Maternal obesity and resistance to breast cancer treatments among offspring: Link to gut dysbiosis

Abstract

Background: About 50 000 new cases of cancer in the United States are attributed to obesity. The adverse effects of obesity on breast cancer may be most profound when affecting the early development; that is, in the womb of a pregnant obese mother. Maternal obesity has several long-lasting adverse health effects on the offspring, including increasing offspring's breast cancer risk and mortality. Gut microbiota is a player in obesity as well as may impact breast carcinogenesis. Gut microbiota is established early in life and the microbial composition of an infant's gut becomes permanently dysregulated because of maternal obesity. Metabolites from the microbiota, especially short chain fatty acids (SCFAs), play a critical role in mediating the effect of gut bacteria on multiple biological functions, such as immune system, including tumor immune responses.Recent Findings: Maternal obesity can pre-program daughter's breast cancer to be more aggressive, less responsive to treatments and consequently more likely to cause breast cancer related death. Maternal obesity may also induce poor response to immune checkpoint inhibitor (ICB) therapy through increased abundance of inflammation associated microbiome and decreased abundance of bacteria that are linked to production of SCFAs. Dietary interventions that increase the abundance of bacteria producing SCFAs potentially reverses offspring's resistance to breast cancer therapy. Conclusion:Since immunotherapies have emerged as highly effective treatments for many cancers, albeit there is an urgent need to enlarge the patient population who will be responsive to these treatments. One of the factors which may cause ICB refractoriness could be maternal obesity, based on its effects on the microbiota markers of ICB therapy response among the offspring. Since about 40% of children are born to obese mothers in the Western societies, it is important to determine if maternal obesity impairs offspring's response to cancer immunotherapies.

Gut microbiome influences incidence and outcomes of breast cancer by regulating levels and activity of steroid hormones in women

“…In general, patients with breast cancer and benign breast lesions show a reduced gut microbiome diversity than healthy individuals. Obesity is known to reduce the diversity of the gut microbiome, and is a risk factor for the incidence and progression of breast cancer 81–83 . For instance, the proportion of A. municiphila is decreased and is inversely correlated with body fat in patients with breast cancer.…”

“…Thus, these studies highlight the importance of a healthy and enriched gut microbiota for the patients to respond to therapy. Finally, maternal obesity influences the responsiveness of daughter to anticancer and immunomodulating treatment 82 . However, dietary habits that promote the growth of microbiome capable of synthesizing short‐chain fatty acids may aid in reversing the daughter's resistance to breast cancer therapy.…”

“…Obesity is known to reduce the diversity of the gut microbiome, and is a risk factor for the incidence and progression of breast cancer. 81 , 82 , 83 For instance, the proportion of A. municiphila is decreased and is inversely correlated with body fat in patients with breast cancer. However, administration of probiotics, such as Bifidobacterium longum BB536 and Lactobacillus rhamnosus HN001, improves the gut bacterial diversity and metabolic functioning.…”

“…Finally, maternal obesity influences the responsiveness of daughter to anticancer and immunomodulating treatment. 82 However, dietary habits that promote the growth of microbiome capable of synthesizing short‐chain fatty acids may aid in reversing the daughter's resistance to breast cancer therapy. Therefore, the mechanisms and microbial pathways associated with the development and progression of breast cancer should be studied in more detail to provide better treatment options for patients with breast cancer, especially as the steroid hormone levels and the breast local microenvironments differ with menopausal status.…”