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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.
0 Communities
2 Members
0 Resources
25 MeSH Terms
Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.
Reddy IA, Smith NK, Erreger K, Ghose D, Saunders C, Foster DJ, Turner B, Poe A, Albaugh VL, McGuinness O, Hackett TA, Grueter BA, Abumrad NN, Flynn CR, Galli A
(2018) PLoS Biol 16: e2006682
MeSH Terms: Animals, Bariatric Surgery, Behavior, Animal, Bile, Choice Behavior, Cocaine, Dopamine, Gallbladder, Ileum, Male, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Nucleus Accumbens, Reward, Signal Transduction
Show Abstract · Added January 4, 2019
The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.
0 Communities
3 Members
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16 MeSH Terms
Evaluating the American College of Surgeons National Surgical Quality Improvement project risk calculator: results from the U.S. Extrahepatic Biliary Malignancy Consortium.
Beal EW, Lyon E, Kearney J, Wei L, Ethun CG, Black SM, Dillhoff M, Salem A, Weber SM, Tran TB, Poultsides G, Shenoy R, Hatzaras I, Krasnick B, Fields RC, Buttner S, Scoggins CR, Martin RCG, Isom CA, Idrees K, Mogal HD, Shen P, Maithel SK, Pawlik TM, Schmidt CR
(2017) HPB (Oxford) 19: 1104-1111
MeSH Terms: Academic Medical Centers, Adult, Aged, Aged, 80 and over, Area Under Curve, Bile Duct Neoplasms, Biliary Tract Surgical Procedures, Cholangiocarcinoma, Databases, Factual, Decision Support Techniques, Female, Gallbladder Neoplasms, Hepatectomy, Humans, Male, Middle Aged, Pancreaticoduodenectomy, Patient Readmission, Postoperative Complications, Predictive Value of Tests, ROC Curve, Reoperation, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, United States, Young Adult
Show Abstract · Added April 10, 2018
BACKGROUND - The objective of this study is to evaluate use of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online risk calculator for estimating common outcomes after operations for gallbladder cancer and extrahepatic cholangiocarcinoma.
METHODS - Subjects from the United States Extrahepatic Biliary Malignancy Consortium (USE-BMC) who underwent operation between January 1, 2000 and December 31, 2014 at 10 academic medical centers were included in this study. Calculator estimates of risk were compared to actual outcomes.
RESULTS - The majority of patients underwent partial or major hepatectomy, Whipple procedures or extrahepatic bile duct resection. For the entire cohort, c-statistics for surgical site infection (0.635), reoperation (0.680) and readmission (0.565) were less than 0.7. The c-statistic for death was 0.740. For all outcomes the actual proportion of patients experiencing an event was much higher than the median predicted risk of that event. Similarly, the group of patients who experienced an outcome did have higher median predicted risk than those who did not.
CONCLUSIONS - The ACS NSQIP risk calculator is easy to use but requires further modifications to more accurately estimate outcomes for some patient populations and operations for which validation studies show suboptimal performance.
Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
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1 Members
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29 MeSH Terms
Pathologic and Prognostic Implications of Incidental Nonincidental Gallbladder Cancer: A 10-Institution Study from the United States Extrahepatic Biliary Malignancy Consortium.
