Deconvoluting Gut Microbiome-Metabolites Associations in Breast Cancer Patients

Abstract

Breast cancer remains the leading cause of cancer-related deaths among women, despite advancements in diagnostic and treatment modalities. Recent progress in metagenomic analysis has highlighted the potential influence of the gut microbiome on human health and disease outcomes, including breast cancer. Additionally, metabolites produced by gut microbial communities have shown health benefits and potential anticancer activity. However, the specific mechanisms by which these secondary metabolites affect breast cancer are not well understood. This study aimed to investigate the gut microbiome's taxa and secondary metabolites in breast cancer patients. It used machine learning approaches to associate these factors with clinical metadata, elucidating their role in breast cancer. Utilizing metagenomic analysis, this research explored the gut taxonomic landscape of BC patients, while antiSMASH analysis was employed to identify metabolite biosynthetic gene clusters. Machine Learning models were applied to associate these taxa and metabolite BGCs with clinical metadata. This study identified 471 species and 40 metabolites in the metagenomic samples of breast cancer patients. The statistical analysis further revealed a significant association (p<0.05) between the species E. coli and the metabolites siderophore and thiopeptide with breast cancer groups. The random forest model outperformed with a combined area under the curve of 78% in classifying samples into breast cancer groups and healthy controls. This research proposes a hypothesis of the underlying mechanism, supported by literature and statistical evidence (p<0.05), that under iron-limiting conditions, E. coli produces siderophores to scavenge iron from the host, resulting in increased angiogenesis and breast cancer progression due to the iron scarcity xiv of the host. While this hypothesis requires further functional analysis, it opens new avenues for breast cancer therapy development. This study provides a novel perspective on the gut microbiome's role in breast cancer, suggesting potential therapeutic targets and strategies for future research