Importancia de la vena cística en la colecistectomía laparoscópica / Importance of the cystic vein in laparoscopic cholecystectomy

Resumen Objetivo: Existen diferencias en la descripción de la vena cística en la literatura, en muchas ocasiones sin considerarla un elemento importante. Consideramos que es de vital importancia describir la presencia de la vena cística como elemento significativo que puede alterar la vista crítica de seguridad (VCS) durante las colecistectomías y asimismo, originar errores. Materiales y Método: Entre el 1° de enero de 2014 hasta el 31 de diciembre de 2018, se evaluó la presencia de la vena cística durante la disección del triángulo hepatocístico en las colecistectomías. Resultados: 397 colecistectomías laparoscópicas fueron realizadas, en 30 casos se evidenciaron elementos adicionales en el triángulo hepatocístico que requirieron una disección prolija, la cual después de seguir su trayecto y al evaluar otros reparos anatómicos como el surco de Rouvière y la visualización de la vía biliar, se consideró debido a sus características que se trataba de una vena cística en 8 casos (2%). Discusión: La vena cística es una estructura anatómica cuya existencia se debe tener en mente por parte del cirujano que realiza la colecistectomía laparoscópica, porque puede aparecer como un elemento significativo alterando la vista crítica de seguridad. Aunque en nuestra serie como elemento significativo es del 2%, otras series la describen con una frecuencia mucho mayor. Conclusión: Es necesario realizar más estudios sobre la presencia e importancia como reparo anatómico debido a su valor para prevenir lesiones de la vía biliar y como factor de confusión en la vista crítica de seguridad.

Aim: There are differences in the description of the cystic vein in the literature, often without considering it an important element. We consider it vital to describe the presence of the cystic vein as a significant element that can disturb the critical view of safety during cholecystectomies, and also cause mistakes. Materials and Method: Between January 1, 2014 and December 31, 2018, the presence of the cystic vein during the dissection of the cystohepatic triangle in cholecystectomies was evaluated. Results: 397 laparoscopic cholecystectomies were performed, in 30 cases additional elements were evidenced in the cystohepatic triangle, which required a careful dissection, which after following its path and when evaluating other anatomical repairs such as the Rouvière sulcus and the visualization of the biliary tract, it was considered due to its characteristics that it was a cystic vein in 8 cases (2%). Discussion: The cystic vein is an anatomical structure whose existence must be kept in mind by the surgeon who performs laparoscopic cholecystectomy, because it can appear as a significant element altering the critical view of safety. Although in our series as a significant element it is 2%, other series describe it with a much higher frequency. Conclusion: It is necessary to carry out more studies on the presence and importance as an anatomical repair due to its value to prevent bile duct injuries and as a factor of confusion in the critical safety view.

Chemical Characterization, Gastrointestinal Motility and Sensory Evaluation of Dark Chocolate: A Nutraceutical Boosting Consumers' Health.

We performed a comprehensive study encompassing chemical characterization and sensory evaluation of two types of dark chocolate, i.e., artisanal (Choco-A) and industrial (Choco-I), as well as an evaluation of onset of gastrointestinal symptoms and gastrointestinal motility in healthy subjects fed with dark chocolate. Proteomic, lipid and metabolite analysis were performed by LC-MS/MS analysis and the total phenol content and antioxidant activity were estimated in both types of chocolate. Fifty healthy volunteers joined the study of the sensory characteristics of both types of chocolate; another 16 subjects underwent the study of gallbladder and gastric emptying by functional ultrasonography and orocecal transit time by lactulose H2-breath test after ingestion of dark chocolate. Identification of polyphenols, amino acids and fatty acids was carried out in both types of chocolate analysed, and results confirmed their richness in polyphenols, amino acid derivatives and fatty acids (FAs) either saturated (stearic, myristic, palmitic, ecosanoic) or unsaturated (oleic and linolenic). For agreeability, Choco-A scored higher than Choco-I for smell, texture, and taste and they did not show significant differences in the gastrointestinal motility. In conclusion as for gastrointestinal motility studies, we report that the ingestion of a small amount of chocolate induced a mild gallbladder, gastric contraction and a fast transit time compared to the test meal in healthy subjects.

