Oncobiotic transformation of the gut microbiome may contribute to the risk of
breast cancer. Recent studies have provided evidence that the microbiome secretes
cytostatic metabolites that inhibit the proliferation, movement, and
metastasis formation of
cancer cells. In this study, we show that
indolepropionic acid (IPA), a bacterial
tryptophan metabolite, has
cytostatic properties. IPA selectively targeted
breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and
metastasis formation of
cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of
inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in
cancer cell stem-ness. IPA exerted its effects through
aryl hydrocarbon receptor (AHR) and
pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human
breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in
breast cancer. Furthermore, AHR activation and PXR expression related inversely to
cancer cell proliferation level and to the stage and grade of the
tumor. The fecal microbiome's capacity for IPA biosynthesis was suppressed in women newly diagnosed with
breast cancer, especially with stage 0. Bacterial
indole biosynthesis showed correlation with lymphocyte infiltration to
tumors in humans. Taken together, we found that IPA is a
cytostatic bacterial metabolite, the production of which is suppressed in human
breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.