Longitudinal gut microbiome dynamics are associated with clinical outcome and toxicity during ibrutinib therapy.

Accumulating evidence indicates that the gut microbiome influences therapeutic efficacy and toxicity across cancer treatments; however, its longitudinal dynamics during targeted therapies remain poorly characterized. Here, we performed whole-genome shotgun metagenomic sequencing of 291 longitudinal stool samples collected over one year from 30 patients with hematologic malignancies treated with ibrutinib. Overall gut microbial diversity remained stable at the population level but exhibited markedly divergent temporal trajectories according to clinical outcome, with progressive recovery in responders and blunted or delayed restoration in non-responders. Longitudinal modeling revealed distinct species- and pathway-level microbial dynamics between patients with treatment response or nonresponse, including enrichment of saccharolytic, short-chain fatty acid-associated taxa and metabolic pathways in responders, and expansion of bile acid-modifying, proteolytic, and inflammation-associated microbial features in non-responders. Functional profiling further demonstrated opposing temporal trends in pathways related to carbohydrate fermentation, amino-acid metabolism, and secondary bile acid synthesis. In addition, both baseline microbiome composition and longitudinal remodeling were associated with the development of ibrutinib-associated diarrhea. Together, these findings reveal coordinated, outcome-specific remodeling of the gut microbiome during ibrutinib therapy and highlight longitudinal microbiome trajectories, rather than static baseline features, as potential biomarkers of treatment response and toxicity, as well as targets for microbiome-directed interventions. In conclusion, our findings highlight a potential role of gut microbiome dynamics in modulating response to BTK inhibition and support the need for larger, prospective studies to validate these observations.