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Pesco-vegetarian food components synergistically promote ferrroptosis in colonocytes to reduce colon cancer risk [bulkRNA-seq]

ABSTRACT: To assess the utility of diet modulation as a promising avenue to modulate ferroptosis in the colon, we examined the combinatorial effect of n-3 vs. n-6 polyunsaturated fatty acids (PUFA) and highly fermentable vs. poorly fermentable fiber on ferroptosis induction in preclinical models and healthy human adults. In vitro treatment of immortalized mouse colonocytes with docosahexaenoic acid, a n-3 PUFA enriched in fish oil, and butyrate, a short chain fatty acid generated by colonic microbial fermentation of fiber, reduced cell viability and interactively (P < 0.05) increased lipid peroxidation, a key biomarker for ferroptosis, compared to counterpart treatments. Addition of the ferroptosis inhibitor, ferrostatin-1, significantly blocked the combined effects of docosahexaenoic acid and butyrate on colonocyte lipid oxidation and cell death in vitro. In vivo treatment of mice fed fish oil and highly fermentable fiber (pectin) vs. control, corn oil (contains n-6 PUFA) and poorly fermentable fiber (cellulose) significantly (P < 0.05) promoted lipid peroxidation and the induction of ferroptosis transcriptional networks exclusively in colonic epithelial cells. In addition, as part of a randomized controlled crossover pilot study in humans, supplemental fermentable fiber (35 g/d soluble corn fiber) and fish oil (6 g/d n-3 PUFA) upregulated intestinal ferroptosis related gene expression, as compared to similar doses of maltodextrin plus corn oil. Our findings demonstrate that dietary fish oil and fermentable fiber act synergistically to induce ferroptosis in colonocytes. These important and often overlooked interactions between diet and the gut microbiome help to explain the anti-cancer benefit of the pesco-vegetarian diet.

ORGANISM(S): Mus musculus

PROVIDER: GSE295394 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Beneficial effects of long-chain omega-3 polyunsaturated fatty acids (n-3 FAs) are generally well-known from epidemiological studies, but the various mechanisms of action are not completely clarified. Regulation of gene expression is one known mechanism of action, but only very limited data of regulated pathways in humans after n-3 FA supplementation are available. Up to now, no studies compared gene expression changes after n-3 FA supplementation between normolipidemic and dyslipidemic subjects. Therefore, the aim of this study was to investigate the effects of n-3 FA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. We conducted an intervention study with normo- and dyslipidemic men aged between 29 and 51 years, which were subdivided into four groups with a balanced age distribution and randomized to either six fish oil capsules per day providing 1.5 g docosahexaenoic acid and 1.0 g eicosapentaenoic acid or corn oil capsules rich in linoleic acid per day for a period of 12 weeks. Venous blood samples were collected at baseline as well as after 4 hours, 1 week and 12 weeks of supplementation. For each investigation time point, the samples of each group were pooled together to minimize inter-individual variability. All subjects have successfully completed the study, but for the microarray experiments, nine subject samples were excluded. Therefore, the microarray experiments are based on the following group characteristics: normolipidemic fish oil group (FO-N): pool of nine RNAs from normolipidemic subjects supplemented with fish oil; normolipidemic corn oil group (CO-N): pool of six RNAs from normolipidemic subjects supplemented with corn oil; dyslipidemic corn oil group (CO-D): pool of eight RNAs from dyslipidemic subjects supplemented with corn oil; dyslipidemic fish oil group (FO-D): pool of nine RNAs from dyslipidemic subjects supplemented with fish oil. The twenty normolipidemic and the twenty dyslipidemic subjects were subdivided into two groups. Thus, a total of four groups with ten men per group passed through the study. To realize a comparable mean age between groups, the formation of groups was performed by stratified allocation according to subject's age. The four study groups were randomly assigned to different study products by an uninvolved collaborator. Subjects ingested either six FO or six corn oil (CO) capsules per day for a period of twelve weeks. The daily n-3 PUFA intake via FO capsules was 2.7 g (1.14 g DHA and 1.56 g EPA). The predominant FA of the CO capsules was the omega-6 (n-6) PUFA linoleic acid (LA, 18:2n-6). Thus, the daily LA intake via CO capsules was 3.05 g LA. The subjects were instructed to ingest the capsules together with food, three in the morning and three in the evening, and to maintain their usual exercise and dietary habits throughout the intervention time. As an exception, at the first intervention day, all six capsules were ingested at the same time in the morning after a standardised breakfast. During each visit, fasting blood samples were collected by venepuncture. Additionally, participants completed a questionnaire to obtain information about changes in medication, dietary (e.g., changes in weekly fish intake, preferred fish dishes or species, respectively) and lifestyle habits (e.g., physical activity), as well as the tolerability of the capsules. This record summarizes the results of 16 microarrays. The samples originate from whole blood of normo- and dyslipidemic subjects supplemented with either fish oil or corn oil for 4 h, 1 week and 12 weeks. Microarrays were hybridized in a loop design with one common reference using a dye-swap approach.

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Pesco-vegetarian food components synergistically promote ferrroptosis in colonocytes to reduce colon cancer risk [bulkRNA-seq]

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