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

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-naive 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.