La vesícula biliar como reservorio y protectora del tracto digestivo / The gallbladder as reservoir and protector of the digestive tract

Introducción: Estudios anatomofisiológicos y biomoleculares de la vesícula biliar han permitido redefinir su función no solo como reservorio de la secreción biliar, sino como protectora intestinal, concepto que se fundamenta en su capacidad de control de la bioactividad y la toxicología de los ácidos biliares, el metabolismo del colesterol, los fosfolípidos y otros componentes de la secreción hepatobiliar. Objetivo: Describir las actualidades de la funcionabilidad de la vesícula biliar como reservorio y protectora del tracto digestivo dirigido a que cirujanos generales, gastroenterólogos, clínicos y fisiólogos amplíen sus conocimientos sobre la función de la vesícula biliar. Métodos: Se realiza una revisión crítica de las funciones de la vesícula biliar que favorecen mantener la integridad de la pared intestinal. Conclusión: La descripción actualizada de la funcionabilidad de la vesícula biliar ofrece un resultado relevante dentro del marco conceptual en relación a su función protectora que se traduce en el mantenimiento de la integridad del epitelio y la microbiota intestinal(AU)

Introduction: Anatomic-physiological and biomolecular studies of the gallbladder have made it possible to redefine its function not only as a reservoir for bile secretion, but also as intestinal protector. This concept is supported by its capacity to control the bioactivity and toxicology of bile acids, cholesterol metabolism, phospholipids and other components of hepatobiliary secretion. Objective: Present an update on the role of the gallbladder as reservoir and protector of the digestive tract intended for general surgeons, gastroenterologists, clinicians and physiologists to broaden their knowledge about the functions of the gallbladder. Methods: A critical review was conducted of the functions of the gallbladder which facilitate maintenance of the integrity of the intestinal wall. Conclusion: The updated description of the functions of the gallbladder is a relevant contribution to the conceptual framework of its protective function, which ensures the maintenance of the integrity of the epithelium and the intestinal microbiota(AU)

Innervation of the proximal human biliary tree.

The autonomic nervous system plays a role in a variety of liver regenerative and metabolic functions, including modulating bile secretion and cholangiocyte and hepatobiliary progenitors of the canals of Hering. However, the nature and location of nerves which link to the proximal biliary tree have remained uncertain. We investigate the anatomic relationship of nerves to the proximal biliary tree including the putative stem/progenitor cell niche of the canal of Hering. Using double immunostaining (fluorescence, histochemistry) to highlight markers of cholangiocytes (biliary-type keratins), nerves (S100, neurofilament protein, PGP9.5, tyrosine hydroxylase), and stellate cells (CRBP-1), we examined sections from normal adult livers from autopsy or surgical resections. There is extensive contact between nerves and interlobular bile ducts, bile ductules, and canals of Hering (CoH). In multiple serial sections from 4 normal livers, biliary-nerve contacts were seen in all of these structures and were more common in the interlobular bile ducts (78/137; 57%) than in the ductules and CoH (95/294; 33%) (p < 0.001). Contacts appear to consist of nerves in juxtaposition to the biliary basement membrane, though crossing through basement membrane to interface directly with cholangiocytes is also present. These nerves are positive for tyrosine hydroxylase and are, thus, predominately adrenergic. Electron microscopy confirms nerves closely approximating ductules. Nerve fiber-hepatic stellate cell juxtaposition is observed but without stellate cell approximation to cholangiocytes. We present novel findings of biliary innervation, perhaps mediated in part, by direct cholangiocyte-nerve interactions. The implications of these findings are protean for studies of neuromodulation of biliary physiology and hepatic stem/progenitor cells.

Glucagon-Like Peptide 2 Inhibits Postprandial Gallbladder Emptying in Man: A Randomized, Double-Blinded, Crossover Study.

