# Aging-associated changes in gut microbiome drive sepsis severity

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2022 · $159,840

## Abstract

ABSTRACT:
It is well established that the incidence and severity of sepsis are increased in older adults, however, targeting
of aging-associated alterations in host immune responses has not been successful in clinical trials. As
gastrointestinal flora are the primary source of pathogenic bacteria causative of sepsis in the geriatric
population (contributing to pneumonia, urinary tract infections, and abdominal infection), we hypothesized that
sepsis severity reflects pathogenic shifts in the aging gut microbiome. The novel concept described in this
proposal not only addresses a key knowledge gap in sepsis research, but also offers a new conceptual theory
that will be the basis for robust future investigations into the management of sepsis in the aging population.
In preliminary studies, we demonstrated aging-induced accentuation of sepsis severity by using cecal ligation
and puncture (CLP), a gold standard model of gastrointestinal flora-induced sepsis. CLP-induced sepsis
severity was augmented in aged mice, yielding increased evidence of systemic inflammation, organ injury, and
mortality. Strikingly, this aging-associated augmentation of severity could be replicated in young mice by the
intraperitoneal injection of aged (but not young) stool. These findings suggest that the aged microbiome
(inclusive of microbiota and associated virulence factors) is the key driver of exaggerated sepsis severity
associated with aging. We have also demonstrated microbiota shifts towards known pathogenic genera with
aging and that live bacteria are necessary to cause this phenotype.
In this proposal, we will rigorously determine microbiota shifts throughout the murine lifespan and correlate
these shifts with divergence in fecal slurry induced sepsis severity (Aim 1). Secondly, in collaboration with the
Gnotobiotic Core at the University of Colorado, we will experimentally manipulate the gut microbiome of germ-
free mice to replicate either young or aged gut microbiome. We will then perform CLP on these animals and
measure disease severity (Aim 2). Lastly, we will manipulate the aged gut microbiome in vivo by employing
antibiotic therapy targeted for pathogenic genera demonstrated in our microbiome data. We will assess our
ability to alter sepsis severity through this pragmatic therapeutic strategy (Aim 3).
We believe that the proposed experiments will further our mechanistic understanding of the pathophysiology
underlying exaggerated sepsis severity in the aging population and identify novel, feasible, and clinically
relevant therapeutic targets. Furthermore, the work proposed in this application will allow Dr. Colbert to
develop a unique scientific niche bridging critical illness, host-pathogen interaction, and approaches to
microbiome biology.

## Key facts

- **NIH application ID:** 10434767
- **Project number:** 5K08AG061144-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James F Colbert
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $159,840
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434767

## Citation

> US National Institutes of Health, RePORTER application 10434767, Aging-associated changes in gut microbiome drive sepsis severity (5K08AG061144-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434767. Licensed CC0.

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