Ethun CG, Le N, Lopez-Aguiar AG, Pawlik TM, Poultsides G, Tran T, Idrees K, Isom CA, Fields RC, Krasnick BA, Weber SM, Salem A, Martin RCG, Scoggins CR, Shen P, Mogal HD, Schmidt C, Beal E, Hatzaras I, Shenoy R, Russell MC, Maithel SK
(2017) Am Surg 83: 679-686
MeSH Terms: Aged, Chemotherapy, Adjuvant, Female, Gallbladder Neoplasms, Humans, Incidental Findings, Male, Neoplasm Staging, Prognosis, Survival Rate, United States
Show Abstract · Added April 10, 2018
Most gallbladder cancers (GBCs) are discovered incidentally after routine cholecystectomy. The influence of timing of diagnosis on disease stage, treatment, and prognosis is not known. Patients with GBC who underwent resection at 10 institutions from 2000 to 2015 were included. Patients diagnosed incidentally (IGBC) and nonincidentally (non-IGBC) were compared. Primary outcome was overall survival (OS). Of 445 patients with GBC, 266 (60%) were IGBC and 179 (40%) were non-IGBC. Compared with IGBC, non-IGBC patients were more likely to have R2 resections (43% vs 19%; P < 0.001), advanced T-stage (T3/T4: 70% vs 40%; P < 0.001), high-grade tumors (50% vs 31%; P < 0.001), lymphovascular invasion (64% vs 45%; P = 0.01), and positive lymph nodes (60% vs 43%; P = 0.009). Receipt of adjuvant chemotherapy was similar between groups (49% vs 49%). Non-IGBC was associated with worse median OS compared with IGBC (17 vs 32 months; P < 0.001), which persisted among stage III patients (12 vs 29 months; P < 0.001), but not stages I, II, or IV. Despite accounting for other adverse pathologic factors (grade, T-stage, lymphovascular invasion, margin, lymph node), adjuvant chemotherapy was associated with improved OS only in stage III IGBC, but not in non-IGBC. Compared with incidental discovery, non-IGBC is associated with reduced OS, which is most evident in stage III disease. Despite being well matched for other adverse pathologic factors, adjuvant chemotherapy was associated with improved survival only in stage III patients with incidentally discovered cancer. This underscores the importance of timing of diagnosis in GBC and suggests that these two groups may represent a distinct biology of disease, and the same treatment paradigm may not be appropriate.
0 Communities
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MeSH Terms
Gallbladder Cancer Presenting with Jaundice: Uniformly Fatal or Still Potentially Curable?
Tran TB, Norton JA, Ethun CG, Pawlik TM, Buettner S, Schmidt C, Beal EW, Hawkins WG, Fields RC, Krasnick BA, Weber SM, Salem A, Martin RCG, Scoggins CR, Shen P, Mogal HD, Idrees K, Isom CA, Hatzaras I, Shenoy R, Maithel SK, Poultsides GA
(2017) J Gastrointest Surg 21: 1245-1253
MeSH Terms: Aged, Bilirubin, Blood Vessels, CA-19-9 Antigen, Drainage, Female, Gallbladder Neoplasms, Humans, Jaundice, Obstructive, Lymphatic Vessels, Male, Middle Aged, Neoplasm Invasiveness, Postoperative Complications, Reoperation, Survival Rate, United States
Show Abstract · Added April 10, 2018
BACKGROUND - Jaundice as a presenting symptom of gallbladder cancer has traditionally been considered to be a sign of advanced disease, inoperability, and poor outcome. However, recent studies have demonstrated that a small subset of these patients can undergo resection with curative intent.
METHODS - Patients with gallbladder cancer managed surgically from 2000 to 2014 in 10 US academic institutions were stratified based on the presence of jaundice at presentation (defined as bilirubin ≥4 mg/ml or requiring preoperative biliary drainage). Perioperative morbidity, mortality, and overall survival were compared between jaundiced and non-jaundiced patients.
RESULTS - Of 400 gallbladder cancer patients with available preoperative data, 108 (27%) presented with jaundice while 292 (73%) did not. The fraction of patients who eventually underwent curative-intent resection was much lower in the presence of jaundice (n = 33, 30%) than not (n = 218, 75%; P < 0.001). Jaundiced patients experienced higher perioperative morbidity (69 vs. 38%; P = 0.002), including a much higher need for reoperation (12 vs. 1%; P = 0.003). However, 90-day mortality (6.5 vs. 3.6%; P = 0.35) was not significantly higher. Overall survival after resection was worse in jaundiced patients (median 14 vs. 32 months; P < 0.001). Further subgroup analysis within the jaundiced patients revealed a more favorable survival after resection in the presence of low CA19-9 < 50 (median 40 vs. 12 months; P = 0.003) and in the absence of lymphovascular invasion (40 vs. 14 months; P = 0.014).
