# The gut microbiome, interactions with primed colon states, and effects on adenoma formation and progression

> **NIH NIH U54** · FRED HUTCHINSON CANCER CENTER · 2024 · $277,212

## Abstract

Project Summary
Emerging data have linked the gut microbiome to colorectal adenomas, the established early lesions in
colorectal cancer (CRC) and de facto targets during screening colonoscopy. However, deficit in our knowledge
of the basic science of the gut microbiome and the specific driver mechanisms for inducing adenoma formation
and progression has impeded translation. We hypothesize that the microbiome is an adenoma nonautonomous
inducer of colorectal “priming,” the term we use in this application to refer to molecular/cellular alterations
critical for adenoma formation and progression. The near-term objective of this proposal is to define whether
and how the microbiome and the primed colon act in concert to drive adenoma formation. The long-term
objective of this proposal is to develop microbiome-based strategies for precision prevention of adenomas and
ultimately CRC. In Aim 1, we will identify interdependencies of the microbiome and the primed colon. We will
leverage insights from a novel, validated metagenomic analysis. Using gnotobiotic mice, we will study
interactions between a primed colon, tumorigenic gut bacteria, and tumorigenesis. We use analytic approaches
such as mediation analysis to quantify the extent to which the microbiome and a primed colon each mediate
the other’s tumorigenic effects. In Aim 2, we will identify the adenoma-associated gut microbiome features that
characterize aggressive vs indolent adenomas in humans. We will analyze a unique cohort of longitudinally
monitored adenomas through deep sequencing, in situ bacterial imaging, rigorously defined genetic/molecular
profiles generated in Project 1, and machine learning to identify adenoma-associated microbiome features that
interact with primed colon attributes to drive adenoma progression. In Aim 3, we will determine if microbiome-
induced senescent fibroblasts drive progression behavior in adenoma cells in ex vivo adenoma organoids
through specific CRC-associated senescence-associated secretory phenotype (SASP) factors. Using primary
colon fibroblasts derived from gnotobiotic mice colonized with a CRC-associated bacterial consortium, we will
assess oncogenic effects on adenoma progression behavior in an ex vivo organoid model. We will determine
whether tumorigenic effects of the microbiome are mediated through induction of the senescent colon primed
state, and we will mechanistically test roles for candidate CRC-associated SASP factors in driving progression
behavior of adenoma cells in ex vivo human adenoma organoids. Our findings could serve as the basis for
biology-backed, intervenable, precision prevention of adenomas and ultimately CRC.

## Key facts

- **NIH application ID:** 10926955
- **Project number:** 5U54CA274374-03
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Neelendu Dey
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $277,212
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926955

## Citation

> US National Institutes of Health, RePORTER application 10926955, The gut microbiome, interactions with primed colon states, and effects on adenoma formation and progression (5U54CA274374-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10926955. Licensed CC0.

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