Helminth-induced prostaglandin signalling 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 (CAC). Previous research has independently linked a high dietary omega (?)-6:?-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 ?-6:?-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 ß-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 w-6:w-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. Overall design: Naive mice were fed a low omega-6 diet or a modified AIN-76A diet with a high omega-6:omega-3 ratio (mAIN-76A) for one week, then infected with 200 Heligmosomoides polygyrus bakeri L3 larvae for 14 days (Hpb), or maintained as naïve uninfected controls, before RNA-seq analysis of the colon.