# Microbiota-dependent regulation of the gut-brain axis

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $211,875

## Abstract

Project Summary
Inflammatory bowel disease (IBD) is often neuropsychiatric disorders, such as anxiety, depression and panic
disorders. However, the etiology of IBD-associated neuropsychiatric disorders remains understudied. The
focus of this R21 research proposal is to define the molecular and cellular mechanisms through
which changes in the intestinal microbiota influence neuronal circuits and brain health that underlie
neuropsychiatric disorders associated with IBD.
The microbiota is known to regulate mammalian physiology, metabolism and immune homeostasis, and
dysbiosis has been linked to the pathogenesis of diverse diseases including IBD. Recently, there is increasing
evidence that changes in the intestinal microbiota can have a direct impact on the brain. Studies have
reported correlations between gastrointestinal abnormalities and neuropsychiatric disorders, such as autism,
cerebral palsy and depression. Animal studies indicate that the absence or modification of the gut microbiota
affects neurogenesis, cortical myelination, as well as a variety of behaviors, such as stress, anxiety, cognitive
behaviors and panic disorders. Metabolomic studies have shown that metabolites derived from the microbiota
and host metabolites altered by the microbiota may influence metabolic, immunologic, and behavioral
phenotypes in mice and humans. Collectively, these studies suggest that altered microbiota in IBD
patients may contribute to the neuropsychiatric comorbidities associated with IBD.
In preliminary analyses, we employed treatment of wild-type mice with a cocktail of broad-spectrum
antibiotics to significantly alter the microbiota and examined host behavior in the fear extinction test – a pre-
clinical model of fear-related anxiety disorders. Direct manipulation of the microbiota had a profound effect
on fear extinction in these mice. Moreover, GF mice exhibited similar defects in fear extinction that was
associated with significantly decreased levels of serum serotonin and dopamine, both of which are reported
to play important roles in fear extinction. These findings indicate that the microbiota has an effect on
host behavior in the fear extinction model.
To dissect the mechanisms by which changes in the intestinal microbiota influence brain function and
behavior, in Aim 1, we will employ in vivo two-photon microscopy to directly test whether manipulation of the
intestinal microbiota influences neuronal synapse remodeling in mice in the context of fear extinction. In Aim
2, we will employ comparative metabolomics to test how changes in the microbiota influence the metabolite
profile in mouse serum and CSF in the context of fear extinction. Using these combined approaches of
manipulating the microbiota, coupled with cutting-edge methods of live neuronal imaging and metabolomic
profiling, we will generate fundamental new insights into how alterations in the intestinal microbiota
are associated with the neuropsychiatric comorbidities associated with IBD...

## Key facts

- **NIH application ID:** 10007755
- **Project number:** 5R21AI142213-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** David Artis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2019-09-05 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007755

## Citation

> US National Institutes of Health, RePORTER application 10007755, Microbiota-dependent regulation of the gut-brain axis (5R21AI142213-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10007755. Licensed CC0.

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