# Targeting microbially-derived juvenile protective factors to resolve neuroinflammation and delirium

> **NIH NIH R03** · DUKE UNIVERSITY · 2020 · $161,000

## Abstract

ABSTRACT
Postoperative complications such as delirium represent an immense public health challenge that will continue to
intensify as life-expectancy and the number of surgeries during a lifespan continue to increase. Despite efforts
to optimize preventive measures, the incidence of postoperative delirium can affect up to 87% of older adults,
depending on age and surgical procedures, and remains without an effective treatment. Patients with mild-
cognitive impairment (MCI) are most at risk for developing postoperative delirium. Even routine surgical
procedures such as common knee replacement or fracture repair, may result in life-threatening outcomes
including increased risk for long-term cognitive dysfunction. Thus, new therapeutic strategies are urgently
needed. Our long-term goal is to define novel Juvenile Protective Factors (JPFs) derived from intestinal
microbiota and to determine their capacity to protect against the development and progression of aging-related
neurodegenerative and perioperative disorders. The objective here is to compare molecular signatures in
intestinal microbiome samples from healthy juveniles and patients at risk for developing postoperative delirium,
which includes older adults and adults with MCI. Our central hypothesis is that juvenile-associated intestinal
microbiota generate JPFs that confer resiliency to age-associated neuroinflammation and postoperative delirium.
This hypothesis will be tested by pursuing 2 specific aims: 1) analyze the bacterial communities and their
molecular signatures in juvenile, aged, and MCI fecal samples; and 2) determine the functional impact of different
human microbiota communities on postoperative neuroinflammation and delirium-like behavior. The feasibility of
collecting and analyzing these large datasets and models has been established in our laboratories by a unique
translational team. Our preliminary data provide evidence that specific metabolites, known to protect against
neuronal death, are enriched in feces from juvenile mice. In this innovative approach, we will transplant fecal
samples from donor human juvenile, elderly, or MCI patients into germ-free recipient mice in a clinically-relevant
surgical mouse model of postoperative neuroinflammation and delirium-like behaviors. Our rationale for the
proposed research is that successful completion will demonstrate a novel link between aging-related changes in
microbiota and resiliency to postoperative neuroinflammation and cognitive deficits. This work will be significant
by improving our understanding of how intestinal microbiota control fundamental brain pathology (ie,
neuroinflammation and cogntive decline) that may reveal a unique approach to effective treatment for
perioperative neurologic complications.

## Key facts

- **NIH application ID:** 9977764
- **Project number:** 5R03AG064260-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Niccolo Terrando
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,000
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977764

## Citation

> US National Institutes of Health, RePORTER application 9977764, Targeting microbially-derived juvenile protective factors to resolve neuroinflammation and delirium (5R03AG064260-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9977764. Licensed CC0.

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