Secondary Bile Acids Interact with Hematopoietic Progenitors and Promote Myelopoiesis via the Vitamin D Receptor

Myelopoiesis is the process by which all circulating myeloid cells, including
granulocytes, and monocyte/macrophages are produced from bone marrow hematopoietic
stem and progenitor cells (HSPCs). While this process is critical to maintain sufficient daily
numbers of myeloid cells, the signals that regulate myelopoiesis are not fully understood.
A recent body of literature suggests that the gut microbiome and its metabolites can
regulate hematopoiesis during homeostasis and inflammation.
We demonstrate here that host derived, microbially metabolized, secondary bile
acids are sufficient to enhance myelopoiesis. Colony forming assays demonstrated that
treatment of whole bone marrow with secondary bile acids, deoxycholic acid (DCA), or
lithocholic acid (LCA), but not primary bile acid and DCA precursor, cholic acid (CA),
expanded immunotypic and functional (CFU-GM), granulocyte monocyte progenitors
(GMPs). We demonstrate that treatment with DCA and LCA not only significantly elevated
GMPs, but also common myeloid progenitors (CMPs), as well as neutrophils and
macrophages. DCA treatment of a sorted HSPC population, LSK (Lin-, SCA-1+, C-KIT+)
cells, resulted in the expansion of myeloid colonies in the absence of stromal cells.
Importantly, we did not observe an enhancement of myelopoiesis when treating sorted
CMPs or GMPs, demonstrating that secondary bile acids promote myeloid cell
development early in hematopoiesis. We determined that DCA-enhanced myelopoiesis
required the secondary bile acid sensing vitamin D receptor (VDR) both in vitro as well as
in vivo. Single cell RNA-sequencing revealed that GMPs from DCA treated cultures
exhibited gene expression consistent with elevated cellular proliferation and myeloid
differentiation. Altogether, our data uncover a novel pathway via which secondary bile acids
communicate with HSPCs to promote myelopoiesis in a VDR-dependent manner.