# Detrimental effects of age-related gut dysbiosis on stroke outcomes are mediated via the aryl hydrocarbon receptor

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $32,683

## Abstract

Stroke is a leading cause of morbidity and mortality. The gut microbiota-immune-brain axis is a key regulator of
the immune response to stroke. Immune cells constantly adapt to the gut environment using specialized
receptors such as the ligand-activated transcription factor, aryl hydrocarbon receptor (AHR). AHR integrates
environmental, dietary, microbial, and metabolic cues to control the immune system. Moreover, accumulating
evidence implicates AHR in the inflammatory response to stroke. For example, elevated plasma levels of
endogenous AHR activators are positively correlated with infarct volume and mortality in stroke patients.
Recent data suggests that post-stroke inhibition of AHR can be neuroprotective. However, these data were
obtained from young male animal models. This distinction is important because stroke prevalence increases
with age and it disproportionately affects women. In this project, I will investigate whether age and sex affect
the neuroprotective effect of AHR inhibitors (AHRI). Further, age-related changes in the microbiota are
associated with shifts in the metabolic pathways that regulate AHR ligands. I hypothesize that the benefits of
post-stroke AHRI therapy are due to a reduction in the detrimental effects of gut dysbiosis. Using a reversible
middle-cerebral artery occlusion model (MCAO), I will examine whether post-stroke AHRI treatment of aged
mice of both sexes improves neurological outcomes. Additionally, I will determine whether AHRI reduces the
deleterious effects of experimentally-induced dysiosis after MCAO. Lastly, I will examine whether a
combination therapy with AHRI and fecal microbiota transplant (FMT) from youthful donors act synergistically
to improve stroke outcomes. Our preliminary data shows that AHR expression on flow-sorted immune cells
decreases with aging in the brain but increases with aging in the lamina propria of distal ileum and cecum. Our
results show that AHR expression is increased in gut immune cells of young mice after FMT from aged donors
(i.e. reflects the age of the donors). The results from this proposal can identify a molecular mechanism of the
gut-immune-brain axis dysfunction after stroke. Future management of stroke patients may involve acute AHRI
therapy with sub-acute manipulation of the gut microbiota via FMT from healthy donors.

## Key facts

- **NIH application ID:** 10217060
- **Project number:** 5F31NS118984-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Pedram Peesh
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $32,683
- **Award type:** 5
- **Project period:** 2020-06-16 → 2022-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217060

## Citation

> US National Institutes of Health, RePORTER application 10217060, Detrimental effects of age-related gut dysbiosis on stroke outcomes are mediated via the aryl hydrocarbon receptor (5F31NS118984-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217060. Licensed CC0.

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