# Defining the role of short-chain fatty acids in adolescent opioid reinforcement and epigenetic regulation

> **NIH NIH K01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $108,394

## Abstract

PROJECT SUMMARY/ABSTRACT
Adolescence is the time of life when drug use is initiated; for this reason, adolescence represents a sensitive
period for the development of substance use disorder. Adolescents are undergoing many physiological
changes at this time, including marked changes in the medial prefrontal cortex (mPFC), a brain region
responsible for inhibiting motivational drive. However, changes in the brain are co-occurring with changes in
the periphery. The adolescent gut microbiome is also in flux and shifts in the predominant species of bacteria
during this time have been linked to systemic inflammation, anxiety-like behavior, and stress responses. There
is a growing appreciation for peripheral factors in psychiatric disturbance and our lab has shown that the gut
microbiome might contribute to substance use disorder. Our preliminary results indicate that adults with gut
microbiome depletion have altered cocaine conditioned place preference (CPP). However, adolescent, but not
adult, mice demonstrated decreased morphine CPP after short-term gut microbiome knockdown, suggesting
that adolescents are more sensitive to disruption of the gut microbiome. While the gut microbiome
communicates with the brain in more than one way, one major route of communication is via microbiome-
derived metabolites. The short chain fatty acids (SCFAs) are breakdown products of fiber; these metabolites
readily cross the blood brain barrier and act as histone deacetylase inhibitors. Given the ability of SCFAs to
alter histone post-translational modifications and likely gene expression, we performed transcriptomic profiling
of adolescent and adult mPFC after manipulation of the gut microbiome. Microbiome-depleted adolescent mice
treated with morphine had 3x the amount of differentially regulated genes compared to depleted adults given
morphine. Gene ontology analysis identified patterns of genes involved in chromatin modification including
enhanced activity of histone deacetylase inhibitors, decreased histone acetyltransferase activity, decreased
DNA binding, and decreased RNA transcription in adolescents with a reduced gut microbiome given morphine,
but not in similarly treated adults. Our previous studies have suggested that the reduction in SCFAs produced
by microbiome depletion might underlie modulation of drug reward; supplementation of SCFAs eliminated the
effect of microbiome knockdown on cocaine place preference. The current proposal will build upon our
preliminary results to investigate the role of the adolescent gut microbiome on fentanyl self-administration and
will seek mechanistic understanding of its influence by examining the contribution of gut microbiome-derived
metabolites in opioid reinforcement and chromatin modification in mPFC.

## Key facts

- **NIH application ID:** 10643363
- **Project number:** 7K01DA050906-03
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Rebecca Hofford
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $108,394
- **Award type:** 7
- **Project period:** 2021-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643363

## Citation

> US National Institutes of Health, RePORTER application 10643363, Defining the role of short-chain fatty acids in adolescent opioid reinforcement and epigenetic regulation (7K01DA050906-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10643363. Licensed CC0.

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