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Intestinal bile acids directly modulate the structure and function of TcdB toxin.
Tam J, Icho S, Utama E, Orrell KE, Gómez-Biagi RF, Theriot CM, Kroh HK, Rutherford SA, Lacy DB, Melnyk RA
(2020) Proc Natl Acad Sci U S A 117: 6792-6800
MeSH Terms: Bacterial Toxins, Bile Acids and Salts, Caco-2 Cells, Clostridioides difficile, Clostridium Infections, HCT116 Cells, Humans, Intestines, Receptors, Cell Surface
Show Abstract · Added March 24, 2020
Intestinal bile acids are known to modulate the germination and growth of Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant of disease. We show that individual primary and secondary bile acids reversibly bind and inhibit TcdB to varying degrees through a mechanism that requires the combined oligopeptide repeats region to which no function has previously been ascribed. We find that bile acids induce TcdB into a compact "balled up" conformation that is no longer able to bind cell surface receptors. Lastly, through a high-throughput screen designed to identify bile acid mimetics we uncovered nonsteroidal small molecule scaffolds that bind and inhibit TcdB through a bile acid-like mechanism. In addition to suggesting a role for bile acids in pathogenesis, these findings provide a framework for development of a mechanistic class of antitoxins.
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9 MeSH Terms
Utilizing Untargeted Ion Mobility-Mass Spectrometry To Profile Changes in the Gut Metabolome Following Biliary Diversion Surgery.
Poland JC, Schrimpe-Rutledge AC, Sherrod SD, Flynn CR, McLean JA
(2019) Anal Chem 91: 14417-14423
MeSH Terms: Anastomosis, Surgical, Animals, Bile Acids and Salts, Bile Ducts, Cholesterol, Chromatography, Liquid, Duodenum, Fatty Acids, Volatile, Feces, Gastrointestinal Microbiome, Ileum, Jejunum, Male, Mass Spectrometry, Mice, Inbred C57BL
Show Abstract · Added December 17, 2019
Obesity and obesity-related disorders are a global epidemic affecting over 10% of the world's population. Treatment of these diseases has become increasingly challenging and expensive. The most effective and durable treatment for Class III obesity (body mass index ≥35 kg/m) is bariatric surgery, namely, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy. These procedures are associated with increased circulating bile acids, molecules that not only facilitate intestinal fat absorption but are also potent hormones regulating numerous metabolic pathways. We recently reported on a novel surgical procedure in mice, termed distal gallbladder bile diversion to the ileum (GB-IL), that emulates the altered bile flow after RYGB without other manipulations of gastrointestinal anatomy. GB-IL improves oral glucose tolerance in mice made obese with high-fat diet. This is accompanied by fat malabsorption and weight loss, which complicates studying the role of elevated circulating bile acids in metabolic control. A less aggressive surgery in which the gallbladder bile is diverted to the proximal ileum, termed GB-IL, also improves glucose control but is not accompanied by fat malabsorption. To better understand the differential effects achieved by these bile diversion procedures, an untargeted ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) method was optimized for fecal samples derived from mice that have undergone bile diversion surgery. Utilizing the UPLC-IM-MS method, we were able to identify dysregulation of bile acids, short-chain fatty acids, and cholesterol derivatives that contribute to the differential metabolism resulting from these surgeries.
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15 MeSH Terms
Metabolic Effects of Bile Acids: Potential Role in Bariatric Surgery.
