# A translational approach to interrogate the gut microbiome in sepsis-associated acute kidney injury

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,094

## Abstract

PROJECT SUMMARY
Sepsis, a syndrome of life-threatening organ dysfunction associated with the host response to infection, afflicts
approximately 50 million people worldwide annually. Acute kidney injury (AKI) is a frequent complication of
sepsis, contributing to morbidity, mortality, and increased costs, yet we still do not understand why some septic
patients develop AKI while others do not. This clinical heterogeneity has been a major barrier to progress in
clinical practice and research. In both animal models and humans, the bacterial communities of the gut are
associated with the severity of systemic injury and risk of death in critical illness. Yet, to date, the contribution
of gut microbiota to the pathogenesis of sepsis-associated AKI has been unexplored in both experimental
models and human cohort studies. In pilot work, I have discovered that among genetically-identical but
microbiologically-divergent mice with sepsis, the community composition of cecal microbiota is significantly
associated with the severity of AKI. A single bacterial family (Lachnospiraceae) explains 25% of the variation in
kidney injury severity. Further, in a retrospective cohort study of patients with suspected sepsis, I have found
that early exposure to anti-anaerobic antibiotics (which deplete the gut of anaerobic commensals) increases
patients’ risk of developing AKI (odds ratio 1.68, adjusted for confounders). Therefore, in this proposal, I seek
to establish and interrogate the gut microbiome as a source of biological heterogeneity in sepsis. My rationale
is that the gut microbiome is an unexplored therapeutic target for the prevention and treatment of AKI. This
proposal will test the hypothesis that the gut microbiome contributes to the pathogenesis of sepsis-associated
AKI. I will test this hypothesis through two Specific Aims: 1) Identify and interrogate the gut bacteria in human
patients that predict the onset and outcomes of sepsis-associated AKI; and 2) Determine the microbially-
derived mediators of AKI in a murine model of sepsis. Experiments for these Aims will be completed with the
use of 1) a large biorepository of human rectal swabs collected at the University of Michigan from 2016 to 2020
and 2) a well-established murine model of sepsis and experimental gut microbiome modulation techniques.
The results from these innovative studies may identify novel therapeutic targets for the prevention and
treatment of AKI and its complications. In executing this research plan, I will receive rigorous training in
experimental design, implementation, and interpretation that will help me become a successful, independent
scientist.

## Key facts

- **NIH application ID:** 10995018
- **Project number:** 1F31DK138603-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katherine Winner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,094
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995018

## Citation

> US National Institutes of Health, RePORTER application 10995018, A translational approach to interrogate the gut microbiome in sepsis-associated acute kidney injury (1F31DK138603-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10995018. Licensed CC0.

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