Microbial colonization of the gut and brain development in infancy

HIV MICROBIOME WORKSHOP 2017

Disclosure InformationHIV Microbiome Workshop 2017Speaker: Rebecca Knickmeyer

I have the following financial relationships to disclose Grant/Research support from: Nestle/Wyeth

I will not discuss off label use or investigational use in my presentation.

The Microbiome-Gut-Brain-Axis

Figure from Collins et al. (2012) Nat Rev Microbiol

ANXIETY

10 wk

3 wk

Based on work by Neufeld et al (2011) Commun Integr Biol& Clarke et al (2012) Mol Psychiatry

The Importance of Infancy

Figure from Bokulich (2016) Sci Transl Med

Total Intracranial Volume

Neonate One Two Four Adult0

250000

500000

750000

1000000

1250000

1500000

1750000

mm

3

35% 82% 90% 96%

Percent of adult volume

Neo 1yr 2yrKnickmeyer et al (2008) J Neurosci

Tebbenkamp et al (2014) Curr Opin Neurol

Birnbaum et al (2014) Am J Psychiatry

The Importance of Infancy

Li et et al (2012) Cereb Cortex Gao et al (2014) Brain Structure and Function

Yuan et al (2014) Neuroimage

Study Design

Does the microbiome affect neurodevelopment in humans during this critical period?

Alexander Carlson

Andrea Azcarate-Peril

Subjects

Collect/Measure

Analysis

89 Infants1 Year of Age

Fecal Samples

n=89

Structural MRIn=46, n=27Functional

MRIN=39

1 & 2 Year Cognitive Scores

n=86,n=69

Microbiome Association with Cognitive

Outcomes, Brain Structure, and

Functional Connectivity

Carlson et al (2017) Biological Psychiatry

Infant Diversity

Infant Enterostates

Cognitive Performance at 2 Years of Age Differs by Cluster

Barbara Goldman

Cognitive Performance at 2 Years is Associated with Alpha Diversity

Change in Mullen Scores from 1 to 2 years Differs by Cluster

Clusters Differ in Predicted Gene Functions

-0.003

-0.002

-0.001

0

0.001

0.002

0.003

beta C2

beta C3

Year 1 Year 2

Cluster Right Superior Occipital

C2 > C3 > C1

Bilateral Caudate

C2 < C3 < C1

Alphadiversity NONE

Left Precentral (CH) ↑Left Amygdala (OS) ↑

Right Angular Gyrus (CH) ↑

Minimal Influence of Microbiome on Brain Volumes

Amygdala Functional Connectivity Differs between Clusters and Correlates with Alpha Diversity in One-Year Olds

Inter-network Connectivity Differs Between Clusters and Correlates with Alpha Diversity and Expressive Language Scores

Future Directions: Infant Anxiety

Fecal Samples Saliva Samples Blood Spots MRI

Cardiac Recording Strange Situation Masks Task

Future Directions: Moderators, Mechanisms, and Mice

Determine how host genetics influence microbial colonization during infancy.

Generate novel hypotheses about the biochemical pathways mediating microbial effects on the human brain using broad spectrum metabolomics.

Demonstrate causality by transplanted infant fecal microbiota into germ-free mice. Use mice for proof-of-principle “clinical trials”

investigating the functional benefits of probiotics and/or prebiotics on brain development

Positive Impact Modulation of gut microbiota may be a tractable strategy for

developing novel therapeutics for complex CNS disorders. Clinical and public health policy implications

Promote optimal development of the gut microbiome

Improve cognition

Reduce risk for psychiatric disorders

QUESTIONS?