Bile acids in intestinal homeostasis and allogeneic hematopoietic transplantation

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PROJECT SUMMARY/ABSTRACT – PROJECT 2 Bile acids (BAs) are synthesized in the liver from cholesterol, conjugated with taurine or glycine, stored in the gallbladder and released into the duodenum in response to food ingestion. In the intestine, conjugated primary BAs undergo amino acid deconjugation by bacterial bile salt hydrolases (BSHs) followed by several modifications including 7α-dehydroxylation by anaerobic bacteria to produce secondary BAs. Although a main function of BAs is to promote the intestinal absorption and transport of dietary lipids, it is now recognized that BAs also regulate diverse physiological processes. Vancomycin- resistant enterococcus (VRE) is one of the leading causes of bloodstream infection in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in hospitals around the world including the United States. Dominant intestinal colonization in patients undergoing allo-HCT can lead to bloodstream VRE infection, high mortality rates, and patient-to-patient transmission in hospitals. Notably, VRE can be eradicated from the intestine by fecal transplantation and several symbiotic bacterial species have been shown to promote VRE intestinal clearance. However, the mechanism by which members of the microbiota inhibit VRE colonization remains unknown. To understand the mechanism that regulates VRE colonization by the microbiota and how VRE affects the intestine during allo-HCT, we have developed a VRE model in the mouse by transferring a vancomycin-resistance plasmid from a human VRE strain to a mouse Enterococcus fecalis strain by conjugation. Upon treatment with antibiotics, mouse VRE accumulated in the mouse intestine to levels comparable to human VRE in patients undergoing allo-HCT. Using the mouse VRE model, we have identified a role for BAs in the regulation of VRE colonization in the intestine. Deconjugation of glycine or taurine-conjugated BAs is the key rate-limiting step in BA metabolism which is mediated by bacterial BSH enzymes. We have identified mouse symbiotic bacteria that mediate BA deconjugation and promote the production of cholic acid (CA) and DCA from conjugated BAs which correlates with the generation of VRE-inhibitory activity. We also found that the amounts of primary and secondary BAs in the intestine are decreased after allo-HCT. The overreaching hypothesis is that specific BA-processing bacteria, BAs and host factors including the bile acid receptor FXR regulate VRE colonization and graft-versus-host disease (GVHD) after allo-HCT. To address these hypotheses, we propose three specific Aims to understand the role of BAs and BA-induced signaling in VRE colonization and GVHD.