Microbiota-Inflammation Crosstalk in Myeloproliferative Neoplasms: MPN-Specific Human Data, Mechanistic Plausibility...

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders driven mainly by somatic mutations in JAK2, CALR or MPL, but their clinical phenotype is also shaped by chronic inflammation, immune dysregulation, vascular complications and microenvironmental remodeling. Emerging evidence suggests that the gut microbiota may contribute to this inflammatory and immunometabolic landscape; however, the current literature remains heterogeneous and its translational relevance is still insufficiently defined. This critical narrative review maps the available evidence linking the gut microbiota, microbial metabolites and systemic microbial signatures to MPN biology. We distinguish direct human MPN data from indirect mechanistic evidence derived from studies of intestinal barrier dysfunction, thrombo-inflammation, hematopoietic regulation, allogeneic hematopoietic cell transplantation and infection risk. Across human MPN cohorts, the most consistent findings are not uniform changes in global microbial diversity, but rather alterations in specific immunoregulatory taxa, particularly reduced Firmicutes/Faecalibacterium-related communities and dysbiotic signatures associated with JAK2V617F status. Mechanistically, dysbiosis and impaired intestinal barrier integrity may facilitate low-grade endotoxemia, TLR4/NF-κB activation, cytokine amplification, endothelial activation and platelet priming. In parallel, microbial metabolites may influence hematopoietic stem cell programs, the bone marrow niche, megakaryopoiesis and thrombopoiesis. Treatment exposure and diet are relevant modifiers of the microbiota-inflammation axis, although available interventional data remain preliminary. Mendelian randomization and multi-omics studies provide hypothesis-generating evidence for microbiota-metabolome-MPN interactions, but require longitudinal validation, functional studies and contamination-aware analytical pipelines, especially for low-biomass blood and bone marrow samples. Microbiota-targeted strategies, including nutritional interventions and fecal or washed microbiota transplantation, represent promising but still investigational approaches, particularly in immunocompromised or post-transplant settings. Future studies should integrate microbiome, metabolome, genome, proteome, inflammatory biomarkers and clinical outcomes while controlling for diet, antibiotics, treatment exposure and driver mutation status. Such an approach may clarify whether the microbiota is a biomarker, mediator or therapeutic target in MPNs.