INTRODUCTION: A recent study in mice points to the gut-derived hormone glucagon-like peptide 2 (GLP-2) as an important regulator of gallbladder motility inducing gallbladder relaxation and refilling. In this study, we evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in healthy men. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effect of 4-hour intravenous infusions of high-dose GLP-2 (10 pmol × kg × min), low-dose GLP-2 (1 pmol × kg × min), and placebo (saline) on postprandial gallbladder motility. A 300-kcal liquid-mixed meal (added 1.5 g of acetaminophen for indirect measurement of gastric emptying) was served 30 minutes after start of intravenous infusions. Gallbladder volume was assessed by ultrasonography. RESULTS: Fifteen healthy men, age 24.3 (22.4-26.1) years (mean [95% confidence interval]) and body mass index 22.5 (21.7-23.4) kg × m, were included. Basal plasma GLP-2 concentration was 14 (11-17) pmol/L. During low-dose and high-dose GLP-2 infusions, steady-state postprandial plasma GLP-2 concentrations amounted to 201 (188-214) and 2,658 (2,443-2,873) pmol/L, respectively, compared with maximum postprandial plasma GLP-2 concentration of 34 (25-44) pmol/L during placebo. Gallbladder emptying (assessed as baseline-subtracted area under the curve for gallbladder volume) was reduced by low-dose GLP-2 (-0.8 [0.7-1.9] L × min, P < 0.0001) and nearly abolished by high-dose GLP-2 (1.3 [-1.7 to 0.01] L × min, P = 0.029) compared to placebo (-2.0 [-2.8 to -1.1] L × min). Compared to placebo, gastric emptying was reduced by high-dose GLP-2 (P = 0.0060 and 0.019), whereas low-dose GLP-2 did not affect gastric emptying (P = 0.13 and 0.85). DISCUSSION: Exogenous GLP-2 exerts a dose-dependent inhibitory effect on postprandial gallbladder emptying in healthy men.

Role of gallbladder-preserving surgery in the treatment of gallstone diseases in young and middle-aged patients in China: results of a 10-year prospective study.

BACKGROUND: The aim of the study was to prospectively investigate the long-term effects of gallbladder-preserving cholecystolithotomy in a selected population of Chinese patients. METHODS: Between January 2007 and December 2016, all gallstone patients who met the criteria for gallbladder-preserving cholecystolithotomy in our hospital were included in the study and followed prospectively. The primary endpoint was the time of recurrence of cholecystolithiasis, and the secondary endpoint was the end of the study. The data were collected in half-year intervals. RESULTS: We surveyed 81 male patients and 135 female patients. Most patients (176/216) had only 1 gallstone in the gallbladder. All patients underwent gallbladder-preserving cholecystolithotomy successfully. After the operation, 200 of the 216 patients were symptom free. There was no difference in the percentage of gallbladder emptying (the gallbladder emptying index) between the time prior to the operation and 6 months after gallbladder-preserving cholecystolithotomy (0.47 ± 0.18 vs 0.49 ± 0.18, P = .837). Twenty patients (9.3%) developed recurrent gallstones during the follow-up period. There was no difference in stone recurrence between patients who were treated with ursodeoxycholic acid for 6 months postoperatively and those treated with ursodeoxycholic acid for 12 months (P = .589). Most instances of recurrence occurred within 2 years of gallbladder-preserving cholecystolithotomy. Overall, the recurrence rates at 6, 12, and 24 months were 2.3%, 3.7%, and 7.6%, respectively. CONCLUSION: Gallbladder-preserving cholecystolithotomy is a safe and effective operative procedure for selected Chinese patients. The function of the gallbladder can be maintained after gallbladder-preserving cholecystolithotomy. The recurrence of cholelithiasis is infrequent in this Chinese population with a mean follow-up of 59 (range 8 to 120) months, and most patients with recurrent gallbladder stones experience no symptoms or only minor symptoms.

