Microbial vitamin biosynthesis links gut microbiota dynamics to chemotherapy toxicity

• DOI: 10.1128/mbio.00930-25
• Publication Date: 2025-05-20T13:00:08Z
• Authors: Lars E. Hillege; Kai R. Trepka; Benjamin G. H. Gu...; Xueyan Fu; Romy Aarnoutse; Maia R. Paymar; Christine Olson; Chen Zhang; Edwin Ortega; Lorenzo Ramirez; Judith de Vos-Geelen; Liselot Valkenbur...; Irene E. G. van H...; Arnold Baars; Johanna H. M. J. ...; John Penders; Adam Deutschbauer; Chloe E. Atreya; Wesley A. Kidder; Marjolein L. Smidt; Janine Ziemons; Peter J. Turnbaugh

ABSTRACT Dose-limiting toxicities pose a major barrier to cancer treatment. While preclinical studies show that the gut microbiota influences and is influenced by anticancer drugs, data from patients paired with careful side effect monitoring remains limited. Here, we investigate capecitabine (CAP)-microbiome interactions through longitudinal metagenomic sequencing of stool 56 advanced colorectal patients. CAP significantly altered microbiome, enriching for menaquinol (vitamin K2) biosynthesis genes. Transposon library screens, targeted gene deletions, media supplementation revealed protects Escherichia coli drug toxicity. Stool metabolite levels were associated decreased peripheral sensory neuropathy. Machine learning models trained in this cohort predicted an independent cohort. Taken together, these results suggest treatment-associated increases microbial vitamin serve chemoprotective role bacterial host cells. Further, our findings provide foundation in-depth mechanistic dissection, human intervention studies, extension other treatments. IMPORTANCE Side effects are common during treatment cancer. The trillions microbes found within sensitive but treatment-induced shifts remain poorly understood. We profiled treated carefully monitored effects. observed marked expansion genes producing K2 (menaquinone). Vitamin rescued growth was then used information about develop predictive model toxicity validated These production protect both bacteria cells toxicity, providing new opportunities motivating need better understand how dietary intake micronutrients like influence outcomes.