Obesity increases the risk of postmenopausal breast cancer. Obesity also influences the gut microbiome. The gut microbiome represents the totality of microorganisms living within the body and can influence the development of many different types of diseases, including breast cancer. Obesity is associated with an increase in the Firmicute-to-Bacteriodetes bacterial phyla ratio in the gut microbiome promoting dysbiosis and inflammation. We previously demonstrated that diet and obesity shift both the gut and breast tissue microbiome using a non-human primate model. To investigate the impact of omega-3 PUFA supplementation on the gut and breast microbiome, we used a combination of a preclinical murine model and human fecal samples collected from overweight and obese postmenopausal women enrolled in a weight loss clinical trial supplemented with placebo or high dose omega-3 PUFA (clinicaltrials.gov identifier: NCT02101970). Female C57BL/6 mice fed a Western (0.2% kcal from omega-3 PUFA) or a Western +omega-3 PUFA diet (1.3% kcal omega-3 PUFA) for 16 weeks demonstrate differences in intestinal permeability as measured by circulating plasma LPS, in vivo FITC-dextran permeability assay, and intestinal tight junction protein ZO-1 gene expression. Elevated LPS bioavailability associated with metabolic endotoxemia has been associated with breast cancer risk. Omega-3 PUFA supplementation shifts the gut and mammary gland (MG) microbiome. 16S sequencing of DNA isolated from matched fecal and MG samples demonstrate that omega-3 PUFA supplementation independently regulated both microbiomes. Moreover, omega-3 PUFA supplementation in a Western diet reduced Firmicute-to-Bacteriodetes ratio in the murine MG tissue. Obese and overweight postmenopausal women (n=46) were enrolled in a weight loss clinical trial (combination of calorie restriction and exercise) and were administered a placebo or 3.25 g/day combined eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids omega-3 PUFA supplements for 6 months. Bacterial sequencing of DNA isolated from fecal collections at baseline and after 6 months of intervention shows significant decrease in Firmicutes-to-Bacteriodetes ratio regardless of intervention group. However, when clustering subjects by relative weight loss and intervention (<10% weight loss on placebo; <10% weight loss on omega-3; >10% weight loss on placebo, or >10% weight loss on omega-3), women in the <10% weight loss on omega-3 PUFA group displayed significant reduction in the Firmicutes-to-Bacteriodetes ratio from baseline that was not observed in the <10% weight loss on placebo group. These data suggest that women who did not achieve substantial weight loss but were supplemented with omega-3 PUFA, show an improved gut microbiome for potential enhancement of health outcomes. Taken together, these data demonstrate that increasing omega-3 PUFA intake to approximately 2% of total daily calories can shift the gut and mammary gland microbiome to a pattern associated with improved intestinal permeability parameters and less chronic inflammation, which in turn is associated with reduced risk of postmenopausal breast cancer.

Citation Format: Katherine L. Cook, Adam S Wilson, David R Soto-Pantoja, Bruce F. Kimler, Shahid Umar, Carol J. Fabian. Omega-3 polyunsaturated fatty acid supplementation shifts the gut and breast microbiome to influence inflammation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-03.