Abstract
Once known exclusively for their role in nutrients absorption, primary bile acids, chenodeoxycholic and cholic acid, and secondary bile acids, deoxycholic and lithocholic acid, are signaling molecules, generated from cholesterol breakdown by the interaction of the host and intestinal microbiota, acting on several receptors including the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5) and the Farnesoid-X-Receptor (FXR). Both receptors are placed at the interface of the host immune system with the intestinal microbiota and are highly represented in cells of innate immunity such as intestinal and liver macrophages, dendritic cells and natural killer T cells. Here, we review how GPBAR1 and FXR modulate the intestinal and liver innate immune system and contribute to the maintenance of a tolerogenic phenotype in entero-hepatic tissues, and how regulation of innate immunity might help to explain beneficial effects exerted by GPBAR1 and FXR ligands in immune and metabolic disorders.
Highlights
Once known exclusively for their role in nutrients absorption, primary bile acids, chenodeoxycholic and cholic acid, and secondary bile acids, deoxycholic and lithocholic acid, are signaling molecules, generated from cholesterol breakdown by the interaction of the host and intestinal microbiota, acting on several receptors including the G proteincoupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5) and the FarnesoidX-Receptor (FXR)
Both receptors are found in non-epithelial cells, including intestinal muscles and neurons (GPBAR1), biliary cells (FXR and G-protein bile acid receptor 1 (GPBAR1)), liver sinusoidal cells, and intestinal and liver endothelial cells (FXR and GPBAR1) [5]. Both receptors, as well as VDR and LXRs, are highly represented in immune cells, monocytes and macrophages, dendritic cells (DCs) and natural killer (NK) (ILC1) and NKT cells, and to lesser extent in T and B cells [7,8,9,10]. It is unclear whether the low level expression of GPBAR1 and FXR in T and B cells results in any functional activity or is regulated in pathological conditions, activation of bile acids activated receptors (BARs) in macrophages, DCs, and NKT, results in several regulatory functions that are inhibitory in nature, and both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine innate immunity in face of a continuous flow of dietary xenobiotics and antigens generated by the intestinal microbiota [6]
Bile acids are synthesized in the liver from cholesterol breakdown and further metabolized by the intestinal microbiota to generate a family of steroidal hormones that exert a wide array of regulatory functions
Summary
Edited by: Nicole Thielens, UMR5075 Institut de Biologie Structurale (IBS), France. Reviewed by: Wendong Huang, Beckman Research Institute, City of Hope, United States. Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal
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