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

Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis, and inflammatory disorders, such as colitis-associated colorectal cancer. Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of colitis-associated colorectal cancer. 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 tumor formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumor 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 tumor 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 signaling to exacerbate tumor development.