The human gallbladder microbiome is related to the physiological state and the biliary metabolic profile.

BACKGROUND: The microbial populations of the human intestinal tract and their relationship to specific diseases have been extensively studied during the last decade. However, the characterization of the human bile microbiota as a whole has been hampered by difficulties in accessing biological samples and the lack of adequate methodologies to assess molecular studies. Although a few reports have described the biliary microbiota in some hepatobiliary diseases, the bile microbiota of healthy individuals has not been described. With this in mind, the goal of the present study was to generate fundamental knowledge on the composition and activity of the human bile microbiota, as well as establishing its potential relationship with human bile-related disorders. RESULTS: Human bile samples from the gallbladder of individuals from a control group, without any record of hepatobiliary disorder, were obtained from liver donors during liver transplantation surgery. A bile DNA extraction method was optimized together with a quantitative PCR (qPCR) assay for determining the bacterial load. This allows the selection of samples to perform functional metagenomic analysis. Bile samples from the gallbladder of individuals suffering from lithiasis were collected during gallbladder resection and the microbial profiles assessed, using a 16S rRNA gene-based sequencing analysis, and compared with those of the control group. Additionally, the metabolic profile of the samples was analyzed by nuclear magnetic resonance (NMR). We detected, for the first time, bacterial communities in gallbladder samples of individuals without any hepatobiliary pathology. In the biliary microecosystem, the main bacterial phyla were represented by Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Significant differences in the relative abundance of different taxa of both groups were found. Sequences belonging to the family Propionibacteriaceae were more abundant in bile samples from control subjects; meanwhile, in patients with cholelithiasis members of the families Bacteroidaceae, Prevotellaceae, Porphyromonadaceae, and Veillonellaceae were more frequently detected. Furthermore, the metabolomics analysis showed that the two study groups have different metabolic profiles. CONCLUSIONS: Our results indicate that the gallbladder of human individuals, without diagnosed hepatobiliary pathology, harbors a microbial ecosystem that is described for the first time in this study. Its bacterial representatives and metabolites are different from those detected in people suffering from cholelithiasis. In this regard, since liver donors have been subjected to the specific conditions of the hospital's intensive care unit, including an antibiotic treatment, we must be cautious in stating that their bile samples contain a physiologically normal biliary microbiome. In any case, our results open up new possibilities to discover bacterial functions in a microbial ecosystem that has not previously been explored.

Gallbladder interstitial Cajal-like cells and gallbladder contractility in patients with cholelithiasis: a prospective study.

INTRODUCTION: A reduced number of interstitial Cajal-like cells (ICLCs) in the gallbladder have been proposed to play a role in the pathogenesis of cholelithiasis. Therefore, this prospective study was conducted to investigate the relationship between gallbladder contractility and the number of gallbladder ICLCs in patients with cholelithiasis. MATERIAL AND METHODS: Patients admitted to the Department of Hepatobiliary Surgery for cholecystectomy were divided into the cholelithiasis (n = 18) and non-cholelithiasis (n = 8) groups based on their clinical data. Patients' clinical data were collected on admission, and B-mode ultrasonography was performed to assess their gallbladder contractility. The resected gallbladder specimens were fixed, paraffin sections mounted on slides, and the immunofluorescence staining with the anti-human CD-117 and anti-human tryptase antibodies was performed to identify ICLSs and mast cells, respectively. The number of ICLCs was counted in 10 high-power fields (HPFs) randomly. RESULTS: Independent sample t-tests revealed differences between the cholelithiasis and non-cholelithiasis groups in the number of ICLCs (mean ± standard deviation: 88.61 ± 28.22 vs. 115.89 ± 27.87 per HPFs, P = 0.032) and gallbladder contractility (43.94% ± 18.50% vs. 61.00% ± 20.50%, P = 0.046). Pearson and Spearman cor-relation analyses revealed no significant correlation between the number of ICLCs and gallbladder contractility. CONCLUSION: The results suggest that the number of gallbladder ICLCs in the wall of the gallbladder of patients with or without cholelithiasis is not a decisive factor affecting gallbladder contractility.

