Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome

Lactoferrin (LF) is a multifunctional glycoprotein that can regulate lipid metabolism, lower cholesterol, reduce body weight, and prevent atherosclerosis.

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Implications for Farnesoid X Receptor Signaling on Bile Acid Metabolism as a Potential Therapeutic Strategy for Nonalcoholic Fatty Liver Disease

The Korean Journal of Obesity ◽

10.7570/kjo.2016.25.4.167 ◽

2016 ◽

Vol 25 (4) ◽

pp. 167-175

Author(s):

Hyekyung Yang ◽

Cheol-Young Park

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Therapeutic Strategy ◽

Acid Metabolism ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Nonalcoholic Fatty Liver

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Effects of Rhein on Bile Acid Homeostasis in Rats

BioMed Research International ◽

10.1155/2020/8827955 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Zhong Xian ◽

Jingzhuo Tian ◽

Lianmei Wang ◽

Yushi Zhang ◽

Jiayin Han ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Edible Plant ◽

Clinical Dose ◽

Acid Accumulation ◽

Liver And Kidney ◽

Hepatic Transporters

Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. However, the effects of repeated intake of rhein on liver function and bile acid metabolism are rarely reported. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered with rhein for 5 weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), and bile salt export pump (BSEP) mRNA, and upregulated the expression of (cholesterol 7α-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose (10 mg/kg and 30 mg/kg) reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is relatively safe to use at a reasonable dose and timing. 30 mg/kg rhein may promote bile acid transport and reduce bile acid accumulation by upregulating the expression of FXR mRNA and Mrp3 mRNA, potentially resulting in the decrease in serum UBCAs.

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FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00356.2017 ◽

2019 ◽

Vol 317 (2) ◽

pp. G108-G115 ◽

Cited By ~ 4

Author(s):

Yi Cao ◽

Yongtao Xiao ◽

KeJun Zhou ◽

Junkai Yan ◽

Panliang Wang ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Rat Model ◽

Target Genes ◽

Bowel Resection ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Short Bowel ◽

Expression Levels ◽

The Impact

Mortality associated with liver disease has been observed in patients with short bowel syndrome (SBS); however, its mechanism remains unclear, but bile acid (BA) dysmetabolism has been proposed as a possible cause. The farnesoid X receptor (FXR) is the key regulator of BA synthesis. Here, we showed that, in a rat model of short bowel resection associated with liver disease (SBR-ALD), the BA composition of hepatic tissues reflected a larger proportion of primary and secondary unconjugated BAs, whereas that of the colon contents and serum showed an increased ratio of secondary unconjugated BAs. Both hepatic and intestinal regulation of BA synthesis was characterized by a blunted hepatic FXR activation response. The mRNA expression levels of cholesterol 7a-hydroxylase ( CYP7A1), sterol 12a-hydroxylase ( CYP8B1), and sterol 27 hydroxylase ( CYP27A1), the key enzymes in BA synthesis, were upregulated. After intervention with the FXR agonist GW4064, both the liver histology and serum transaminase activity were improved, which demonstrated the attenuation of SBR-ALD. The BA compositions of hepatic tissue, the colon contents, and serum recovered and were closer to those of the sham group. The expression levels of hepatic FXR increased, and its target genes were activated. Consistent with this, the expression levels of CYP7A1, CYP8B1, and CYP27A1 were downregulated. Ileum tissue FXR and its target genes were slightly elevated. This study showed that the FXR agonist GW4064 could correct BA dysmetabolism to alleviate hepatotoxicity in SBR animals. GW4064 intervention resulted in a decrease in fecal bile excretion and elevated plasma/hepatic conjugated BA levels. GW4064 increased the reabsorption of conjugated BAs by inducing apical sodium-dependent bile salt transporter expression in the ileum. Concomitantly, FXR activation in the presence of GW4064 decreased BA production by repressing the expression of key synthetases, including CYP7A1, CYP8B1, and CYP27A1. These findings provide a clinical research direction for the prevention of liver disease in patients with SBS. NEW & NOTEWORTHY This study assessed the impact of treatment with GW4064, a farnesoid X receptor agonist, on the development of short bowel resection (SBR) associated with liver disease in a rat model of SBR. GW4064 was able to correct bile acid dysmetabolism and alleviate hepatotoxicity in SBR animals.

