FXR-Dependent Modulation of the Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid

Friedman, Elliot S.; Li, Yun; Shen, Ting-Chin David; Jiang, Jack; Chau, Lillian; Adorini, Luciano; Babakhani, Farah; Edwards, Jeffrey E.; Shapiro, D. A.; Zhao, Chunyu; Carr, Rotonya M.; Bittinger, Kyle; Li, Hongzhe; Wu, Gary D.

doi:10.1053/j.gastro.2018.08.022

Cited by 95 publications

(84 citation statements)

References 41 publications

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“…HFD was shown to induce increased phylum Firmicutes or the Firmicutes/Bacteroidetes ratio, whereas BD surgery enhanced Bacteroidetes in WT mice (4). Recent findings showed that FXR activation altered gut microbiota composition in humans (37). The current data show a distinct distribution of cecal microbiota in LFD-and HFD-fed FXRko mice with a decrease of phylum Bacteroidetes.…”

Section: Discussionsupporting

confidence: 46%

Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR)

Pierre

Gomes

et al. 2019

Obesity

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Objective The current study investigated whether bile diversion (BD) improves metabolic phenotype under farnesoid X receptor (FXR) deficiency. Methods BD was performed in high‐fat diet (HFD)‐fed FXR knockout (FXRko) and wild‐type (WT) animals. Metabolic phenotypes, circulating enteroendocrine hormones, total bile acids (BAs) and BA composition, and cecal gut microbiota were analyzed. Results FXR‐deficient mice were resistant to HFD‐induced obesity; however, FXR‐deficient mice also developed hyperglycemia and exhibited increased liver weight, liver steatosis, and circulating triglycerides. BD increased circulating total BAs and taurine‐b‐muricholic acid, which were in line with normalized hyperglycemia and improved glucose tolerance in HFD‐fed WT mice. FXR deficiency also increased total BAs and taurine‐b‐muricholic acid, but these animals remained hyperglycemic. While BD improved metabolic phenotype in HFD‐fed FXRko mice, these improvements were not as effective as in WT mice. BD increased liver expression of fibroblast growth factor 21 and peroxisome proliferator‐activated receptor γ coactivator‐1β and elevated circulating glucagon‐like peptide‐1 levels in WT mice but not in FXRko mice. FXR deficiency altered gut microbiota composition with a specific increase in phylum Proteobacteria that may act as a possible microbial signature of some diseases. These cellular and molecular changes in FXRko mice may contribute to resistance toward improved metabolism. Conclusions FXR signaling plays a pivotal role in improved metabolic phenotype following BD surgery.

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Section: Discussionsupporting

confidence: 46%

Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR)

Pierre

Gomes

et al. 2019

Obesity

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“…In a phase 1 RCT in man, treatment with obeticholic acid for 17 days, that suppressed bile acid synthesis, produced a reversible induction of Gram-positive bacteria that are found in the small intestine. There was also an increase in the representation of microbial genomic pathways involved in DNA synthesis and amino acid metabolism with obeticholic acid treatment [158].…”

Section: Obeticholic Acid and Other Drugsmentioning

confidence: 98%

NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications

Targher

Byrne

Tilg

2020

Gut

473

365

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Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world’s adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.

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“…The use of BA receptor agonists and antagonists and their indirect effects (BA pool, synthesis, circulation, and the gut microbiome composition) is summarized in Figure 2. The human and mouse gut microbiome fluctuates with the increase or decrease of BAs, which can lead to increased inflammation and intestinal malabsorption (19,37,80,(84)(85)(86). In depth exploration of BA signaling and circulation during chronic liver diseases may provide insight to disease amelioration or treatment strategies.…”

Section: Resultsmentioning

confidence: 99%

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

et al. 2020

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In the past ten years, our understanding of the importance of bile acids has expanded from fat absorption and glucose/lipid/energy homeostasis into potential therapeutic targets for amelioration of chronic cholestatic liver diseases. The discovery of important bile acid signaling mechanisms, as well as their role in metabolism, has increased the interest in bile acid/bile acid receptor research development. Bile acid levels and speciation are dysregulated during liver injury/damage resulting in cytotoxicity, inflammation, and fibrosis. An increasing focus to target bile acid receptors, responsible for bile acid synthesis and circulation, such as Farnesoid X receptor and apical sodium-dependent bile acid transporter to reduce bile acid synthesis have resulted in clinical trials for treatment of previously untreatable chronic liver diseases such as non-alcoholic steatohepatitis and primary sclerosing cholangitis. This review focuses on current bile acid receptor mediators and their effects on parenchymal and non-parenchymal cells. Attention will also be brought to the gut/liver axis during chronic liver damage and its treatment with bile acid receptor modulators. Overall, these studies lend evidence to the importance of bile acids and their receptors on liver disease establishment and progression.

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FXR-Dependent Modulation of the Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid

Cited by 95 publications

References 41 publications

Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR)

Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR)

NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

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