Gut microbiota alterations in myelodysplastic neoplasms are associated with immune dysfunction and the therapeutic mechanism of hypomethylating agents

Abstract 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. In this study, we collected the fecal samples of newly diagnosed MDS, hypomethylating agents (HMA) treated MDS and healthy controls (HC), and analyzed the gut microbiota compositions and functional pathways using metagenomic next-generation sequencing (mNGS). Despite no significant difference between newly MDS and HC in alpha and beta diversity, distinct microbial compositions were observed between newly diagnosed MDS and HC. Notably, Veillonellaceae family was significantly enriched in MDS patients and demonstrated potential diagnostic value with an area under the curve (AUC) of 0.741. Specific bacteroid species demonstrated significant correlations with lymphocyte subtypes, functional activation status, and serum inflammatory cytokines. We observed a negative correlation between Bacteroides uniformis and activated CD4+ (CD4+CD28+/CD4+) T cell populations while positive correlation between Roseburia faecis and activated CD8+ T (HLADR+/CD8+ and CD8+CD38+/CD8+) cell subsets. Moreover, Klebsiella pneumoniae was negatively associated with CD8⁺ T cell populations and inflammatory cytokine levels including TNF-α and IFN-γ, and Bifidobacterium longum demonstrated positive associations with serum concentrations of TNF-α and IFN-γ. Functional profiling revealed altered metabolic pathways in newly diagnosed MDS patients, particularly in amino acid metabolisms (glutamate synthase activity, L-lysine catabolic process to acetate, tryptophan synthase alpha chain, et al) and ATP synthesis (ATP synthesis coupled proton transport, proton transporting ATP synthase complex catalytic core F (1) and NADPH binding). Notably, glutamine/glutamate and tryptophan metabolism pathways were hyperactive in untreated MDS but downregulated following HMA treatment. In conclusion, the gut microbiota altered in MDS patients and was associated with immune dysregulation and inflammation. These microbial and metabolic perturbations 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.