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Novel β-catenin/farnesoid X receptor interaction regulates hepatic bile acid metabolism during cholestasis

Hepatology ◽

10.1002/hep.29584 ◽

2018 ◽

Vol 67 (3) ◽

pp. 829-832

Author(s):

Laurent Ehrlich ◽

Shannon S. Glaser

Keyword(s):

Bile Acid ◽

Acid Metabolism ◽

Farnesoid X Receptor ◽

Receptor Interaction ◽

Bile Acid Metabolism ◽

Hepatic Bile

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β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

Hepatology ◽

10.1002/hep.29371 ◽

2018 ◽

Vol 67 (3) ◽

pp. 955-971 ◽

Cited By ~ 20

Author(s):

Michael D. Thompson ◽

Akshata Moghe ◽

Pamela Cornuet ◽

Rebecca Marino ◽

Jianmin Tian ◽

...

Keyword(s):

Bile Acid ◽

Acid Metabolism ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Receptor Signaling

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The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211017725 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110177

Author(s):

Benjamin H. Mullish ◽

Jessica R. Allegretti

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Gut Microbiome ◽

Acid Metabolism ◽

Disease Process ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Clostridioides Difficile ◽

Gut Barrier Function ◽

Clostridioides Difficile Infection

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

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Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

Journal of Clinical Medicine ◽

10.3390/jcm11010004 ◽

2021 ◽

Vol 11 (1) ◽

pp. 4

Author(s):

Boyan Zhang ◽

Folkert Kuipers ◽

Jan Freark de de Boer ◽

Jan Albert Kuivenhoven

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Ldl Cholesterol ◽

Farnesoid X Receptor ◽

New Drugs ◽

Bile Acid Metabolism ◽

Atherosclerotic Cardiovascular Disease ◽

Faecal Excretion ◽

Alcoholic Fatty Liver

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.

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P054 Modulation of the Gut Microbiota-Farnesoid X Receptor Axis Improves Deoxycholic Acid-induced Intestinal Inflammation in Mice

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.183 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S161-S161

Author(s):

M Xu ◽

Y Shen ◽

M Cen

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Acid Metabolism ◽

Deoxycholic Acid ◽

Intestinal Inflammation ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Gut Dysbiosis ◽

Rdna Sequencing

Abstract Background Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernized diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal microbiota and bile acid metabolism in mice with DCA-induced intestinal inflammation. Methods 4-week-old wild-type C57BL mice were fed with AIN-93G (control diet), AIN-93G+0.2% DCA, AIN-93G+0.2% DCA+6 weeks of fexaramine (FXR agonist), or AIN-93G+0.2% DCA+antibiotic cocktail for 24 weeks. Histopathology, Western blotting, and qPCR were performed on the intestinal tissue. Fecal microbiota was analyzed by 16S rDNA sequencing. Fecal bile acid and short-chain fatty acid (SCFA) levels were analyzed by chromatography. Results Gut dysbiosis and enlarged bile acid pool were observed in DCA-treated mice, accompanied by a lower farnesoid X receptor (FXR) activity in the intestine. Administration of fexaramine mitigated DCA-induced intestinal injury, restored intestinal FXR activity, activated ﬁbroblast growth factor 15, and normalized bile acid metabolism. Furthermore, fexaramine administration increased the abundance of SCFA-producing bacteria. Depletion of the commensal microbiota with antibiotics decreased the diversity of the intestinal microbiota, attenuated bile acid synthesis, and reduced intestinal inflammation induced by DCA. Conclusion DCA induced-intestinal inflammation is associated with alterations of gut microbiota and bile acid proﬁles. Interventions targeting the gut microbiota-FXR signaling pathway may reduce DCA-induced intestinal disease.

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