CONCLUSION - Jaundice is a powerful preoperative clinical sign of inoperability and poor outcome among gallbladder cancer patients. However, some of these patients may still achieve long-term survival after resection, especially when preoperative CA19-9 levels are low and no lymphovascular invasion is noted pathologically.
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1 Members
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MeSH Terms
Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery.
Flynn CR, Albaugh VL, Cai S, Cheung-Flynn J, Williams PE, Brucker RM, Bordenstein SR, Guo Y, Wasserman DH, Abumrad NN
(2015) Nat Commun 6: 7715
MeSH Terms: Adaptation, Biological, Anastomosis, Surgical, Animals, Bariatric Surgery, Bile Acids and Salts, Carrier Proteins, Disease Models, Animal, Energy Metabolism, Fibroblast Growth Factors, Gallbladder, Gastrointestinal Microbiome, Intestine, Small, Liver, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Obesity, Random Allocation
Show Abstract · Added August 26, 2015
Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity (DIO) mouse model and compare metabolic remission when bile flow is diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We find that only bile diversion to the ileum results in physiologic changes similar to RYGB, including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-β-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 signalling axis is reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB.
0 Communities
6 Members
0 Resources
18 MeSH Terms
Generation of islet-like cells from mouse gall bladder by direct ex vivo reprogramming.
Hickey RD, Galivo F, Schug J, Brehm MA, Haft A, Wang Y, Benedetti E, Gu G, Magnuson MA, Shultz LD, Lagasse E, Greiner DL, Kaestner KH, Grompe M
(2013) Stem Cell Res 11: 503-15
MeSH Terms: Animals, Cell Differentiation, Cells, Cultured, Female, Gallbladder, Humans, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Pluripotent Stem Cells, Rats, Signal Transduction
Show Abstract · Added February 3, 2014
Cell replacement is an emerging therapy for type 1 diabetes. Pluripotent stem cells have received a lot of attention as a potential source of transplantable β-cells, but their ability to form teratomas poses significant risks. Here, we evaluated the potential of primary mouse gall bladder epithelial cells (GBCs) as targets for ex vivo genetic reprogramming to the β-cell fate. Conditions for robust expansion and genetic transduction of primary GBCs by adenoviral vectors were developed. Using a GFP reporter for insulin, conditions for reprogramming were then optimized. Global expression analysis by RNA-sequencing was used to quantitatively compare reprogrammed GBCs (rGBCs) to true β-cells, revealing both similarities and differences. Adenoviral-mediated expression of NEUROG3, Pdx1, and MafA in GBCs resulted in robust induction of pancreatic endocrine genes, including Ins1, Ins2, Neurod1, Nkx2-2 and Isl1. Furthermore, expression of GBC-specific genes was repressed, including Sox17 and Hes1. Reprogramming was also enhanced by addition of retinoic acid and inhibition of Notch signaling. Importantly, rGBCs were able to engraft long term in vivo and remained insulin-positive for 15weeks. We conclude that GBCs are a viable source for autologous cell replacement in diabetes, but that complete reprogramming will require further manipulations.
Copyright © 2013 Elsevier B.V. All rights reserved.
2 Communities
1 Members
0 Resources
13 MeSH Terms
Vicarious contrast excretion by the gallbladder in contrast nephropathy.
Umana IE, Dwyer JP
(2009) Kidney Int 75: 446
MeSH Terms: Aged, Contrast Media, Gallbladder, Humans, Iodine, Kidney Diseases, Male, Tomography
Added August 19, 2013
0 Communities
1 Members
0 Resources
8 MeSH Terms
Radical resection improves survival for patients with pT2 gallbladder carcinoma.