Flynn CR, Albaugh VL, Abumrad NN
(2019) Cell Mol Gastroenterol Hepatol 8: 235-246
MeSH Terms: Akkermansia, Animals, Bariatric Surgery, Bile Acids and Salts, Humans, Insulin Resistance, Obesity, Morbid, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Verrucomicrobia
Show Abstract · Added December 17, 2019
Bariatric surgery is the most effective and durable treatment for morbid obesity, with an unexplained yet beneficial side effect of restoring insulin sensitivity and improving glycemia, often before weight loss is observed. Among the many contributing mechanisms often cited, the altered handling of intestinal bile acids is of considerable therapeutic interest. Here, we review a growing body of literature examining the metabolic effects of bile acids ranging from their physical roles in dietary fat handling within the intestine to their functions as endocrine and paracrine hormones in potentiating responses to bariatric surgery. The roles of 2 important bile acid receptors, Takeda G-protein coupled receptor (also known as G-protein coupled bile acid receptor) and farnesoid X receptor, are highlighted as is downstream signaling through glucagon-like polypeptide 1 and its cognate receptor. Additional improvements in other phenotypes and potential contributions of commensal gut bacteria, such as Akkermansia muciniphila, which are manifest after Roux-en-Y gastric bypass and other emulations, such as gallbladder bile diversion to the ileum, are also discussed.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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10 MeSH Terms
Gastroesophageal Reflux Induces Protein Adducts in the Esophagus.
Caspa Gokulan R, Adcock JM, Zagol-Ikapitte I, Mernaugh R, Williams P, Washington KM, Boutaud O, Oates JA, Dikalov SI, Zaika AI
(2019) Cell Mol Gastroenterol Hepatol 7: 480-482.e7
MeSH Terms: Acetylcysteine, Animals, Benzylamines, Bile Acids and Salts, Cell Line, Cyclic N-Oxides, Esophagus, Gastroesophageal Reflux, Humans, Lipids, Mice, Spin Labels, Tumor Suppressor Protein p53
Added March 26, 2019
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13 MeSH Terms
Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels.
Shibao CA, Celedonio JE, Tamboli R, Sidani R, Love-Gregory L, Pietka T, Xiong Y, Wei Y, Abumrad NN, Abumrad NA, Flynn CR
(2018) J Clin Endocrinol Metab 103: 1856-1866
MeSH Terms: Adult, African Americans, Bile Acids and Salts, CD36 Antigens, Case-Control Studies, Energy Metabolism, Fasting, Female, Genotype, Hormones, Humans, Intestinal Absorption, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added May 14, 2018
Context - Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism, but whether it has similar actions in humans is unknown. We examined the impact of a coding single-nucleotide polymorphism in CD36 on postprandial hormone and bile acid (BA) responses.
Objective - To examine whether the minor allele (G) of coding CD36 variant rs3211938 (G/T), which reduces CD36 level by ∼50%, influences hormonal responses to a high-fat meal (HFM).
Design - Obese African American (AA) women carriers of the G allele of rs3211938 (G/T) and weight-matched noncarriers (T/T) were studied before and after a HFM.
Setting - Two-center study.
Participants - Obese AA women.
Intervention - HFM.
Main Outcome Measures - Early preabsorptive responses (10 minutes) and extended excursions in plasma hormones [C-peptide, insulin, incretins, ghrelin fibroblast growth factor (FGF)19, FGF21], BAs, and serum lipoproteins (chylomicrons, very-low-density lipoprotein) were determined.
Results - At fasting, G-allele carriers had significantly reduced cholesterol and glycodeoxycholic acid and consistent but nonsignificant reductions of serum lipoproteins. Levels of GLP-1 and pancreatic polypeptide (PP) were reduced 60% to 70% and those of total BAs were 1.8-fold higher. After the meal, G-allele carriers displayed attenuated early (-10 to 10 minute) responses in insulin, C-peptide, GLP-1, gastric inhibitory peptide, and PP. BAs exhibited divergent trends in G allele carriers vs noncarriers concomitant with differential FGF19 responses.
Conclusions - CD36 plays an important role in the preabsorptive hormone and BA responses that coordinate brain and gut regulation of energy metabolism.
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14 MeSH Terms
Activation of NADPH oxidases leads to DNA damage in esophageal cells.
