scholarly journals Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3709 ◽  
Author(s):  
Piero Portincasa ◽  
Agostino Di Ciaula ◽  
Gabriella Garruti ◽  
Mirco Vacca ◽  
Maria De Angelis ◽  
...  
Keyword(s):  
Bile Acids ◽  
Gut Microbiome ◽  
Portal Tract ◽  
Farnesoid X Receptor ◽  
Metabolic Effects ◽  
Remnant Liver ◽  
Prevention Measures ◽  
Distal Intestine ◽  
Gene Environment ◽  
Fat Soluble Vitamins

Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.

Abstract P473: Obstructive Sleep Apnea Results In Microbial Bile Acid Biotransformations To Promote Atherosclerosis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Amulya Lingaraju ◽  
Stephany Flores Ramos ◽  
Emily Gentry ◽  
Orit Poulsen ◽  
Pieter C Dorrestein ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Bile Acid ◽  
Sleep Apnea ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Atherosclerotic Lesion ◽  
Farnesoid X Receptor ◽  
Lesion Formation ◽  
Aortic Lesion ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is an independent exacerbator of cardiovascular disease (CVD). However, it is unclear how OSA or it’s characteristic components, intermittent hypoxia and hypercapnia (IHC), increase CVD risk. Our previous work has shown that IHC reproducibly changes the gut microbiome dynamics in murine models of atherosclerosis and that these changes could affect host cardiovascular physiology through bile acids and phosphocholines. In our initial targeted metabolomics approach, changes in particular bile acids, such as taurocholic acid, taurodeoxycholic acid, and muricholic acid, were associated with and were predictive of IHC exposure in atherosclerotic Ldlr-/- mice. In a more recent study, we identified the formation of novel, microbially-synthesized conjugated bile acids by the gut microbiome that are more potent farnesoid X receptor agonists than other previously described bile acids, and thus, potentially can affect atherosclerosis formation. To determine whether these novel bile acids are associated with IHC-induced atherosclerosis, we characterized luminal bile acid changes in Ldlr-/- mice in an OSA model. We hypothesize that IHC alters the amount of microbially-synthesized novel bile acids and that these bile acids are associated with IHC-induced atherosclerosis. To test this hypothesis, we subjected atherogenic diet-fed Ldlr-/- mice to either room-air (control) or IHC conditions (n=10/condition) and assessed atherosclerotic lesion formation after 12 weeks post-diet. Mice under IHC conditions had significantly higher aortic lesion formation compared to controls. Assessment of fecal bile acid metabolites indicated changes in novel bile acid levels under IHC conditions. Moreover, correlational analysis showed that these novel bile acid changes were positively correlated with atherosclerotic lesion amounts, mainly driven by IHC conditions. Our results demonstrate that bile acid changes through microbial biotransformations occur under IHC conditions and could be the mechanistic link between OSA-induced microbiome changes and atherosclerosis.

scholarly journals Bile Acids, FXR, and Metabolic Effects of Bariatric Surgery

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Olivier F. Noel ◽  
Christopher D. Still ◽  
George Argyropoulos ◽  
Michael Edwards ◽  
Glenn S. Gerhard
Keyword(s):  
Bariatric Surgery ◽  
Lipid Metabolism ◽  
Bile Acids ◽  
Metabolic Diseases ◽  
Overweight And Obesity ◽  
Farnesoid X Receptor ◽  
Metabolic Effects ◽  
The Novel ◽  
Treatment Of Obesity ◽  
Lipid Metabolism Genes

Overweight and obesity represent major risk factors for diabetes and related metabolic diseases. Obesity is associated with a chronic and progressive inflammatory response leading to the development of insulin resistance and type 2 diabetes (T2D) mellitus, although the precise mechanism mediating this inflammatory process remains poorly understood. The most effective intervention for the treatment of obesity, bariatric surgery, leads to glucose normalization and remission of T2D. Recent work in both clinical studies and animal models supports bile acids (BAs) as key mediators of these effects. BAs are involved in lipid and glucose homeostasis primarily via the farnesoid X receptor (FXR) transcription factor. BAs are also involved in regulating genes involved in inflammation, obesity, and lipid metabolism. Here, we review the novel role of BAs in bariatric surgery and the intersection between BAs and immune, obesity, weight loss, and lipid metabolism genes.

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

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.

scholarly journals Gut Microbiome of Indonesian Adults Associated with Obesity and Type 2 Diabetes: A Cross-Sectional Study in an Asian City, Yogyakarta

2021 ◽  
Vol 9 (5) ◽  
pp. 897
Author(s):  
Phatthanaphong Therdtatha ◽  
Yayi Song ◽  
Masaru Tanaka ◽  
Mariyatun Mariyatun ◽  
Maisaroh Almunifah ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Dietary Habits ◽  
Lifestyle Changes ◽  
Farnesoid X Receptor ◽  
Triangular Distribution ◽  
Obese People ◽  
Obesity And Diabetes

