# Spermidine as a New Therapy for Colitis and Chemopreventive for Colitis-associated Carcinogenesis

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $675,425

## Abstract

SUMMARY:
Inflammatory bowel disease (IBD) afflicts over three million people in the USA, is increasing worldwide, and
leads to colitis-associated carcinogenesis (CAC). We are seeking new adjunctive IBD therapies that are safe,
effective, and inexpensive that could also reduce risk for CAC. Spermidine (Spd) is a polyamine generated from
putrescine and from back-conversion of spermine by spermine oxidase (SMOX). Recent high-impact studies
have shown that Spd supplementation improves cardiovascular health, longevity and quality of life in aging, and
does not increase the risk for cancer. Spd has been used successfully in Phase I clinical trials. We have
developed a sensitive, accurate mass spectrometry-based assay for polyamine detection, which has enhanced
our capabilities for this project. Our recent discoveries support the use of Spd as a new strategy for colitis
treatment and CAC prevention. The long-term goal is to further elucidate the scope and mechanisms underlying
the protective effect of Spd to gain insights needed for future human clinical trials in IBD. Our proposed studies
are supported by our data indicating that: 1) Expression of SMOX, a key source of Spd, is reduced in patients
with ulcerative colitis (UC) and associated dysplasia. 2) Mice with Smox deletion have reduced Spd in the colon
and exacerbation of both dextran sulfate sodium (DSS) colitis, a model with features of UC, and CAC in the
azoxymethane (AOM)-DSS model. 3) Spd supplementation restores colon Spd levels and protects against colitis
and CAC. 4) Spd is the substrate for generation of hypusine, an amino acid produced by deoxyhypusine synthase
(DHPS), which is required for a highly specific form of protein translation, hypusination, involving activation of
eukaryotic translation initiation factor 5A (EIF5A) and formation of hypusinated EIF5A (EIF5AHyp). DHPS levels
are low in UC patients. EIF5AHyp is reduced by Smox deletion and restored by Spd during DSS colitis and AOM-
DSS-induced CAC, regulates macrophage function, and enhances colonic epithelial restitution. 5) Electrophiles,
such as levuglandins (LGs), are damaging products of lipid peroxidation that can lead to immune dysfunction
and neoplastic risk by forming adducts with proteins and DNA; we found increased adducts in human UC and
CAC, and a specific scavenger of electrophiles reduced adduct formation and carcinogenesis in the AOM-DSS
model. Importantly, we demonstrate that Spd can scavenge LGs. We hypothesize that potential benefits of Spd
in colitis and carcinogenesis are due to effects on immune responses, epithelial function, hypusination, and
electrophile scavenging. Our Aims are: 1) To determine the molecular and cellular mechanisms of protection by
Spd in acute and chronic colitis models and CAC, including effects on the transcriptome/metabolome, autophagy,
and immune cell versus epithelial cell function using transgenic mice with cell-specific human SMOX expression.
2) To determine if Spd acts through hy...

## Key facts

- **NIH application ID:** 10180436
- **Project number:** 1R01DK128200-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Keith T. Wilson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $675,425
- **Award type:** 1
- **Project period:** 2021-03-31 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180436

## Citation

> US National Institutes of Health, RePORTER application 10180436, Spermidine as a New Therapy for Colitis and Chemopreventive for Colitis-associated Carcinogenesis (1R01DK128200-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180436. Licensed CC0.

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