Gastroenterology. 2023 Jun 02. pii: S0016-5085(23)00814-4. [Epub ahead of print]
Alain P Gobert,
Thaddeus M Smith,
Yvonne L Latour,
Mohammad Asim,
Daniel P Barry,
Margaret M Allaman,
Kamery J Williams,
Kara M McNamara,
Alberto G Delgado,
Sarah P Short,
Raghavendra G Mirmira,
Kristie L Rose,
Kevin L Schey,
Irene Zagol-Ikapitte,
Jeremy S Coleman,
Olivier Boutaud,
Shilin Zhao,
M Blanca Piazuelo,
M Kay Washington,
Lori A Coburn,
Keith T Wilson.
BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis.
METHODS: We utilized human colon tissue mRNA samples and publicly-available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis.
RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS mRNA and DHPS protein, and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show downregulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis.
CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have therapeutic impact.
Keywords: Colon cancer; Hypusine; Inflammation; Intestinal epithelial cells