# The oral-gut axis in colorectal cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $580,822

## Abstract

PROJECT SUMMARY/ABSTRACT:
Microbes have been implicated in colorectal cancer (CRC) pathogenesis, but definitive knowledge awaits of
the identities of contributing microbes and their biologic effects. There is a critical need to fill this knowledge
gap, because advances in understanding the roles of microbes in CRC pathogenesis will offer new insights
into how CRCs arise and progress along highlighting potential new approaches to prevent and treat CRC by
targeting microbial pathways. It has been reported that selected oral microbes are enriched in the “gut” of
patients with CRC. This finding implicates a potential “oral-gut axis” in CRC. We previously found that oral
inflammation, such as periodontitis, induces aberrant expansion of oral pathobionts, which can translocate to
the distal gastrointestinal tract and ectopically colonize. Consistent with the potential pathogenic role of oral
inflammation in gastrointestinal disease phenotypes, a large human cohort study revealed that periodontal
disease is a risk factor for CRC. A key long-term goal of this project is to define specific oral microbes
associated with CRC and inhibit their contributions to CRC. We have examined the influence of periodontal
inflammation on the development of CRC, using mouse models addressing both periodontitis and CRC. Our
preliminary results demonstrate the following: (i) periodontitis facilitates colonic tumorigenesis in the AOM/DSS
colitis-associated CRC model; (ii) periodontitis leads to the aberrant accumulation of genotoxic bacteria
(colibactin-producing pks+ Escherichia coli) in the oral cavity; (iii) amassed oral genotoxic pks+ E. coli may
translocate to the gut and ectopically colonize; (iv) gut colonization by oral pks+ E. coli promotes the
development of CRC through colibactin; and (v) oral Streptococcus species that co-expand with pks+ E. coli
during periodontal inflammation promote gut colonization by oral pks+ E. coli. Based on these preliminary
results, the overarching hypothesis for this project is that poly-microbial interaction between oral microbes
promotes colonic tumorigenesis. We plan to further explore this hypothesis by pursuing the following two
specific aims: In Aim 1, we will determine the mechanisms by which oral bacteria associated with periodontal
inflammation cooperatively promote tumorigenesis in the colon. We hypothesize oral Streptococcus species
promote the colonization of pks+ E. coli in the colonic epithelium, thereby leading to enhanced tumorigenesis.
In Aim 2, we will clarify the role of colibactin in ectopic gut colonization by oral pks+ E. coli. We hypothesize
colibactin is required to maximize the fitness of E. coli during oral inflammation, stability of the bacterium during
niche relocation, and ectopic gut colonization of the bacterium. The completion of the proposed research will
yield impactful insights into how oral pathobionts contribute to CRC pathogenesis and the findings will clarify
how to develop new therapies for CRC ...

## Key facts

- **NIH application ID:** 10851467
- **Project number:** 1R01CA288546-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nobuhiko Kamada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $580,822
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851467

## Citation

> US National Institutes of Health, RePORTER application 10851467, The oral-gut axis in colorectal cancer (1R01CA288546-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10851467. Licensed CC0.

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