(OR25-05-23) High-Fat Diet Exposure in the Early Life Alters Gut Microbiome Later in Life and Links With Mammary Microenvironment Towards Breast Tumorigenesis in Mice

Objectives: Emerging evidence indicates that a potentially important role for early-life events and exposures have important consequences for cancer development in adult, whereas very little is known about how early-life exposures influence cancer risk later in life.  Gut microbiota has been shown the influence on the incidence and progression of extraintestinal cancers, including breast cancer. Furthermore, gut dysbiosis in early life may have extending effects on the host's health in adulthood. The present study aimed to investigate how high-fat diet (HF) in early life influences gut microbiome later in life and consequently mammary microenvironment towards breast tumorigenesis in mice.

Methods: Twenty-two female C57BL/6 mice were fed a low-fat (LF, 10% kcal fat) or HF (60% kcal fat) diet from the age of 4 wks to 12 wks, which is equivalent to childhood and adolescence. Twelve mice were sacrificed immediately after 8-wk feeding, and another ten mice were switched to a normal lifecycle-supporting diet for additional 12 wks. Gut microbiome was sequenced and mammary metabolic and inflammatory status were determined at both 12 wks immediately after the HF/LF feeding and 24 wks later in life.

Results: The 8-wk HF feeding significantly altered the diversity (Bray & Jaccard p < 0.01), and the difference remained significant after switching diet until 24 wks of age (Bray & Jaccard p < 0.05). Immediately after 8-wk HF feeding, a great number of microbial taxa ( >50) were significantly altered, and after switching to the normal lifecycle diet for 12 wks, about half of those taxa (25) remains significantly changed. Among them, the abundance of Alistipes, Bilophila, and Rikenellaceae stood out to be significantly associated with multiple metabolic and inflammatory biomarkers in plasma and/or mammary tissue, including aromatase, leptin, adiponectin, Ccl2, Cox2, IL13, etc. in a direction largely indicating metabolic disorders and inflammation promoted by 8-wk HF feeding (p < 0.05).

Conclusions: An 8-wk HF feeding in the early life altered mammary metabolic and inflammatory microenvironment later in life potentially via a gut microbiota-breast axis, and these alterations are collectively in favor of breast tumorigenesis.

Funding Sources: This material is based upon work supported in part by USDA/NIFA AFRI grants (2022-67018-36986, ZL) and USDA//NIFA Hatch project (MAS00586, ZL).