# Host DNA methylation as a mechanism of microbiome influence on internalizing behavior

> **NIH NIH R00** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2022 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
More than 5% of US children and 45% of US adolescents have anxiety or depression; these rates have
increased for over a decade. Anxiety and depression are highly comorbid internalizing mental disorders that
often start during childhood and are associated with abnormal hypothalamic-pituitary-adrenal (HPA) axis
function. Early life stress (ELS) increases vulnerability to anxiety and depression throughout life. Accumulating
evidence suggests that ELS may produce long-lasting changes in gut microbiota contributing to abnormal HPA
axis function and behavior, which could play a pivotal role in internalizing behaviors. Many avenues exist
whereby microbiome composition may influence behavior and physiology, one of which is through altering host
epigenetics. ELS reduces folate-producing strains in the gut microbiome and folate is a necessary component
for DNA methylation. Recent work highlights potential interactions between microbiome and host epigenome,
with microbiota involved in regulating the host response to environment signals such as ELS. It is unknown
whether ELS influences gut microbiome composition in early development in humans or how the microbiome
influences HPA activity and internalizing behavior. We hypothesize that early psychosocial stress decreases
folate-producing genre in the gut microbiome which influences HPA DNA methylation and internalizing
behavior. Elucidating how environment and gut microbiome influences behavior will provide insights for a new
generation of effective interventions and treatments for mental health. This proposal capitalizes on two existing
cohorts: the Environmental influences on Child Health Outcomes (ECHO; K99 Phase) and the Arizona Twin
Project (ATP; R00 Phase). Both cohorts have extensive longitudinal, affective behavioral phenotyping during
infancy, toddlerhood, and early childhood. Aim 1 will use existing ECHO longitudinal microbiome and ELS
metadata to determine if maternal depression during early childhood contributes to folate-producing relative
abundance. Aim 2 will determine if host DNA methylation is a mechanism by which the gut microbiota
composition influences internalizing behavior. The R00 Aims will extend our K99 results and determine if ELS
influences microbiome composition in adolescence and assess DNA methylation in relation to internalizing
behaviors. Using twin ACE models we can estimate the genetic and environmental influences of the
relationships between microbiome, DNA methylation, and internalizing behaviors. ACE model results will
pinpoint aspects of the environment, unconfounded by genetic influences that are crucial players in the
mechanistic pathway for mental health. Results will provide valuable information for the wider scientific
community in understanding early environmental influences on mental health through development.

## Key facts

- **NIH application ID:** 10531997
- **Project number:** 4R00HD099307-03
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Candace Renee Lewis
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-05-06 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531997

## Citation

> US National Institutes of Health, RePORTER application 10531997, Host DNA methylation as a mechanism of microbiome influence on internalizing behavior (4R00HD099307-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10531997. Licensed CC0.

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