Sex-biased associations between gut microbiota and hematologic toxicity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Background: Compared to male cancer patients, female patients have a higher incidence and severity of adverse events (AEs) associated with anticancer treatment. The mechanism underlying these disparities is largely unknown, especially in the context of radiotherapy. Notably, the composition and metabolism of the gut microbiota differ between sexes, and such differences have been implicated in multiple physiological and pathological processes. In this study, we aimed to investigate the sex differences in hematologic toxicities during chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and to explore the potential role of the gut microbiota in mediating these differences. Materials and Methods: This real-world study included 329 patients with LARC receiving neoadjuvant chemoradiotherapy (nCRT). Hematologic AEs were evaluated according to Common Terminology Criteria for Adverse Events 5.0. 16S rRNA sequencing, metatranscriptome sequencing, and metabolome detection were performed on longitudinal fecal samples. Mendelian randomization analyses were performed to investigate the correlation between stem cell and gut microbial traits. Results: In this cohort, females had a higher severity of hematologic AEs than males. Using integrated longitudinal multi-omics data, we identified sex-biased bacterial species (e.g., Parasutterella excrementihominis and Bifidobacterium adolescentis ) and microbiota-mediated arginine metabolism associated with hematologic toxicities. Gut microbiome-mediated arginine metabolism is associated with an abundance of hematopoietic stem cells and may be involved in the occurrence of sex-biased radiotherapy-induced hematologic AEs. Conclusion: These results indicate that the differences in gut microbial composition and metabolism between the two sexes are associated with the sex-biased hematologic AEs induced by nCRT. Females require greater attention regarding the hematologic toxicity of chemoradiotherapy, and that gut microbes may serve as potential targets for sex-tailored strategies to restore hematopoietic function following chemoradiotherapy.