Prebiotics and the gut–bone marrow axis: potential remodeling of the hematopoietic/leukemic stem cell niche via short-chain fatty acids and AhR signaling

Gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan-derived indole ligands of the aryl hydrocarbon receptor (AhR), can enter the circulation and modulate the bone marrow microenvironment, influencing hematopoietic and immune homeostasis. Recent studies suggest that these metabolites may reach the bone marrow and affect the hematopoietic and leukemic stem cell (HSC/LSC) niche. Increasing evidence indicates that the gut microbiome influences bone marrow hematopoiesis through metabolic products and host signaling networks, a bidirectional communication described as the gut–bone marrow axis (GBMA). Along this axis, prebiotic-associated SCFAs and tryptophan–indole/AhR ligands may penetrate the bone marrow microenvironment. However, several specific questions remain unresolved: whether defined prebiotic interventions consistently alter circulating and bone marrow-accessible levels of SCFAs and indole/AhR ligands; which bone marrow cell populations these metabolites target and through what mechanisms; whether they differentially affect normal HSCs and LSCs, including across leukemia subtypes; and whether these changes translate into clinically meaningful outcomes. This review synthesizes evidence on how prebiotic-associated SCFAs and indole/AhR signaling may affect HSC and LSC fate through epigenetic regulation, receptor signaling, and bone marrow niche responses. It also evaluates the current translational evidence and outlines priorities for mechanistic studies and prospective clinical trials.