Omega-3 polyunsaturated fatty acid supplementation ...

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From 2021 SABCS Publication Number: P1-09-03

Omega-3 polyunsaturated fatty acid supplementation shifts the gut and breast microbiome to influence
inflammation

Katherine L. Cook1, Adam S Wilson1, David R Soto-Pantoja1, Bruce F. Kimler2, Shahid Umar2 and Carol J.
Fabian2. 1Wake Forest University School of Medicine, Winston Salem, NC;2University of Kansas Medical
Center, Kansas City, KS
K.L. Cook: None. A.S. Wilson: None. D.R. Soto-Pantoja: None. B.F. Kimler: None. S. Umar: None. C.J.
Fabian: None.

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.