Indonesia is a developing country facing the national problem of the growing obesity and diabetes in its population due to recent drastic dietary and lifestyle changes. To understand the link between the gut microbiome, diet, and health of Indonesian people, fecal microbiomes and metabolomes of 75 Indonesian adults in Yogyakarta City, including obese people (n = 21), type 2 diabetes (T2D) patients (n = 25), and the controls (n = 29) were characterized together with their dietary and medical records. Variations of microbiomes showed a triangular distribution in the principal component analysis, driven by three dominant bacterial genera, namely Bacteroides, Prevotella, and Romboutsia. The Romboutsia-driven microbiome, characterized by low bacterial diversity and high primary bile acids, was associated with fat-driven obesity. The Bacteroides-driven microbiome, which counteracted Prevotella but was associated with Ruminococcaceae concomitantly increased with high-carbohydrate diets, showed positive correlation with T2D indices but negative correlation with body mass index. Notably, Bacteroides fragilis was increased in T2D patients with a decrease in fecal conjugated bile acids, particularly tauroursodeoxycholic acid (TUDCA), a farnesoid X receptor (FXR) antagonist with anti-diabetic activity, while these features disappeared in patients administered metformin. These results indicate that the gut microbiome status of Indonesian adults is differently associated with obesity and T2D under their varied dietary habits.

scholarly journals Gut Microbiome of Indonesian Adults Differently Associated with Obesity and type 2 Diabetes under Varied Dietary Habits: A Cross-sectional Study in an Asian Developing City, Yogyakarta

2020 ◽  
Author(s):  
Phatthanaphong Therdtatha ◽  
Yayi Song ◽  
Masaru Tanaka ◽  
Mariyatun Mariyatun ◽  
Miisaroh Almunifah ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Dietary Habits ◽  
Lifestyle Changes ◽  
Farnesoid X Receptor ◽  
Triangular Distribution ◽  
Obese People ◽  
Obesity And Diabetes

Abstract Indonesia is a developing country facing the national problem of the growing obesity and diabetes in its population due to recent drastic dietary and lifestyle changes. To understand the interface between the gut microbiome, diet, and health of Indonesian people, we characterized fecal microbiomes and metabolomes of 75 Indonesian adults in Yogyakarta City, including 21 obese people and 25 type 2 diabetes (T2D) patients, together with their dietary and medical records. Variations of microbiomes showed a triangular distribution in the principal component analysis, driven by three dominant bacterial genera, namely Bacteroides, Prevotella, and Romboutsia. The Romboutsia-driven microbiome, characterized by low bacterial diversity and high primary bile acids, was associated with fat-driven obesity. The Bacteroides-driven microbiome, which counteracted Prevotella but was associated with Ruminococcaceae concomitantly increased with high-carbohydrate diets, showed positive correlation with T2D indices but negative correlation with body mass index. Notably, Bacteroides fragilis was increased in T2D patients with a decrease of fecal conjugated bile acids, particularly tauroursodeoxycholic acid, a farnesoid X receptor antagonist with anti-diabetic activity, while these features disappeared in patients administered metformin. These results indicate that the gut microbiome status of Indonesian adults is differently associated with obesity and T2D under their varied dietary habits.

Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes

2012 ◽  
Vol 302 (1) ◽  
pp. E68-E76 ◽  
Author(s):  
Lihong Chen ◽  
Xiaozhou Yao ◽  
Andrew Young ◽  
Judi McNulty ◽  
Don Anderson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Fold Increase ◽  
Tolerance Test ◽  
Farnesoid X Receptor ◽  
Oral Glucose ◽  
Dependent Manner ◽  
Distal Intestine ◽  
Bile Acid Transporter ◽  
Zdf Rats

Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.

scholarly journals Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lori W. E. van der Schoor ◽  
Henkjan J. Verkade ◽  
Anna Bertolini ◽  
Sanne de Wit ◽  
Elvira Mennillo ◽  
...  
Keyword(s):  
Bile Acids ◽  
Treatment Options ◽  
Preventive Treatment ◽  
Neonatal Hyperbilirubinemia ◽  
Farnesoid X Receptor ◽  
Neurological Damage ◽  
Obeticholic Acid ◽  
Protein Levels ◽  
Gunn Rats ◽  
Plasma Bilirubin

AbstractNeonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

scholarly journals Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Edward C. Deehan ◽  
Eloisa Colin-Ramirez ◽  
Lucila Triador ◽  
Karen L. Madsen ◽  
Carla M. Prado ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Randomized Controlled Trial ◽  
Combination Therapy ◽  
Gut Microbiome ◽  
Controlled Trial ◽  
Fecal Microbiota ◽  
Metabolic Effects ◽  
Microbiota Composition ◽  
Randomized Controlled ◽  
Secondary Outcomes

Abstract Background Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome. Methods This is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12–18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids. Discussion This study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention. Trial registration ClinicalTrials.gov NCT04578652. Registered on 8 October 2020.

scholarly journals Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1104
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Richard L. Young ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Peptide Yy ◽  
Glycogen Synthesis ◽  
Hormone Secretion ◽  
Gastrointestinal Hormones ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Hormone ◽  
Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

Sign in / Sign up

Export Citation Format

Share Document