Prospective study on changes in the donor gallbladder contraction function after left lateral lobe hepatectomy.

This study aimed to evaluate the feasibility of donor gallbladder preservation in liver transplantation. Conventional removal of the donor gallbladder is applied in a majority of pediatric liver transplantation. A total of 42 donors who underwent gallbladder preservation in liver transplantation from October 2013 to December 2015 at the Beijing Friendship Hospital, China, were enrolled for the study. The changes in gallbladder volume and the gallbladder EF of donors before and after surgery were measured through ultrasound, and the changes in the donor gallbladder contraction function before and after surgery were evaluated to help verify the feasibility of gallbladder preservation in living donor left lateral lobe hepatectomy. The gallbladder emptying index dropped to 42.67% in 2 weeks after surgery and gradually increased with the length of recovery time, which could reach 69.14% in 3 months after surgery. At that time, 97.6% of the donors were considered to have recovered their gallbladder contraction function. The gallbladder contraction function at an early stage after gallbladder preservation in liver transplantation is not obviously improved, but it can recover to a normal level in 1 month after surgery, indicating that the gallbladder preservation in hepatectomy of living donor can effectively guarantee the gallbladder contraction function.

Gall bladder: The metabolic orchestrator.

It is commonly held that the gall bladder (GB) is not indispensable for life. However, recent studies strongly suggest that GB removal can lead to the development of metabolic syndrome (MetS). With the recent recognition of the role of bile acids (BAs) in systemic metabolic regulation, it is worthwhile to re-examine the function of the GB, which can be regarded as the physiological "pacemaker" of BA flow. Thus, in the present study, we review the role of the GB in BA flow regulation, describe the epidemiologic evidence that associates cholecystectomy with various components of MetS, and discuss the possible mechanism behind these connections in order to demonstrate the pivotal role that GB plays in metabolic regulation.

Systematic review with meta-analysis: cholecystectomy for biliary dyskinesia-what can the gallbladder ejection fraction tell us?

BACKGROUND: Gallbladder dyskinesia (gallbladder spasm, biliary dyskinesia or chronic acalculous cholecystitis) is a poorly defined entity which presents as biliary-type pain without any identifiable organic pathology. Abnormal gallbladder ejection fraction (GBEF) is used by some to select those likely to benefit from cholecystectomy. The validity of this approach has been questioned. AIM: To systematically review the literature and summarise the evidence surrounding the practice of cholecystectomy based on GBEF for gallbladder dyskinesia. METHODS: We conducted a systematic search of PubMed/MEDLINE and SCOPUS from 1980 to 2016 to identify the relevant literature. RESULTS: Twenty-nine studies including 2891 patients were included in the final analysis. In comparing cholecystectomy with medical management, patients with a normal GBEF did not benefit from cholecystectomy; whereas those with low GBEF had a higher chance (RR, relative risk = 2.37) of symptomatic improvement following surgery. When those classified as "low" and "normal" GBEF were compared in terms of outcome following cholecystectomy, the rate of improvement following surgery was similar in the two groups (RR 1.09) which suggests a placebo effect of surgery. CONCLUSIONS: While a low GBEF may provide some guidance in identifying those with gallbladder dyskinesia who may benefit from cholecystectomy, the available data are inconsistent and based on studies of poor quality which are often subject to bias and the impact of confounding factors. For these reasons, we conclude that the role of scintigraphy and cholecystectomy in the definition and management of this disorder remain unclear pending definitive study.

Radiofrequency ablation of liver cancers adjacent to the gallbladder without gallbladder isolation under contrast-enhanced ultrasound monitoring: a preliminary study.

