germ-free mice

Neurogastroenterol Motil

(2011)

N. Sudo et al.

Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice

J Physiol

(2004)

P. Bercik et al.

The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice

Gastroenterology

(2011)

P. Luczynski et al.

Adult microbiota-deficient mice have distinct dendritic morphological changes: Differential effects in the amygdala and hippocampus

Eur J Neurosci

(2016)

S.C. Kleiman et al.

The intestinal microbiota in acute anorexia nervosa and during renourishment: Relationship to depression, anxiety, and eating disorder psychopathology

Psychosom Med

(2015)

J.M. Fernandez-Real et al.

Gut microbiota interacts with brain microstructure and function

J Clin Endocrinol Metab

(2015)

J.C. Madan et al.

Association of cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants

JAMA Pediatr

(2016)

N.A. Bokulich et al.

Antibiotics, birth mode, and diet shape microbiome maturation during early life

Sci Transl Med

(2016)

Cited by (334)

Infant microbes and metabolites point to childhood neurodevelopmental disorders
2024, Cell
This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.
The effects of fermented food consumption in pregnancy on neonatal and infant health: An integrative review
2024, Journal of Pediatric Nursing
This study was carried out to determine the effects of fermented food in maternal diet during pregnancy on neonatal and infant health.
Fermented food consumption positively affects microbiota development. It is widely acknowledged that maternal microbiota is a crucial component in the microbiota formation of the newborn. However, the short-term and long-term effects of fermented food consumption during pregnancy on newborns/infants have not been fully investigated so far.
The study included studies that were randomized controlled, quasi-experimental, pre-test and post-test controlled, cohort, descriptive and qualitative studies published in English with full-text access and with “moderate” or “strong” scores in quality assessment.
The researchers conducted research on Pubmed, Google Scholar, Web of Science, Scopus, Clinical Keys, Cochrane and Ebsco-Host databases without any time limitation.
As a result, 1419 articles were reviewed and five studies were selected among which two studies demonstrated that fermented food consumption during pregnancy may reduce the risk of atopic dermatitis in the infant, and another study indicated that it may reduce the risk of food protein-induced allergic proctocolitis. One cohort study also reported that fermented food consumption during pregnancy improved sleep duration while another cohort study pointed out that it increased the birth weight of infants.
Evidence supports the positive effects of including fermented foods in pregnancy nutrition on neonatal and infant health. Fermented products can be added to the daily diet as an alternative to probiotic supplements. By adding these foods to the nutritional guidelines, awareness of pregnant women can be raised.
Associations of maternal prenatal psychological symptoms and saliva cortisol with neonatal meconium microbiota: A cross-sectional study
2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Alterations in the diversity and relative abundances of the gut microbiome have been associated with a broad spectrum of medical conditions. Maternal psychological symptoms during pregnancy may impact on offspring development by altering the maternal and the foetal gut microbiome. We aimed to investigate whether self-reported maternal anxiety, depressive symptoms, and distress as well as saliva cortisol levels in late pregnancy alter the bacterial composition of the infant's meconium.
A total of N = 100 mother-infant pairs were included. Maternal psychological symptoms were measured using psychological questionnaires (EPDS, PSS-10, STAI) at 34–36 weeks gestation and salivary cortisol was measured at 34–36 and 38 weeks gestation. Infant meconium samples were collected in the first five days postpartum and analysed using 16S rRNA amplicon sequencing.
Correlations showed that lower alpha diversity of the meconium microbiome was significantly associated with increased maternal prenatal depressive symptoms in late gestation (τ = −0.15, p = .04). Increased saliva cortisol AUCg at T2 was significantly related to higher beta diversity of the meconium samples (Pr(>F) = 0.003*). Pseudomonas was the most abundant phylum and was associated with maternal saliva cortisol total decline. No other associations were found.
Maternal prenatal depressive symptoms are associated with infant faecal microbiome alpha diversity, whereas maternal saliva cortisol AUCg is linked to increased beta diversity and total decline related to increased Psuedomonas. Future studies are warranted to understand how these microbiota community alterations are linked to child health outcomes.
Causal relationship of gut microbiota and metabolites on cognitive performance: A mendelian randomization analysis
2024, Neurobiology of Disease
Emerging evidence has indicated that the alterations in gut microbiota and metabolites are associated with cognitive performance. However, whether these associations imply a causal relationship remains to be definitively established. Here, we conducted two-sample mendelian randomization (MR) studies to explore the causal effects of gut microbiota and metabolites on cognitive performance, using large-scale genome-wide association studies (GWASs). We identified seven positive causalities between host genetic-driven gut microbiota and cognitive performance, including Class Clostridia (p = 0.0002), Order Clostridiales (p = 8.12E-05), Family Rhodospirillaceae (p = 0.042) and Ruminococcustorquesgroup (p = 0.030), Dialister (p = 0.027), Paraprevotella (p = 0.037) and RuminococcaceaeUCG003 (p = 0.007) at the genus level. Additionally, a total of four higher abundance of gut microbiota traits were identified to be negatively related to cognitive performance, including genus Blautia (p = 0.013), LachnospiraceaeFCS020group (p = 0.035), LachnospiraceaeNK4A136group (p = 0.034) and Roseburia (p = 0.00016). In terms of plasma metabolites, we discovered eight positive and six negative relationships between genetic liability in metabolites and cognitive performance (all p < 0.05). No evidence was detected across a series of sensitivity analyses, including pleiotropy and heterogeneity. Collectively, our MR analyses revealed that gut microbiota and metabolites were causally connected with cognitive performance, which holds significant potential for shedding light on the early detection and diagnosis of cognitive impairment, offering valuable insights into this area of research.
An updated overview on the relationship between human gut microbiome dysbiosis and psychiatric and psychological disorders
2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
There is a lot of evidence establishing that nervous system development is related to the composition and functions of the gut microbiome. In addition, the central nervous system (CNS) controls the imbalance of the intestinal microbiota, constituting a bidirectional communication network. At present, various gut-brain crosstalk routes have been described, including immune, endocrine and neural circuits via the vagal pathway. Several empirical data have associated gut microbiota alterations (dysbiosis) with neuropsychiatric diseases, such as Alzheimer's disease, autism and Parkinson's disease, and with other psychological disorders, like anxiety and depression. Fecal microbiota transplantation (FMT) therapy has shown that the gut microbiota can transfer behavioral features to recipient animals, which provides strong evidence to establish a cause-effect relationship. Interventions, based on prebiotics, probiotics or synbiotics, have demonstrated an important influence of microbiota on neurological disorders by the synthesis of neuroactive compounds that interact with the nervous system and by the regulation of inflammatory and endocrine processes. Further research is needed to demonstrate the influence of gut microbiota dysbiosis on psychiatric and psychological disorders, and how microbiota-based interventions may be used as potential therapeutic tools.
Pediatric Nutrition: Implications for the Developing Microbiota–Gut–Brain Axis
2024, The Gut-Brain Axis, Second Edition
The first 1000 days of life represent a critical window of opportunity to optimize neurodevelopment, the failure of which can have long-term implications for both mental health and quality of life. There is increasing evidence of a bidirectional cross-talk between the microbiota, the gut, and the brain, known as the microbiome–gut–brain axis (MGBA). Nutrition in early life contributes to neurodevelopment directly and indirectly through the MGBA. Human milk contains nutrients and bioactive components that support brain development and establishment of a bifidobacteria-predominant microbiota and some studies report greater neurocognitive outcomes among breastfed compared to formula-fed infants. Most studies of the MGBA used rodents, however, the young pig has characteristics that make it a superior model for the human. Herein, we summarize the associations between the MGBA and neurocognitive development in human infants and describe the evidence for modulation of neurocognitive development by nutrients and milk bioactives in the young pig model.