Wise PE, Shi YY, Washington MK, Chapman WC, Wright JK, Sharp KW, Pinson CW
(2001) Am Surg 67: 1041-7
MeSH Terms: Adenocarcinoma, Aged, Aged, 80 and over, Chemotherapy, Adjuvant, Cholecystectomy, Female, Gallbladder Neoplasms, Humans, Lymph Node Excision, Male, Middle Aged, Neoplasm Staging
Show Abstract · Added March 5, 2014
Radical resection (wedge resection of the gallbladder bed and dissection of the hepatoduodenal ligament, portal, and celiac lymph nodes) has been reported to improve survival from pathologic T2 gallbladder carcinoma (pT2 GBCa; invasion through the muscularis without perforation of the serosa). We report our experience and the outcome of patients with pT2 GBCa. Between 1989 and 2000 at Vanderbilt University Medical Center ten patients were found to have pT2 disease after cholecystectomy. The patients had an average age of 64+/-13 years and underwent either radical resection (n = 5) or no further surgical therapy (n = 5). Of the patients who underwent cholecystectomy only, one (20%) is still alive at 27 months and four (80%) died of recurrent GBCa between 6.5 and 21 months. For the patients who underwent radical resection all five are alive at 15 to 83 months with no recurrence. The proportion of patients surviving pT2 GBCa after radical resection was significantly greater than with cholecystectomy alone (P < 0.05). The difference in length of survival between the two groups was also significant (P < 0.05). Morbidity after radical resection was low (pancreatic leak in one patient), and there were no operative mortalities. Radical resection significantly improved survival over cholecystectomy alone for patients with pT2 GBCa. The procedure has low morbidity and mortality rates. Therefore a radical resection operation is indicated for patients with pT2 GBCa.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Establishment and characterization of primary gallbladder epithelial cell cultures in the prairie dog.
Chapman WC, Fisk J, Schot D, Debelak JP, Washington MK, Bluth RF, Pierce D, Williams LF
(1998) J Surg Res 80: 35-43
MeSH Terms: Animals, Cell Division, Cells, Cultured, Epithelial Cells, Gallbladder, Immunohistochemistry, Microscopy, Electron, Sciuridae, Thymidine
Show Abstract · Added March 5, 2014
BACKGROUND - The prairie dog has become the established animal gallstone model. This species has a unique propensity to form cholesterol gallstones in response to dietary manipulations. The development of a reliable gallbladder cell culture technique is critical for understanding pathogenic mechanisms of gallstone formation.
MATERIALS AND METHODS - Prairie dogs underwent laparotomy and cholecystectomy, followed by initiation of cell cultures. [3H]Thymidine incorporation was used to assess cell growth, and cell lines were assessed using routine histochemical and immunohistochemical staining.
RESULTS - Cell yields from prairie dog gallbladders were 4-8 x 10(6) viable cells per animal with viability ranging from 80 to 95%. When plated at 5 x 10(5) cells/cm2, cell clusters, visible within 24 h, coalesced into confluent monolayers within 3-5 days. Cultures remained viable for 6-8 weeks and could be passed for three to four subcultures. Immunohistochemical staining demonstrated a high degree of epithelial purity with immunopositivity for AE1/AE3, and cytokeratin, with no vimentin positivity (mesenchymal antigen). Intracytoplasmic vacuoles demonstrated positive staining for Alcian blue, periodic acid-Schiff, and mucicarmine and an anti-gallbladder mucin antibody confirmed the presence of the glycoprotein mucin.
CONCLUSIONS - This study demonstrates a reliable method for initiation and maintenance of prairie dog gallbladder epithelial cell cultures with a high degree of purity. This technique should allow further studies into the pathogenesis of cholesterol gallstones in this model.
Copyright 1998 Academic Press.
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9 MeSH Terms