# Alcohol, Gut Dysbiosis, Endotoxemia, and Colorectal Cancer

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2020 · $269,589

## Abstract

PROJECT SUMMARY
Alcohol consumption has been linked to increased risk of colorectal cancer (CRC). However, the underlying
mechanisms have not yet been fully defined. Emerging evidence from animal studies suggest that alcohol
associated gut dysbiosis and subsequent gut barrier dysfunctions and endotoxemia may be an important and
underexplored pathway. However, the impact of long-term alcohol intake on not only the taxonomic makeup
but also the functional capacity of the gut microbiome among healthy individuals has not been established, and
how these dysbiosis will influence colorectal carcinogenesis remain unknown. Alcohol-associated passage of
luminal endotoxin into systemic circulation is hypothesized to activate both adaptive and innate immune
systems characterized by a release of antibodies, cytokines, and other inflammatory mediators, which may
increase subsequent risk of inflammation related diseases, including obesity, and diabetes, both of which are
well-established risk factors for CRC. However, the role of endotoxemia in colorectal carcinogenesis has not
been studied. We therefore hypothesize that long-term alcohol intake induce gut dysbiosis, impair the gut
barrier function, and followed by endotoxemia and inflammation to increase risk of CRC. We will test this
hypothesis leveraging rich data collected a large and well-characterized prospective cohort (the Health
Professional Follow-up Study) with a healthy sub-cohort with stool collection and metagenomic and
metatranscriptomic profiling (Aim 1a) and 250 nested CRC cases and 250 controls with archived pre-
diagnostic blood and ongoing plasma proteomic profiling (Aim 1b and 1c). Specifically, we will investigate
whether long-term alcohol intake induce gut dysbiosis through perturbations in microbial composition (e.g.
Proteobacteria) and function of tumor-permissive immune signatures and procarcinogenic pathways among
healthy individuals (Aim 1a). We will also investigate whether alcohol-associated colorectal carcinogenesis is
mediated by gut barrier dysfunction and endotoxemia through first identifying circulating markers of gut wall
integrity loss, bacteria translocation, endotoxemia, inflammation associated with alcohol intake (Aim 1b), and
then investigate their associations with subsequent risk of CRC (Aim 1c). Our findings will provide novel
mechanistic insight into gut microbial and endotoxemia mediated pathogenesis of alcohol-related CRCs. We
will also provide clinically translatable data including specific microbial targets, and circulating biomarkers and
network that reflect susceptibilities to subsequent risk of alcohol-related CRCs.

## Key facts

- **NIH application ID:** 9895402
- **Project number:** 1R21AA027608-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Yin Cao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $269,589
- **Award type:** 1
- **Project period:** 2020-02-20 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895402

## Citation

> US National Institutes of Health, RePORTER application 9895402, Alcohol, Gut Dysbiosis, Endotoxemia, and Colorectal Cancer (1R21AA027608-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895402. Licensed CC0.

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