19, 55 Risk variants in the NOD2 gene are also associated with small intestinal occurrence of Cohn’s disease, which is mediated by a compromised expression of Paneth cell defensins.10, 22 Here, the lack of Paneth cell function, especially by the α-defensins HD5 and HD6,10, 22 leads to decreased mucosal

killing activity and shift in the bacterial composition, Palbociclib which likely facilitates bacterial overgrowth and translocation and secondary mucosal and systemic inflammation. In summary, in the healthy state a complex interplay between commensal microbes and the intestinal mucosa results in the establishment of a delicate balance and an intact barrier against pathogens, which prevents inflammation.56 In view of the findings reported here, we hypothesize that in predisposed animals liver cirrhosis leads to the disruption of this host–bacteria balance, mediated by relative deficiency of Paneth cell defensins, particularly in the ileum. This defect weakens intestinal antimicrobial defenses, may lead to progressive changes in the composition of the intestinal microbiota,57-59 and promotes BT. This novel aspect of disease pathophysiology suggests that therapeutic strategies should aim at restoring the host mucosal barrier in cirrhosis. Finally, the data presented emphasize the presence of the liver–gut axis,

underscoring its bidirectional communication. Additional Supporting Information may be found in the online version of this article. “
“Bile acid metabolism is intimately linked to the control of energy homeostasis and glucose and lipid metabolism.

The nuclear receptor farnesoid X receptor (FXR) plays a major role Cilomilast in the enterohepatic cycling of bile acids, but the impact of nutrients on bile acid homeostasis is poorly characterized. Metabolically active hepatocytes cope with increases in intracellular glucose concentrations by directing glucose into storage (glycogen) or oxidation (glycolysis) pathways, as well as to the pentose phosphate shunt and the hexosamine biosynthetic pathway. Here we studied whether the glucose nonoxidative hexosamine biosynthetic pathway modulates FXR activity. Our results show that FXR interacts with and is O-GlcNAcylated by O-GlcNAc transferase in its N-terminal AF1 domain. Increased FXR O-GlcNAcylation enhances FXR gene expression and protein stability Morin Hydrate in a cell type-specific manner. High glucose concentrations increased FXR O-GlcNAcylation, hence its protein stability and transcriptional activity by inactivating corepressor complexes, which associate in a ligand-dependent manner with FXR, and increased FXR binding to chromatin. Finally, in vivo fasting-refeeding experiments show that FXR undergoes O-GlcNAcylation in fed conditions associated with increased direct FXR target gene expression and decreased liver bile acid content. Conclusion: FXR activity is regulated by glucose fluxes in hepatocytes through a direct posttranslational modification catalyzed by the glucose-sensing hexosamine biosynthetic pathway.