The gut-bone marrow axis in acute leukemia: an evidence-graded review of microbiota-immune crosstalk and therapeutic implications

The gut microbiota is increasingly associated with immune dysfunction, treatment-related complications, and clinical outcomes in acute leukemia (AL), but the literature remains dominated by observational cohorts and mechanistic extrapolation from non-leukemia settings. This review critically evaluates gut dysbiosis, microbial metabolites, immune-cell remodeling, and microbiota-directed interventions in AL through an evidence-graded, leukemia-centered framework. We distinguish AL-specific human associations, AL-specific experimental evidence, mechanistic evidence from other disease contexts, and hypotheses that remain to be tested. The available data support a context-dependent gut-bone marrow model in which dysbiosis may influence AL through three non-exclusive routes: loss of barrier-supportive microbial functions with increased translocation of microbial products; systemic distribution of microbial metabolites and inflammatory mediators that act on bone marrow stromal, myeloid, and lymphoid compartments; and trafficking of microbiota-educated immune cells from the intestine to distant tissues. Among candidate mediators, AL-specific experimental evidence is strongest for reduced butyrate availability, intestinal barrier injury, lipopolysaccharide leakage, and accelerated leukemia progression in murine AML. By contrast, direct microbiota-derived metabolite-induced transcriptional reprogramming of human leukemia blasts, including whether butyrate regulates the same targets in blasts as in colonocytes or mature immune cells, has not been established. We further show that apparently conflicting microbial signatures can be explained by differences in disease subtype, age, treatment phase, antibiotic exposure, diet, sampling, analytical platform, and functional redundancy among taxa. On this basis, we propose a two-hit model and a set of testable hypotheses for paired stool-plasma-bone marrow studies, metabolite tracing, immune-cell clonotype tracking, and mechanism-based intervention trials. This evidence-graded gut-bone marrow perspective defines the distinct contribution of the review and provides a more conservative basis for interpreting microbiota-targeted strategies in AL.