Infant Gut Microbiome Associated With Cognitive Development

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.

Keywords: Brain; Cognition; Gut; Infant; MRI; Microbiota.

Figure 1. Infant gut microbiome at 1 year of age clusters into three groups

A. Distance metrics (unweighted Unifrac, weighted Unifrac, Jensen-Shannon, Root Jensen-Shannon, Bray-Curtis) were scored with average silhouette width (SW), Calinski-Harabasz (CH), and prediction strength to identify the number of clusters with most support. Modest support for clustering into three groups was supported by SW and CH. B. (Top) Boxplots of genera selected as seed regions for co-occurrence networks. (Bottom) Co-occurrence networks show positive and negative correlations between different genera.

Figure 2. Performance on Mullen Scales of Early Learning at 2 years of age differs between clusters

A. Individual value plot showing performance on the Mullen Early Learning Composite by cluster (p-value = 0.006). B. Individual value plot showing secondary analysis of the Mullen Scale performance by cluster (receptive language q-value = 0.005, expressive language q-value = 0.005). Covariates for both analyses: cesarean section, paternal ethnicity, currently breastfeeding, sex, maternal education, paternal age, paternal ethnicity, twin status, income.

Figure 3. Alpha diversity is negatively correlated with cognitive scores at 2 years of age

A. Plots of primary analysis, Early Learning Composite versus alpha diversity measures, show negative correlations. Covariates: older siblings, paternal ethnicity, sex, maternal education, paternal age, twin status, income B. Secondary analyses with the separate Mullen Scales show a negative association of expressive language with alpha diversity. Covariates: older siblings, paternal ethnicity, sex, maternal education, paternal age, twin status, income.

Figure 4. Clusters differ by three measures of alpha diversity

Individual value plots of Faith’s Phylogenetic Diversity, Shannon Index, Observed Species, and Chao1 by cluster. Covariates: cesarean section, paternal ethnicity, currently breastfeeding, older siblings.

Figure 5. Change in receptive language and expressive language scales from 1 to 2 years of age differs between clusters

Plot of average raw scores by cluster from 1 to 2 years of age. (receptive language q=0.007, expressive language q=0.007) Covariates: sex, age at Mullen testing, maternal education, paternal education, paternal ethnicity, twin status, total household income, maternal psychiatric history