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Fiorucci S.,University of Perugia | Distrutti E.,Azienda Ospedaliera di Perugia
Trends in Molecular Medicine

The composition of the bile acid pool is a function of the microbial metabolism of bile acids in the intestine. Perturbations of the microbiota shape the bile acid pool and modulate the activity of bile acid-activated receptors (BARs) even beyond the gastrointestinal tract, triggering various metabolic axes and altering host metabolism. Bile acids, in turn, can also regulate the composition of the gut microbiome at the highest taxonomic levels. Primary bile acids from the host are preferential ligands for the farnesoid X receptor (FXR), while secondary bile acids from the microbiota are ligands for G-protein-coupled bile acid receptor 1 (GPBAR1). In this review, we examine the role of bile acid signaling in the regulation of intestinal microbiota and how changes in bile acid composition affect human metabolism. Bile acids may offer novel therapeutic modalities in inflammation, obesity, and diabetes. © 2015 Elsevier Ltd. Source

Renga B.,University of Perugia | Migliorati M.,University of Perugia | Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | And 3 more authors.
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms

Multidrug resistance protein-4 (MRP4) is a member of the multidrug resistance associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive up-regulation in response to cholestatic injury or bile acid feeding. In this study we demonstrate that farnesoid X receptor (FXR) regulates MRP4 in vivo and in vitro. In vivo deletion of FXR induces MRP4 gene expression. In vitro treatment of HepG2 cells with FXR ligands, chenodeoxycholic acid (CDCA), cholic acid (CA) and the synthetic ligand GW-4064 suppresses basal mRNA level of the MRP4 gene as well as the co-treatment with CDCA and 6-(4-Chlorophenyl)imidazo[2,1- b][1,3]thiazole-5-carbaldehyde- O-(3,4-dichlorobenzyl)oxime (CITCO), an activator of constitutive androstane receptor (CAR). We found in the human MRP4 promoter a CAR responsive element (CARE) embedded within an FXR responsive element (FXRE). We cloned this region and found that FXR suppresses CAR activity in luciferase assay. Finally, we demonstrated that FXR competes with CAR for binding to this overlapping binding site. Our results support the view that FXR activation in obstructive cholestasis might worsen liver injury by hijacking a protective mechanism regulated by CAR and provides a new molecular explanation to the pathophysiology of cholestasis. © 2011 Elsevier B.V. Source

Renga B.,University of Perugia | Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | D'Amore C.,University of Perugia | And 6 more authors.

Background: Toll like receptors (TLRs) sense the intestinal microbiota and regulate the innate immune response. A dysregulation of TLRs function participates into intestinal inflammation. Farnesoid X Receptor (FXR) is a nuclear receptor and bile acid sensor highly expressed in entero-hepatic tissues. FXR regulates lipid metabolism and innate immunity. Methodology/Principal Findings: In this study we have investigated whether FXR gene expression/function in the intestine is modulated by TLRs. We found that in human monocytes activation of membrane TLRs (i.e. TLR2, 4, 5 and 6) downregulates, while activation of intracellular TLRs (i.e. TLR3, 7, 8 and 9) upregulates the expression of FXR and its target gene SHP, small heterodimer partner. This effect was TLR9-dependent and TNFα independent. Intestinal inflammation induced in mice by TNBS downregulates the intestinal expression of FXR in a TLR9-dependent manner. Protection against TNBS colitis by CpG, a TLR-9 ligand, was lost in FXR-/- mice. In contrast, activation of FXR rescued TLR9-/- and MyD88-/- mice from colitis. A putative IRF7 response element was detected in the FXR promoter and its functional characterization revealed that IRF7 is recruited on the FXR promoter under TLR9 stimulation. Conclusions/Significance: Intestinal expression of FXR is selectively modulated by TLR9. In addition to its role in regulating type-I interferons and innate antiviral immunity, IRF-7 a TLR9-dependent factor, regulates the expression of FXR, linking microbiota-sensing receptors to host's immune and metabolic signaling. © 2013 Renga et al. Source

Fiorucci S.,University of Perugia | Cipriani S.,University of Perugia | Mencarelli A.,University of Perugia | Renga B.,University of Perugia | And 2 more authors.
Current Molecular Medicine

In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptor named the TGR5. With a different rank of potency primary and secondary bile acids activate a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x-receptor (PXR, NR1H2), and the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases. © 2010 Bentham Science Publishers Ltd. Source

Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | Renga B.,University of Perugia | Bruno A.,University of Perugia | And 3 more authors.

Background: Signals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders. Aims: To investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders. Results: ApoE-/- mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20×109 colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS) in drinking water. Administering DSS to ApoE-/- mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-γ, Farnesoid-X-receptors and vitamin D receptor. Conclusions: Low grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis. © 2012 Mencarelli et al. Source

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