Characterization of the gut-bone marrow axis through bile acid signaling

Communication between the intestine and other organs such as the lungs, brain or bones is mediated by several metabolites, like short-chain fatty acids or bile acids, that relay information about nutritional and microbiota status. Bile acids are endogenous surfactants that are key in the intestinal absorption of dietary fats. Bile acids also function as bona fide hormones mediating pleiotropic effects thanks to several receptors that are responsive to these molecules, including dedicated receptors such as farnesoid X receptor or Takeda G-protein receptor 5 (TGR5). TGR5 modulates the functions of both digestive and extra-digestive systems, regulating metabolism in a multitude of tissues. The effects of TGR5 have been described in a variety of cells, including adipocytes, osteoblasts and endothelial cells. Adipocytes, osteoblasts and endothelial cells are key components of the hematopoietic niche, a structure that regulates hematopoietic stem and progenitor cell function, including quiescence self-renewal and commitment towards differentiated cells. TGR5 has been described to have an immunomodulatory in cells of the myeloid lineage role but its effect on the bone marrow has not been described yet. The activity of the bone marrow is regulated by the microbiome as germ-free or antibiotic-treated mice show alterations in hematopoiesis. Since the bile acid pool shapes and is shaped by the microbiome, we hypothesize that bile acids serve as signalling molecules that modulate bone marrow activity.To unveil the potential communication of the gut and the bone marrow via bile acid signalling, we will focus on understanding the alterations in the bone marrow of mice lacking TGR5 using a combination of in vitro and in vivo approaches. For this project, we will first define the global impact of TGR5 on steady-state and stress hematopoiesis using a TGR5 KO murine model. We will then dissect the action of TGR5 in the bone marrow by separately evaluating its effect in the hematopoietic compartment and the niche. Finally, we will screen a library of bile acids to obtain insight into their potential for the improvement of hematopoietic recovery in situations of high demand. Our preliminary results indicate that the lack of TGR5 increases the number of hematopoietic cells in the bone marrow and decreases the short-term repopulating capacity of bone marrow cells upon bone marrow transplantation. Furthermore, it brings about changes in the bone marrow stroma as we have found an increase in adipogenic precursor cells concomitant with a decrease in osteochondrogenic progenitor cells. Moreover, our preliminary results indicate that stroma cells isolated from TGR5 KO mice might be less supportive of hematopoietic cell proliferation in vitro. Our ultimate goal is to use the knowledge obtained from this project to provide a basis to guide rational modifications of the microbiome and steer the production of bile acids in a demand-adapted manner. In doing so, our objective is to open novel therapeutic avenues to aid in the recovery of patients suffering from hematopoietic failure by harnessing the gut-bone marrow axis.