Systemic Effects of Ketogenic Diet–Modulated Gut Microbiome-Derived Phenol Sulfate on Breast Cancer Progression

Abstract

Cancer is increasingly recognized not only as a disease driven by tumor-intrinsic factors, but also as a systemic condition shaped by host metabolism. To target tumors’ metabolic adaptations, the ketogenic diet (KD) has attracted significant interest in its potential anti-tumor effects. While prior studies have largely attributed KD-mediated tumor suppression to reduced glucose availability and altered tumor-intrinsic metabolism, the role of the gut microbiome and microbiome-derived metabolites in modulating the effects of the KD remains poorly understood. Here, we investigate the mechanisms underlying KD-mediated tumor suppression through an integrated analysis of diet-induced gut microbiome remodeling and systemic metabolism. Using orthotopic mouse models of breast cancer, we show that the KD robustly suppresses primary tumor growth across molecular subtypes while inducing coordinated systemic and intratumoral metabolic reprogramming. Through metabolomic profiling, we identify phenol sulfate (PS), a gut microbiome–derived metabolite, as a consistent and highly discriminatory diet-responsive feature associated with tumor progression. We find that PS levels are elevated under control diet conditions and reduced under KD across independent tumor models. Functional studies establish that PS is not merely correlative but causally linked to tumor growth. In vitro, PS promotes cancer cell proliferation in a dose-dependent manner. In vivo, PS supplementation is sufficient to restore tumor growth under both KD-mediated and antibiotic-mediated microbiome remodeling, demonstrating that PS acts downstream of the microbiome as a key mediator of tumor-promoting effects. Collectively, these findings define a previously uncharacterized diet–gut microbiome–circulating metabolite axis regulating tumor progression and identify phenol sulfate as a functionally relevant metabolite linking dietary intervention to tumor suppression.