Secondary bile acids disrupt hematopoietic stem cell homeostasis.

Abstract

Gut microbiota dysbiosis caused by a high-fat diet disrupts hematopoietic stem cell (HSC) homeostasis; however, the underlying mechanisms remain unclear. Here, we identify gut microbial secondary bile acid deoxycholic acid (DCA) as a key mediator of HSC dysfunction in mice. Plasma DCA levels were elevated during aging, consistent with previously reported increases in high-fat diet-fed mice. Chronic DCA administration upregulated Spred1 in mouse HSCs, as also observed during aging, contributing to HSC loss. DCA treatment in Spred1-deficient mice triggered myeloproliferative neoplasm-like disease, highlighting Spred1's role in mediating a trade-off between HSC aging and tumor suppression. Unexpectedly, DCA-counteracting ursodeoxycholic acid also promoted age-associated expansion of myeloid-biased mouse HSCs. In contrast, a high-fiber diet lowered plasma DCA levels and mitigated aging-associated HSC decline. Our findings reveal that systemic gut microbial metabolites, particularly secondary bile acids, critically affect HSC fate, and suggest that dietary interventions targeting the gut microbiota can regulate hematopoietic homeostasis.