PURPOSE: The purpose of this study was to investigate the feasibility, safety and efficacy of intra-procedural contrast-enhanced ultrasound (CEUS) monitoring of the radiofrequency ablation (RFA) of liver cancers adjacent to gallbladder (GB) without GB isolation. MATERIALS AND METHODS: From May 2016 to July 2017, patients with liver cancers adjacent to GB (≤10 mm) who intended to undergo ultrasound-guided RFA without GB isolation in our hospital were prospectively enrolled. During the RFA procedures, CEUS was employed to evaluate the therapeutic response and the perfusion of the intact GB wall. The outcomes of GB and liver cancers were followed up and recorded. RESULTS: 23 patients (18 male, 5 female) with 23 liver cancers (mean 18 mm, range 8-34 mm) adjacent to GB were enrolled. There were 12 tumors that abutted the GB while 11 tumors located within 10 mm of the GB. After the RFA procedures, intra-procedural CEUS evaluation demonstrated the perfusion of the GB wall was intact in all 23 patients and technical success rate of RFA was 100% (23/23). According to the contrast-enhanced CT/MR one month after RFA, the technical efficacy rate was 100% (23/23). During the follow-up period (range: 12-23 months, median: 17 months), no local tumor progression occurred and no major complications arised. Overall survival at 1-year was 100%. Thickening of GB wall was detected in 11 patients. The thickness of GB wall returned to the pre-ablation level in five patients. CONCLUSION: CEUS-monitored RFA of liver cancers adjacent to GB without GB isolation was feasible, safe and effective.

[Effects of glucagon-like peptides on gallbladder motility].

As cases of gallbladder-related adverse events have been reported in patients treated with glucagon-like peptide (GLP)-1 receptor agonists and GLP-2 receptor agonists, studies have investigated the effects of these hormones on the enterohepatic circulation of bile acids and gallbladder motility. Results suggest, that bile acids and GLP-2 counteract postprandial cholecystokinin-mediated gallbladder contraction, while GLP-1 may delay gallbladder refilling. This provides important information on the effect and safety of drugs based on GLP-1 and GLP-2, respectively.

Effects of a Gluten-Containing Meal on Gastric Emptying and Gallbladder Contraction.

The ingestion of gluten has been associated with gastrointestinal symptoms even in the absence of detectable immune responses. Little is known about the pathophysiological effects of gluten on the upper gastrointestinal tract. We aimed to assess whether the ingestion of gluten leads to an impairment of the physiological mechanisms of gastric emptying, gallbladder contraction and relaxation. A total of 17 healthy subjects underwent ultrasound evaluation of gastric emptying dynamics and gallbladder contractions at baseline and every 30 min after a standard gluten-containing and gluten-free meal (250 kcal, 70% carbohydrates). The pattern of gastric emptying was similar after a standard meal with or without gluten, but differed in terms of the peak of the antral filling curve, which was wider (mean area 5.69, median 4.70, range 3.71‒9.27 cm² vs. mean 4.89, median 4.57, 2.27‒10.22 cm², p = 0.023) after the gluten-containing meal. The pattern of gallbladder contractions was different after the gluten-free meal (p < 0.05), with higher gallbladder volumes in the late refilling phases. The results of this study show that gluten ingestion exerts objective effects on gastric and gallbladder motility. Although the underlying pathophysiological mechanism remains unknown, these results could account for some of the gluten-related symptoms reported by patients with celiac disease and non-celiac gluten sensitivity.

Occurrence of the specific long spike burst pattern in the ovine proximal gallbladder as an indication of myoelectric regional variability.