View all citing articles on Scopus

View full text

Archival ReportInfant Gut Microbiome Associated With Cognitive Development

Abstract

Background

Methods

Results

Conclusions

Section snippets

Study Population

Infant Microbiota Cluster Into Three Groups

Discussion

Acknowledgments and Disclosures

Cell Host Microbe

Cell

Brain Behav Immun

Behav Brain Res

J Psychiatr Res

Anaerobe

Mol Autism

Physiol Behav

Brain Behav Immun

Brain Behav Immun

Cell Host Microbe

Cell Host Microbe

Neuroimage

Cell Host Microbe

Cell Host Microbe

Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour

Nat Rev Neurosci

Microbiota and host determinants of behavioural phenotype in maternally separated mice

Nat Commun

Normal gut microbiota modulates brain development and behavior

PNAS

Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism

Mol Psychiatry

Effects of intestinal microbiota on anxiety-like behavior

Commun Integr Biol

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner

Mol Psychiatry

Reduced anxiety-like behavior and central neurochemical change in germ-free mice

Neurogastroenterol Motil

Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice

J Physiol

The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice

Gastroenterology

Adult microbiota-deficient mice have distinct dendritic morphological changes: Differential effects in the amygdala and hippocampus

Eur J Neurosci

The intestinal microbiota in acute anorexia nervosa and during renourishment: Relationship to depression, anxiety, and eating disorder psychopathology

Psychosom Med

Gut microbiota interacts with brain microstructure and function

J Clin Endocrinol Metab

Association of cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants

JAMA Pediatr

Antibiotics, birth mode, and diet shape microbiome maturation during early life

Sci Transl Med

Archival Report
Infant Gut Microbiome Associated With Cognitive Development