Abstract

ABSTRACT Background Myelodysplastic neoplasms (MDS) represent a group of heterogeneous clonal disorders characterized by immune dysregulation in their pathogenesis. Gut microbiota dysbiosis plays a critical role in immune modulation. Methods We collected the fecal samples of 23 newly diagnosed MDS, 10 hypomethylating agents (HMA) treated MDS and 13 age and sex matched healthy controls (HC), and analyzed the gut microbiota compositions and functional pathways using metagenomic next‐generation sequencing (mNGS). Results Distinct microbial compositions were observed between newly diagnosed MDS and HC. Notably, the Veillonellaceae family was significantly enriched in MDS patients. Specific bacteroid species demonstrated significant correlations with lymphocyte subtypes, functional activation status, and serum inflammatory cytokines. Functional profiling revealed altered metabolic pathways in newly diagnosed patients, particularly in amino acid metabolism and ATP synthesis. Notably, glutamine/glutamate and tryptophan metabolism pathways were hyperactive in untreated MDS but downregulated following HMA treatment. Conclusions The gut microbiota altered in MDS patients and was associated with immune dysregulation and inflammation, which may contribute to MDS pathogenesis and mediate therapeutic effects of HMA treatment, highlighting the gut microbiota‐metabolism axis as a potential therapeutic target for MDS management.