# Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology

> **NIH VA I21** · MINNEAPOLIS VA  MEDICAL CENTER · 2022 · —

## Abstract

Each year ~2 million adult Americans develop sepsis and nearly 270,000 Americans die as a result of sepsis.
In the U.S. VA health system in 2009, >35,000 Veterans were hospitalized with sepsis, and ~80% survived to
hospital discharge (current numbers are likely higher). Veterans also have a high rate of hospital readmission
following sepsis. Hospital costs associated with treating sepsis exceed $24B/year, making it the most
expensive medical condition treated in the U.S. Faced with costly and burdensome patient care, it is imperative
to better understand the pathophysiologic states experienced by these patients to deliver targeted care. Mice
are one of the most important tools used in biomedical research, due in part to their ability to model complex
physiological systems in humans. However, environmental microbial exposure is an important difference
between basic human and laboratory mouse biology that must be considered when using mouse models to
evaluate immune system fitness. Humans are naturally exposed to both commensal and pathogenic microbes
daily from birth, and the immune system of adult humans has been trained and shaped by each microbe. In
contrast, laboratory mice are often housed under specific pathogen-free (SPF) conditions. SPF housing has
been instrumental in increasing experimental reproducibility, but it has simultaneously further distanced the
mouse model from humans, largely because SPF mice live their lives with limited microbial exposure. Our
proposal will leverage a novel mouse model that mimics critical aspects of the human immune system – where
exposure to multiple ongoing and resolved infections is the norm. We will integrate transcriptomics,
metabolomics, proteomics, and cytokine profiling to define the molecular basis of the pathophysiology and
resolution of sepsis.
The proposed validation studies will be key for supporting the use of microbially-experienced ‘dirty’ mice in
sepsis research. There are no reported direct comparisons of immune responses in dirty septic mice to human
patients. We posit that direct comparison of acute response in septic patients to sepsis models in dirty mice will
show a closer correlation than the comparison between human and SPF mice. It has been argued that rodent
models do not resemble the pathophysiology of human sepsis, an assumption boosted by studies claiming the
molecular changes observed in human sepsis are different from the ones observed in rodents. Yet, the rodent
system is an invaluable tool to advance current understanding of the immune system that will produce
important information to understand septic pathology and provide clues for seeking ways to ameliorate the
conditions. The main concern raised about dirty mice is the potential of increased variability in the commensal
and pathogenic microbes they have encountered. If one intention of new mouse models for biomedical
research is to better model humans with a diverse microbial experience, then using mice with a similarly...

## Key facts

- **NIH application ID:** 10257687
- **Project number:** 1I21BX005679-01
- **Recipient organization:** MINNEAPOLIS VA  MEDICAL CENTER
- **Principal Investigator:** Thomas S Griffith
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257687

## Citation

> US National Institutes of Health, RePORTER application 10257687, Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology (1I21BX005679-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10257687. Licensed CC0.

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