# Impact of Stress on Alcohol-Associated Gut Injury and Systemic Response

> **NIH VA I01** · MEMPHIS VA MEDICAL CENTER · 2024 · —

## Abstract

Alcohol-associated diseases and disorders (AAD) account for over 5% of global health problems. AAD
is more common among veterans, and more than 30% of young men in the military are heavy drinkers, twice as
much as their civilian counterparts. Alcohol misuse is high in veterans exposed to combat-related traumatic
stress or experiencing post-traumatic stress disorder (PTSD). AAD and PTSD symptoms feedback into one
another and impede the recovery from both disorders. Therefore, treating AAD patients comorbid with PTSD is
complicated and requires a deeper understanding of the cross-talk between alcohol and stress. Behavioral
intervention is not efficacious in moderate to heavy alcohol drinkers, and its benefit in PTSD is inconsistent. The
common conditions associated with AAD and PTSD are endotoxemia and systemic inflammation. Clinical and
experimental evidence indicates that intestinal dysbiosis (depleted beneficial species, increased pathobionts,
and decreased diversity) is necessary for developing endotoxemia and systemic inflammation. Therefore,
dysbiosis is a crucial therapeutic target for treating AAD and PTSD. The critical barrier in this field is that the
mechanisms involved in alcohol and stress-induced dysbiosis are poorly defined. There is no treatment with
clear evidence of efficacy available for treating AAD or AAD comorbid with PTSD. Our long-term goal is to
describe the pathophysiology of AAD-stress comorbidity and develop novel therapeutic strategies by targeting
the gut microbiota. Our preliminary studies have identified that: 1) chronic restraint stress (CRS) and
corticosterone exacerbate ethanol (EtOH)-induced gut barrier dysfunction, endotoxemia, systemic inflammation,
liver damage, and neuroinflammation in mice. 2) Corticosterone reinforces EtOH-induced dysbiosis and
depletion of Paneth cell a-defensin mRNA. 3) Deleting intestinal glucocorticoid receptor (GR) prevents
corticosterone and EtOH-induced gut permeability and systemic response. 4) Knockout of intestinal NR3C1
(encoding GR) prevents corticosterone and EtOH-induced defensin mRNA depletion and dysbiosis. 5)
Corticosterone and EtOH reduce intestinal mRNA for T-cell receptor 4 (TCF4), the transcription factor required
for a-defensin production. These findings form the scientific premise and support
the central hypothesis that the Paneth cell GR drives stress and alcohol-associated dysbiosis, gut
permeability, and systemic responses by suppressing a-defensin production. Our overall objective is to define
the role of Paneth cell GR and the downstream mechanism in stress and alcohol-associated organ damage and
identify the therapeutic potential of a-defensins in treating AAD comorbid with chronic stress. This objective will
be achieved by determining that 1) Paneth cell GR is required for stress and alcohol-induced TCF4 down-
regulation, a-defensin depletion, and microbiota dysbiosis. 2) TCF4 down-regulation mediates GR's role in stress
and alcohol-induced a-defensin depletion...

## Key facts

- **NIH application ID:** 10744221
- **Project number:** 5I01BX003014-06
- **Recipient organization:** MEMPHIS VA MEDICAL CENTER
- **Principal Investigator:** RADHAKRISHNA RAO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744221

## Citation

> US National Institutes of Health, RePORTER application 10744221, Impact of Stress on Alcohol-Associated Gut Injury and Systemic Response (5I01BX003014-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10744221. Licensed CC0.

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