Maternal n-3 polyunsaturated fatty acids restructure gut microbiota of offspring mice and decrease their susceptibility to mammary gland cancer.

Our previous studies have revealed that a maternal diet rich in n-3 polyunsaturated fatty acids (PUFAs) is associated with decreased mammary cancer risk in offspring. However, the underlying mechanism remains unclear. The present study aimed to investigate the possible mechanism by which maternal n-3 PUFAs decrease the mammary cancer risk of offspring in terms of gut microbiota. C57BL/6 pregnant mice were fed a control standard chow (CON), fish oil supplemented diet (n-3 Sup-FO), flaxseed oil supplemented diet (n-3 Sup-FSO) or n-3 PUFA deficient diet (n-3 Def) (n = 10) throughout gestation and lactation. After weaning, all offspring were fed a AIN-93G diet. The tumor incidence and volume were significantly increased in n-3 Def offspring compared with the other groups. Maternal n-3 PUFA supplementation resulted in a significantly increased α-diversity of the gut microbiota in n-3 Sup-FO and n-3 Sup-FSO offspring compared with that in n-3 Def offspring. The relative abundances of Akkermansia, Lactobacillus and Mucispirillum observed in adult offspring of both the n-3 Sup-FO and n-3 Sup-FSO groups were higher than those observed in the control group, whereas the maternal n-3 Def diet was associated with decreased abundances of Lactobacillus, Bifidobacterium and Barnesiella in 7-week-old offspring. The levels of the pro-inflammatory factors IL-1ß, IL-6 and TNF-α were significantly lower in n-3 PUFA supplemented offspring than in n-3 Def offspring. In addition, the abundance of Mucispirillum was positively associated with the concentration of the anti-inflammatory factor IL-10, whereas the abundances of Bifidobacterium and Akkermansia were negatively associated with IL-1ß and IL-6, respectively. Based on the bacterial composition of the gut microbiota, metabolites were predicted and the results showed that arachidonic acid metabolism and the MAPK signaling pathways were more enriched, while the butyric acid metabolic pathway was less enriched in offspring of the n-3 Def group than in those of the other three groups. Our findings suggest that decreased pro-inflammatory factors and changed gut microbiota are associated with the protective effects of maternal n-3 PUFAs against offspring's mammary tumorigenesis.

Relationship between the n-3 index, serum metabolites and breast cancer risk.

The present study aimed to investigate the relationship between the n-3 index, serum metabolites and breast cancer risk. A total of 104 newly diagnosed breast cancer patients and 70 healthy controls were recruited. The erythrocyte phospholipid fatty acid composition was determined by gas-liquid chromatography, and the n-3 index was calculated with the percentage of eicosapentaenoic acid plus docosahexaenoic acid in total fatty acids. Serum metabolomic profiles were analyzed by UHPLC-Q-Exactive Orbitrap/MS. The results showed that the erythrocyte phospholipid n-3 index was significantly lower in breast cancer patients than in healthy controls, and it was inversely associated with breast cancer risk (OR = 0.60; 95% CI: 0.36-0.84). Metabolomics analyses showed that serum 16α-hydroxy dehydroepiandrosterone (DHEA) 3-sulfate, lysophatidylethanolamines (LPE) 22:0/0:0 and hexanoylcarnitine were significantly higher, while thromboxane B3, prostaglandin E3 (PGE3) and 18ß-glycyrrhetinic acid were significantly lower in breast cancer patients than those in healthy controls. In addition, serum 16α-hydroxy DHEA 3-sulfate was inversely correlated with the n-3 index (r = -0.412, p = 0.036). In conclusion, our findings suggest that the lack of n-3 PUFAs might be a potential risk factor for breast cancer, and the serum metabolite 16α-hydroxy DHEA 3-sulfate may play an important role in linking n-3 PUFA deficiency and breast disease etiology.