Effect of maternal obesity on breast cancer among offspring: role of the gut microbiota

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In Minnesota, American Indian (34.1%) and non-Hispanic Black (33.4%) women are over twice as likely to be obese during pregnancy than non-Hispanic White women of whom 16.6% are obese during pregnancy. This high incidence reflects the causes of maternal obesity such as low socioeconomic status, high crime rate, and excess exposure to air pollution. Maternal obesity has widespread adverse effects on the offspring including increasing their risk of dying from breast cancer. Maternal obesity also permanently disrupts the mutually beneficial interaction between the offspring and offspring’s gut microbiota, causing gut dysbiosis. Gut dysbiosis in the offspring is characterized by a reduction in the gut bacteria that produce fecal short-chain fatty acids (SCFA). SCFAs play pivotal roles in maintaining healthy immune functions, cellular metabolism, and other critical functions. These compounds act mostly through their receptors GPR43 and GPR41, which are expressed in immune cells and multiple other cell types. Here, we will test the central hypothesis that the composition of commensal gut microbes in the offspring of obese dams is causally responsible for an offspring’s increased susceptibility to mammary tumorigenesis, an effect that likely also reflects altered immunity. We will test this causal link by performing fecal microbiota transfers (FMTs). The role of GPR43 and GPR41 in mediating the impact of maternal obesity on offspring will be tested using CRISPR/Cas9 knockout mice. The potential for clinical translation of our findings will be established by supplementing obese pregnant dams with a commercially available probiotic mix of SCFA-producing gut bacteria and dietary fiber that increases SCFA production. Such a combination has been earlier found to be most effective in reversing loss of critical microbes of healthy gut microbiota from individuals who have consumed an unhealthy Western diet for multiple generations. We will use allografted E0771 and Py230 mammary tumor models and MMTV-PyMT mice developing mammary tumors at about age 3 months. Shotgun metagenome sequencing and mass spectrometry will be applied to study gut microbiota and their metabolites, respectively. Changes in immune cell infiltration and activity will be measured in multiple tissues and compared with the expression of GPR43 and GPR41 in immune cells. Our studies could lead to effective and safe prevention strategies against breast cancer and its growth in the daughters of obese mothers, and be particularly beneficial for communities suffering from health disparities.