Abstract
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-1β, 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-1β 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.
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Key Points
Data about the role of n-3 PUFAs in microbiota are limited. Studies targeting at the relationship between maternal n-3 PUFA intake and the gut microbiota of offspring and subsequent breast cancer susceptibility are quite limited. In the present study, the authors investigated the effects of maternal high-fat and low-fat control diets on mammary tumorigenesis and the gut microbiota of offspring, and tested the hypothesis that maternal supplementation with n-3 PUFAs could alleviate the high-fat induced gut microbiota dysbiosis and decrease the susceptibility of offspring mice to mammary gland cancer in adulthood. The results showed that maternal n-3 PUFA supplementation, both from fish oil and flaxseed oil, significantly decreased the susceptibility to DMBA-induced mammary cancer, and the beneficial effect appeared to be associated with the persistent restructuring of infant gut microbiota. The results showed that high fat diets decreased the α-diversity of the gut microbiota in mothers and the changes were delivered to offspring compared with the low-fat control group, whereas n-3 PUFA supplemented in the maternal high-fat diet could significantly alleviate this effect.
The maternal exposure to the n-3 PUFA diet resulted in a significantly higher proportion of gut microbiota related to α-linolenic acid metabolism, butyric acid metabolism and propanoate metabolism and an evident lower proportion of gut microbiota enriched in the arachidonic acid metabolism pathway, MAPK signaling pathway, PPAR signaling pathway and pathways in cancer compared with the n-3 Def group. Butyrate and propanoate are the primary SCFAs present in the gut lumen, and are generally linked to the anti-inflammatory properties.
n-3 PUFAs in the maternal diet induced an anti-inflammatory environment in offspring, which have long-term benefits for metabolic health in later life. The increased anti-inflammatory cytokine and decreased pro-inflammatory cytokine in offspring, induced by the maternal n-3 PUFA diet, are critical to decrease the breast cancer susceptibility.
In this study, IL-10 was significantly inhibited and TNF-α, IL-1β and IL-6 were significantly increased in plasma of n-3 Def offspring. These results indicated that inhibition of proinflammatory cytokines, such as TNF-α, IL-1β and IL-6 and preventing the reduction of the anti-inflammatory cytokine IL-10 in offspring were associated with the cancer- preventive properties of the maternal n-3 PUFA diet.
In conclusion, the present study confirmed that maternal exposure to n-3 PUFAs during gestation and lactation could reduce the offspring’s susceptibility to mammary gland cancer in later life. The protective effect of n-3 PUFAs in this transgenerational process might be partly explained by the long lasting restructuring of gut microbiota and the decreased proinflammatory factors