Gut bacterium metabolite fuels breast cancer in mice and organoids, Foshan team finds

A multidisciplinary research team led by Foshan Second People's Hospital and The First People's Hospital of Foshan / Southern University of Science and Technology has uncovered a direct signaling axis linking gut microbiota to breast cancer progression. Using multi-omics analysis of treatment-naïve patients, cell lines, mouse models, and patient-derived organoids, the scientists demonstrated that the commensal gut bacterium Ruminococcus lactaris produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a circulating oncometabolite that impairs chemotherapy response. The findings were published in 中国科学通报：英文版 sciencedirect.com中国科学通报：英文版sciencedirect.comOpen source ↗.

Microbial metabolite and host signaling circuit

Metagenomic and metabolomic analyses showed that R. lactaris was significantly enriched in patients with poor response to neoadjuvant chemotherapy. Although the host hexosamine biosynthetic pathway generates the majority of systemic UDP-GlcNAc, microbial de novo synthesis creates a critical shift that promotes tumor progression. Once in the bloodstream, bacterial UDP-GlcNAc is absorbed by tumor cells and activates host O-GlcNAc transferase (OGT). This activation leads to the O-GlcNAcylation and stabilization of the transcription factor NFIB, which binds to the promoters of both OGT and the proto-oncogene KIT, establishing a self-amplifying feedback loop that drives cancer proliferation and migration.

Chemotherapy resistance and enzyme inhibition

In both cell cultures and mouse models, systemic UDP-GlcNAc attenuated the anti-tumor efficacy of paclitaxel. Cancer cells exposed to paclitaxel alongside the microbial metabolite exhibited substantially higher viability compared to paclitaxel monotherapy. Additionally, the team observed that Streptomyces kanamyceticus can convert UDP-GlcNAc into aminoglycoside antibiotics, which suppress Gram-negative competitors and foster an ecological niche favorable to R. lactaris expansion.

Pharmacological inhibition of OGT using the small-molecule inhibitor OSMI-1, as well as genetic silencing, completely disrupted this feed-forward signaling pathway in germ-free mice, specific-pathogen-free mice, and patient-derived breast cancer organoids. Tumor growth was suppressed despite the persistent presence of R. lactaris and elevated UDP-GlcNAc levels, confirming OGT as a viable molecular target to reverse bacteria-driven therapy resistance sciencedirect.com中国科学通报：英文版sciencedirect.comOpen source ↗.