The Gut-Bone Marrow Axis: Deciphering the Mechanistic Impact of Microbial Metabolites on Hematopoietic Homeostasis...

The gut microbiota is increasingly recognized as a dynamic endocrine-like microbial network that exerts systemic effects far beyond the gastrointestinal tract. Emerging evidence supports the existence of a "gut-bone marrow axis" through which gut-derived signals orchestrate hematopoietic homeostasis. However, shifting from correlative observations to causal mechanisms remains a major challenge in defining precise microbial impacts on hematopoietic outcomes. In this review, we systematically synthesize current knowledge on the molecular mechanisms by which microbial products-specifically short-chain fatty acids (SCFAs) and bile acids-translocate into the systemic circulation to modulate hematopoietic stem cell (HSC) function, lineage commitment, and the bone marrow microenvironment. Furthermore, we discuss how gut dysbiosis acts as a driver of hematopoietic dysfunction, contributing to the pathogenesis of anemia, bone marrow failure, and hematologic malignancies such as leukemia. Beyond mechanistic insights, this review critically evaluates the therapeutic promise of emerging microbiota-targeted interventions, including precision probiotics, prebiotics, and FMT, which hold the potential to modulate hematopoietic function and support recovery. Although preclinical evidence is accumulating, these approaches are underpinned by limited yet mechanistically informative clinical evidence. Thus, these emerging interventions require rigorous mechanistic validation and well-designed clinical trials. Herein, by integrating multi-systemic perspectives, we provide a comprehensive framework for future research and clinical strategies aimed at leveraging the microbiota to treat hematologic disorders.