Bhardwaj V, Gokulan RC, Horvat A, Yermalitskaya L, Korolkova O, Washington KM, El-Rifai W, Dikalov SI, Zaika AI
(2017) Sci Rep 7: 9956
MeSH Terms: Barrett Esophagus, Bile Acids and Salts, Cells, Cultured, DNA Damage, Epithelial Cells, Humans, NADPH Oxidase 1, NADPH Oxidase 2, Reactive Oxygen Species
Show Abstract · Added March 26, 2019
Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species. ROS originate from mitochondria and NADPH oxidases. We specifically identified NOX1 and NOX2 enzymes to be responsible for ROS generation. Inhibition of NOX2 and NOX1 with siRNA or chemical inhibitors significantly suppresses ROS production and DNA damage induced by BA/A. Mechanistically, our data showed that exposure of esophageal cells to acidic bile salts induces phosphorylation of the p47 subunit of NOX2 and its translocation to the cellular membrane. This process is mediated by protein kinase C, which is activated by BA/A. Taken together, our studies suggest that inhibition of ROS induced by reflux can be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by GERD.
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9 MeSH Terms
Bile acids and bariatric surgery.
Albaugh VL, Banan B, Ajouz H, Abumrad NN, Flynn CR
(2017) Mol Aspects Med 56: 75-89
MeSH Terms: Animals, Bile Acids and Salts, Diabetes Mellitus, Type 2, Enterohepatic Circulation, Gastrectomy, Gastric Bypass, Gastrointestinal Microbiome, Gene Expression Regulation, Glucose, Homeostasis, Humans, Insulin Resistance, Obesity, Morbid, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Rodentia, Signal Transduction
Show Abstract · Added June 6, 2017
Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids. In this review we highlight how bile acids potentially contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after these procedures. The impact of altered bile acid levels in enterohepatic circulation is also associated with changes in gut microflora, which may further contribute to some of these beneficial effects. We highlight the beneficial effects of experimental surgical procedures in rodents that alter bile secretory flow without gastric restriction or altering nutrient flow. This information suggests a role for bile acids beyond dietary fat emulsification in altering whole body glucose and lipid metabolism strongly, and also suggests emerging roles for the activation of the bile acid receptors farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5) in these improvements. The limitations of rodent studies and the current state of our understanding is reviewed and the potential effects of bile acids mediating the short- and long-term metabolic improvements after bariatric surgery is critically examined.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Prevention of DNA damage in Barrett's esophageal cells exposed to acidic bile salts.
Bhardwaj V, Horvat A, Korolkova O, Washington MK, El-Rifai W, Dikalov SI, Zaika AI
(2016) Carcinogenesis 37: 1161-1169
MeSH Terms: Acetophenones, Acids, Adenocarcinoma, Antioxidants, BRCA1 Protein, Barrett Esophagus, Bile Acids and Salts, Cell Line, Tumor, DNA Damage, DNA Repair, Esophageal Neoplasms, Gastric Acid, Gastroesophageal Reflux, Humans, Reactive Oxygen Species
Show Abstract · Added March 26, 2019
Esophageal adenocarcinoma (EA) is one of the fastest rising tumors in the USA. The major risk factor for EA is gastroesophageal reflux disease (GERD). During GERD, esophageal cells are exposed to refluxate which contains gastric acid frequently mixed with duodenal bile. This may lead to mucosal injury and Barrett's metaplasia (BE) that are important factors contributing to development of EA. In this study, we investigated DNA damage in BE cells exposed to acidic bile salts and explored for potential protective strategies. Exposure of BE cells to acidic bile salts led to significant DNA damage, which in turn, was due to generation of reactive oxygen species (ROS). We found that acidic bile salts induce a rapid increase in superoxide radicals and hydrogen peroxide, which were determined using electron paramagnetic resonance spectroscopy and Amplex Red assay. Analyzing a panel of natural antioxidants, we identified apocynin to be the most effective in protecting esophageal cells from DNA damage induced by acidic bile salts. Mechanistic analyses showed that apocynin inhibited ROS generation and increases the DNA repair capacity of BE cells. We identified BRCA1 and p73 proteins as apocynin targets. Downregulation of p73 inhibited the protective effect of apocynin. Taken together, our results suggest potential application of natural compounds such as apocynin for prevention of reflux-induced DNA damage and GERD-associated tumorigenesis.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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