Variation in the infant gut microbiome is associated with cognitive development and brain morphometry

Abstract

BACKGROUND: Studies conducted in rodents provide compelling evidence that the gut microbiome influences brain development and function. In particular, experimental manipulations which alter the intestinal microbiota impact exploratory, social, and communicative behaviors, as well as cognitive performance. In humans, altered gut microbiota have been reported in individuals with autism and depression, but no studies have addressed when these relationships emerge or directly examined which brain regions may be involved. Early development is likely of critical importance as the first year of life is the foundational period for microbial colonization of the gut and the most rapid and dynamic phase of postnatal brain development. The objective of the current study was to determine how microbial composition at 1 year of age impacts cognitive development and to identify neural circuits mediating this relationship using high resolution magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and resting state fMRI (rfcMRI). METHODS: Fecal samples were collected from 89 typically developing one-year old infants. 16s rRNA amplicon sequencing was used for identification and relative quantification of bacterial taxa. Measures of alpha diversity were generated and distance metrics and cluster scoring methods were used to identify genus level enterotypes. Cognition was assessed at 1 and 2 years of age using the Mullen Scales of Early Learning. Brain scans were acquired on a Siemens head-only 3T TIM-Trio scanner (Siemens Medical System, Erlangen, Germany) during unsedated natural sleep. RESULTS: There was moderate support for clustering subjects into three enterotypes by the relative abundance of different bacterial genera. One cluster was characterized by high levels of Faecelibacterium, one by high levels of Bacteroides, and one by high levels of an unclassified genus of Ruminococcaceae. Mullen scores at age 2 differed significantly between clusters with the cluster characterized by Bacteroides abundance showing higher cognitive ability on the overall composite score as well as the expressive language subscale. Alpha diversity measures were also significantly associated with overall composite score at age 2 and the expressive language subscale. Higher diversity was associated with poorer outcomes. Exploratory analyses of regional gray matter volumes in 46 1-year-old children suggested that the gut microbiome influences neural circuits for visual processing, emotion regulation, and reward. We are current testing whether these relationships are also evident when assessing anatomical and functional connectivity. CONCLUSION: Microbial colonization of the gut at 1 year of age predicts later cognitive development particularly in the area of communicative behavior, a key domain disrupted in many psychiatric disorders. Ongoing studies by our group are aimed at determining whether patterns of microbial colonization at 2 weeks and 1 year of age are related to other behaviors relevant to psychiatric risk including fear reactivity. We are also actively investigating the role of immune signaling molecules and tryptophan metabolism in mediating microbial effects on neurodevelopment in human infants. Ultimately this line of research is expected to identify early interventions and therapeutics to promote a healthy microbiome, thereby improving cognitive outcomes and reducing risk for psychiatric disorders.