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Abstract Background and Objective Studies in humans and mice have demonstrated that the gut hormone glucagon-like peptide 2 (GLP-2) promotes gallbladder relaxation and refilling. Here, we assessed the effect of exogenous GLP-2 on gallbladder motility in the fasted state of healthy men with and without infusion of the potent gallbladder-contracting hormone cholecystokinin (CCK). Methods In a randomized, double-blind, placebo-controlled, crossover study, 15 male participants (mean [SD]: age 24.7 [3.6] years; body mass index 22.9 [1.6] kg/m2) underwent 4 experimental days receiving 2 infusions on each day: either CCK (0.4 pmol × kg−1 × min−1, time 0-180 minutes) + GLP-2 (10 pmol × kg−1 × min−1, time 30-240 minutes), CCK + placebo, placebo + GLP-2, or placebo + placebo, respectively. Gallbladder volume was measured at baseline and throughout the 4-hour study day using ultrasonography. Results Compared to placebo + placebo, GLP-2 + placebo did not affect gallbladder volume, but when infused in combination with CCK, GLP-2 completely abolished the strong gallbladder-contracting effect seen during CCK + placebo infusion, restoring baseline levels of gallbladder volume. Conclusion Exogenous GLP-2 counteracts exogenous CCK-induced gallbladder emptying in healthy men, pointing to a possible therapeutic potential for GLP-2 as a relaxing modulator of gallbladder smooth muscle tone (eg, as a bridge to surgery in biliary colic). The effect may also explain the gallbladder-related adverse events reported for GLP-2 receptor agonists used in the treatment of short bowel syndrome. Clinical Trial Registration number NCT04651868

Background/objectives: The emptying of the gall bladder in response to feeding is pivotal for the digestion of fat, but the role of various food ingredients in contracting the gall bladder postprandially is not well understood. We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively. Subjects/methods: Study 1: exploratory study evaluating the effects of 10 different food ingredients on gall bladder emptying in eight healthy subjects. The choice of ingredients varied from common items like coffee, tea and milk to actives like curcumin and potato protease inhibitor. Study 2: mechanistic study investigating the cholecystokinin (CCK) dose response to the best performer ingredient from Study 1 in 21 healthy subjects four ways. Results: The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK. Conclusions: These serial test-retest studies showed that the fasted gall bladder volume varied remarkably between individuals and that individual day-to-day variability had wide coefficients of variation. Improved knowledge of how to stimulate bile release using food ingredients will be useful to improve in vitro – in vivo correlation of bioavailability testing of hydrophobic drugs. It could improve performance of cholesterol-lowering plant stanol and sterol products and possibly aid understanding of some cholesterol gallstone disease.

Food stimulates changes to gastrointestinal secretion and motility patterns, however, the effect of smaller quantities of lipid, such as that contained in a lipid-based drug formulation, has not been detailed. This study aimed to examine the effects of small quantities of lipid on gastric emptying and biliary secretion. The influence of oral administration of three lipid-based formulations and a negative control formulation on gastric emptying and biliary secretion was evaluated in 16 healthy male subjects using gamma scintigraphy, ultrasonography and duodenal aspiration. Low quantities (2 g) of long chain lipid stimulated gall bladder contraction and elevated intestinal bile salt, phospholipid and cholesterol levels. Changes in gastric emptying were also evident, although these did not reach statistical significance. Administration of a similar quantity of medium chain lipid, however, had little effect on gastric emptying and gallbladder contraction and did not stimulate appreciable increases in intestinal concentrations of biliary-derived lipids. The quantities of long chain lipid that might be administered in a pharmaceutical formulation stimulate gallbladder contraction and elevate intestinal levels of bile salt and phospholipid. This effect is a likely contributor to the ability of lipid based formulations to enhance the absorption of poorly water-soluble drugs.

ContextDespite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed.ObjectiveThe aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes.DesignRandomized, placebo-controlled, and double-blinded crossover study.SettingThis study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark.PatientsFifteen metformin-treated patients with type 2 diabetes; all participants completed the study.InterventionsFour experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg−1 × min−1) or saline.Main Outcome MeasurePlasma GLP-1 excursions as measured by baseline-subtracted area under the curve.ResultsSingle-dose metformin further enhanced bile acid–mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1–mediated induction of insulin secretion or suppression of glucagon was observed.ConclusionsMetformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.This study demonstrates that single-dose metformin enhances bile acid–induced induction of plasma GLP-1 excursions after cholecystokinin-mediated gallbladder emptying in patients with type 2 diabetes.

Repair of defects in the common bile duct is hampered by a lack of healthy donor tissue. Developing human extrahepatic cholangiocyte organoids and testing them in mouse models may provide a way to overcome this limitation. 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 .

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.

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. 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. 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). Exogenous GLP-2 exerts a dose-dependent inhibitory effect on postprandial gallbladder emptying in healthy men.

Progesterone (P), 17β‐estradiol (E2), and dihydrotestosterone (DHT) affect gallbladder motility. When gallbladders were taken from women and men, women had more estrogen and P receptors than men. Both P and E2 had an inhibitory effect upon gallbladder contractility in men and premenopausal and postmenopausal women. Similar findings have been reported in gallbladder strips from male and female guinea pigs. In the present study, there was no significant difference in the amount of E2‐, P‐, or DHT‐induced relaxation of CCK‐induced tension when the responses in gallbladder strips from male and female guinea pigs were compared. Three metabolites of P were used: 17‐hydroxyprogesterone (17‐P), 20α‐hydroxyprogesterone (20‐P), and 21‐hydroxyprogesterone (21‐P). There was no significant difference in the responses from strips from male and female guinea pigs. In order to determine if the effects of E2 and P were additive, strips from male animals were exposed to either E2 or P and the amount of relaxation recorded. After recovery, the strips were exposed to E2 or P in reverse order to ensure the order of treatment had no effect. Then, the strips were treated with both E2 and P simultaneously and the relaxation recorded. This procedure was repeated with strips from female guinea pigs. The effect of E2 and P was found to be additive; however, the response of the strips from each sex were not significantly different. It is concluded that the sex of the guinea pig has no significant effect on the response to the sex hormones used. The hormones estrogen, progesterone, and dihydrotestosterone all relaxed cholecystokinin‐induced tension. There was no significant difference in the amount of relaxation each hormone produced when the results from male or female guinea pig gallbladder strips were compared.

The purpose of this investigation was to evaluate the use of a commercially available lactose-free fatty-meal food supplement, as an alternative to sincalide cholescintigraphy, to develop a standard methodology, and to determine normal gallbladder ejection fractions (GBEFs) for this supplement. Twenty healthy volunteers all had negative medical histories for hepatobiliary and gallbladder disease, had no personal or family history of hepatobiliary disease, and were not taking any medication known to affect gallbladder emptying. All were prescreened with a complete blood cell count, comprehensive metabolic profile, gallbladder and liver ultrasonography, and conventional cholescintigraphy. Three of the 20 subjects were eliminated from the final analysis because of an abnormality in one of the above studies. After gallbladder filling on conventional cholescintigraphy, the subjects ingested the supplement and an additional 60-min study was acquired. GBEFs were calculated and ranged from 33% to 95% (mean +/- SD, 62.6% +/- 21.3%). Statistical analysis determined the lower range of normal to be 32.6%. Maximal gallbladder emptying occurred between 55 and 60 min. A standard methodology and normal GBEFs (> or =33%) were established for supplement-stimulated cholescintigraphy.

The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is actively regulated by an endocrine pathway and suggest a postprandial timing mechanism that controls gallbladder motility.