# Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $551,318

## Abstract

Many diseases of old age like colorectal cancer and Alzheimer’s disease, as well as the process of aging itself,
have been linked to changes in the composition of microbes in our gut. Moreover, the ability of our gut to exclude
toxic microbial components from our bloodstream (so-called gut barrier function) deteriorates with increasing
age and results in inflammation which, in-turn, can accelerate aging and promote various chronic diseases. Our
long-term goal is to identify bacteria with anti-aging, anti-inflammatory or other beneficial effects on human health
and to understand their mechanism of action. So far, we have discovered that Parabacteroides distasonis (Pd),
a normal gut bacterium, lowers inflammation and strengthens gut barrier function in mice. Furthermore, Pd
increased lifespan and slowed age-relator loss of vigor when fed to fruit flies. The objectives of this application
are to determine whether Pd can extend lifespan and healthspan in mice, understand the importance of a protein
involved in maintaining gut barrier function called ZO-1, and finally to identify the active factor of Pd and its target
molecule. We hypothesize that gut barrier function deteriorates during aging due to loss of ZO-1 expression,
resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of function. Furthermore,
specific gut bacteria, such as Pd, can be exploited to prevent or slow age-related gut barrier dysfunction, thereby
reducing inflammation and preserving health. The specific aims of the study are to: 1) determine if Pd can
increase lifespan and healthspan in mice; 1a) understand how proteins involved in gut barrier maintenance are
altered by aging and Pd exposure; 2) determine whether altering ZO-1 expression in the colon affects lifespan
and healthspan in mice; 3) identify the active factor of Pd; 3a) identify the mouse target of Pd and 4) determine
the mechanism of fruit fly lifespan extension by Pd. The aims of this study will be addressed by conducting
several inter-related experiments in cells, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier
function, inflammation and various measures of health throughout life, of mice fed diet with or without with added
Pd. Next, we will compare the same readouts between mice with normal, deleted and high ZO-1 expression in
the intestine. Importantly, mice will be subjected to a battery of tests to assess their frailty and cognitive
health – including several measures of memory and brain inflammation that have direct relevance to
Alzheimer’s disease and its Related Dementias (ADRD). To identify the active factor of Pd, we will identify
additional species of bacteria that are able to increase gut barrier function (via ZO-1) and find the genes they
have in common with Pd. These will then be mutated or transferred to other bacteria one by one. Finally, we will
delete the pyd gene, the fly version of ZO-1, and compare the lifespan and age-related loss of vigor t...

## Key facts

- **NIH application ID:** 10863931
- **Project number:** 5R01AG069917-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jimmy W Crott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $551,318
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863931

## Citation

> US National Institutes of Health, RePORTER application 10863931, Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan (5R01AG069917-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10863931. Licensed CC0.

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