Gut microbiome and metabolome reveal hormone-related and functional alterations in ER-positive breast cancer: a case–control study

Abstract The gut microbiome has been linked to breast cancer, largely through microbial functions involved in estrogen metabolism (the “estrobolome”); however, specific microbial targets remain poorly defined in human studies. Here, we profiled the gut microbiome using whole-metagenome shotgun sequencing, and plasma and stool metabolites were quantified using targeted metabolomics, in a study of 70 postmenopausal female cases with treatment-naïve ER-positive breast cancer and 70 controls. Reduced species-level alpha and beta diversity were associated with breast cancer, whereas microbial functional-level diversity was not. Higher levels of DHEA-sulfate, estriol, and isoflavone phytoestrogen metabolites and lower lignan phytoestrogen metabolites were associated with breast cancer, while circulating estrogens and estrogen-related microbial functions were not. Beyond hormone-related pathways, higher levels of conjugated bile acids and carnitines were also associated with breast cancer. Compared to controls, cases exhibited depletion of Blautia obeum, Alistipes shahii , A. finegoldii , A. putredinis , and Anaerotruncus rubiinfantis , along with reduced abundance of functions related to menaquinol-8 biosynthesis, TCA cycle-related energy metabolism, and NAD salvage, indicating depletion of specific metabolic pathways rather than overall functional diversity. These results indicate a potential etiologic role for host–microbe metabolic interactions in breast cancer that extends beyond estrogen-centered mechanisms and warrants validation in independent cohorts.