Project description:Microbial transformation of bile acids affects intestinal immune homeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. Additionally, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.
Project description:Nudix hydrolase 7 (NUDT7) is a peroxisomal (acyl-)CoA-degrading enzyme that is highly expressed in the liver. We previously showed that liver-specific NUDT7 overexpression affects peroxisomal lipid metabolism, but does not prevent the increase in total liver CoA levels that occurs with fasting. Herein, we show that deletion of Nudt7 alters the composition of the hepatic acyl-CoA pool in mice fed a low fat diet, but only in males fed a western diet does the lack of NUDT7 increase total liver CoA levels. This effect is driven by the accumulation of medium-chain dicarboxylic acyl-CoAs, which are products of the oxidation of dicarboxylic fatty acids in the peroxisomes. We also show that, under conditions of increased cholesterol intake and elevated bile acid synthesis, Nudt7 deletion increases the production of tauro-muricholic acids, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion. Collectively, our findings reveal a key role for NUDT7 in the regulation of the final products of bile acid synthesis and dicarboxylic fatty acid oxidation
Project description:Data acquired for conjugated bile acids with amino acids analysis of human fecal samples by targeted LC-MS. These samples are a part of a study investigating a new BSH function as an amine N-acyl transferase that conjugates amines to form bacterial bile acid amidates (BBAAs).
Project description:Engineered bacterial strains with bile salt hydrolase that changed in their expression levels with high diet and diurnal changes were synthesized. These synthetic strains were cultures in BHI media with bile acids spiked in.
Project description:Escherichia coli transformed with bile salt hydrolase gene from Bifidobacterium is treated with conjugated (TCA/GCA) and unconjugated (CA/DCA) bile acids and grown overnight.
Project description:Engineered bacterial strains with bile salt hydrolase that changed in their expression levels with high diet and diurnal changes were synthesized. These synthetic strains were cultures in BHI media with bile acids spiked in.
Project description:E. coli DH5a expressing bile salt hydrolase variants in the presence of 1 mM glycocholate (GCA), taurocholate (TCA), or cholate (CA).
