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Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer

Smith, Katherine A. ORCID: https://orcid.org/0000-0001-8150-5702, Reed, Ella K., Guschina, Irina, Tyrrell, Victoria J., Butters, Claire, Darby, Matthew G., Katsandegwaza, Brunette, Chetty, Alisha, Horsnell, William G. C., O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460 and Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 2025. Helminth-induced prostaglandin signalling and dietary shifts in PUFA metabolism promote colitis-associated cancer. Journal of Lipid Research
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Abstract

Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis, and inflammatory disorders, such as colitis-associated colorectal cancer (CAC). Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of CAC. However, whether these two factors interact to exacerbate disease risk and whether oxylipins contribute to this is unknown. In this study, we report that infection with the helminth Heligmosomoides polygyrus bakeri (Hpb) exacerbates tumour formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumour burden correlated with heightened levels of arachidonic acid (AA) and AA-derived lipoxygenase (LOX) oxylipins in the colon, including the 12/15-LOX product 12-hydroxyeicosatetraenoic acid, prior to disease onset. Although helminth infection further increased the production of 12/15-LOX oxylipins and increased expression of Alox15, responsible for producing these metabolites, inhibition of cyclooxygenase-dependent prostaglandin production with aspirin prevented helminth-exacerbation of disease. Helminth-infected mice exhibited increased phosphorylation of β-catenin in the colon, which was inhibited by EP2 and 4 antagonists. Moreover, administration of an EP agonist increased tumour burden in naive mice fed a high ω-6:ω-3 PUFA ratio diet, to the levels seen in helminth-exacerbation of disease. These data suggest that dietary changes in fatty acid composition coordinate with helminth-induced activation of EP signalling to exacerbate tumour development.

Item Type: Article
Status: In Press
Schools: Schools > Medicine
Schools > Biosciences
Publisher: Elsevier
ISSN: 0022-2275
Date of First Compliant Deposit: 6 June 2025
Date of Acceptance: 5 June 2025
Last Modified: 13 Jun 2025 14:30
URI: https://orca.cardiff.ac.uk/id/eprint/178846

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