The myoelectrical activity of the ovine gallbladder has not been fully recognised. Five rams were fitted with six small intestinal and three gallbladder electrodes and a strain gauge force transducer was mounted near the gallbladder fundic electrode. In two series of successive experiments, the electromyographical and mechanical recordings were recorded over a period of 5-7 hours. The occurrence of the slow waves in the small bowel was regular, unlike those in the gallbladder. In the gallbladder infundibulum, the specific pattern, called the long spike burst pattern (LSBP), was observed. It comprised usually one or two parts of prolonged duration. The first part resembled the classical (short lasting) spike burst in the small bowel, and its amplitude was lower than that of the second part. The spike burst frequency of the second part was 2-3 times lower than that of the first part. During phase 1-like and phase 2a-like activities, the intensity of the gallbladder LSBP was reduced while enhanced after feeding. In fasted rams, the duration of a specific pattern, observed in the gallbladder infundibulum, was longer than in non-fasted animals and its amplitude was low. Similar events were recorded in the gallbladder corpus, but the specific pattern was shorter and irregular. In the gallbladder fundus, mostly irregular short spike bursts were recorded. It is concluded that in sheep, specific types of the long-lasting groups of spikes occur in the upper gallbladder areas exhibiting myoelectrical regional variability. The character of an LSBP depends on feeding conditions.

Effect of a high-fat-high-cholesterol diet on gallbladder bile acid composition and gallbladder motility in dogs.

OBJCTIVE To investigate the effects of dietary lipid overload on bile acid metabolism and gallbladder motility in healthy dogs. ANIMALS 7 healthy Beagles. PROCEDURES In a crossover study, dogs were fed a high-fat-high-cholesterol diet (HFCD) or a low-fat diet (LFD) for a period of 2 weeks. After a 4-month washout period, dogs were fed the other diet for 2 weeks. Before and at the end of each feeding period, the concentrations of each of the gallbladder bile acids, cholecystokinin (CCK)-induced gallbladder motility, and bile acid metabolism-related hepatic gene expression were examined in all dogs. RESULTS The HFCD significantly increased plasma total cholesterol concentrations. The HFCD also increased the concentration of taurochenodeoxycholic acid and decreased the concentration of taurocholic acid in bile and reduced gallbladder contractility, whereas the LFD significantly decreased the concentration of taurodeoxycholic acid in bile. Gene expression analysis revealed significant elevation of cholesterol 7α-hydroxylase mRNA expression after feeding the HFCD for 2 weeks, but the expression of other genes was unchanged. CONCLUSIONS AND CLINICAL RELEVANCE Feeding the HFCD and LFD for 2 weeks induced changes in gallbladder bile acid composition and gallbladder motility in dogs. In particular, feeding the HFCD caused an increase in plasma total cholesterol concentration, an increase of hydrophobic bile acid concentration in bile, and a decrease in gallbladder sensitivity to CCK. These results suggested that similar bile acid compositional changes and gallbladder hypomotility might be evident in dogs with hyperlipidemia.

Measurement of the mechanical properties of the human gallbladder.

Gallbladder is a small organ of the body which is located in the right side of the liver. It is responsible of storing the bile and releasing it to the intestine. The gallbladder can subject to the mechanical deformation/loading as a result of the cholecystitis, cholesterolosis of the gallbladder, etc. However, so far the mechanical properties of the human gallbladder have not been measured. This study was aimed at conducting an experimental study to measure the mechanical properties of the human gallbladder under the axial and transversal tensile loadings. To do that, the gallbladder tissue of 16 male individuals was excised during the autopsy and subjected to a series of axial and transversal loadings under the strain rate of 5 mm/min. The amount of elastic modulus as well as the maximum/failure stress of the tissues were calculated via the resulted stress-strain diagrams and reported. The results revealed that the axial and transversal elastic modulus were 641.20 ± 28.12 (mean ± SD) and 255 ± 24.55 kPa, respectively. The amount of maximum stresses was also 1240 ± 99.94 and 348 ± 66.75 kPa under the axial and transversal loadings, respectively. The results revealed a significantly higher axial stiffness (p < .05, post hoc Scheffe method) compared to the transversal one. These findings have implications not only for understanding the axial and transversal mechanical properties of the human gallbladder tissue, but also for providing a diagnosis tool for the doctors to have a suitable threshold value of the healthy gallbladder tissue.

Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway.

OBJECTIVE: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown. METHODS: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r-/- and Tgr5-/- mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo. RESULTS: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5-/- mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r-/- but not in Tgr5-/- mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner. CONCLUSIONS: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease.