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Biochimica Et Biophysica Acta.... Apr 2018Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition,... (Review)
Review
Cholangiocytes, the epithelial cells lining the bile ducts, are an important subset of liver cells. They are involved in the modification of bile volume and composition, and respond to endogenous and exogenous stimuli. Along the biliary tree, two different kinds of cholangiocytes exist: small and large cholangiocytes. Each type has different features and biological role in physiologic and pathologic conditions, and their immunobiology is important for understanding biliary diseases. Cholangiocytes provide the first line of defence against luminal microbes in the hepatobiliary system. Indeed, they express a variety of pattern recognition receptors and may start an antimicrobial defence activating a set of intracellular signalling cascades. In response to injury, cholangiocytes that are normally quiescent become reactive and acquire a neuroendocrine-like phenotype with the release of proinflammatory mediators and antimicrobial peptides, which support biliary epithelial integrity. These molecules act in an autocrine/paracrine manner to modulate cholangiocyte biology and determine the evolution of biliary damage. Failure or dysregulation of such mechanisms may influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. In this review, we focus on the response of cholangiocytes in inflammatory conditions, with a particular focus on the mechanism driving cholangiocytes adaptation to damage. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Topics: Animals; Bile; Bile Duct Neoplasms; Bile Ducts; Carcinogenesis; Cholangiocarcinoma; Cholangitis; Cytokines; Disease Progression; Epithelial Cells; Gastrointestinal Microbiome; Humans; Signal Transduction
PubMed: 28754451
DOI: 10.1016/j.bbadis.2017.07.024 -
BMC Medicine Aug 2023Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor, and its diagnosis is still a challenge. This study aimed to identify a novel bile marker for CCA...
BACKGROUND
Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor, and its diagnosis is still a challenge. This study aimed to identify a novel bile marker for CCA diagnosis based on proteomics and establish a diagnostic model with deep learning.
METHODS
A total of 644 subjects (236 CCA and 408 non-CCA) from two independent centers were divided into discovery, cross-validation, and external validation sets for the study. Candidate bile markers were identified by three proteomics data and validated on 635 clinical humoral specimens and 121 tissue specimens. A diagnostic multi-analyte model containing bile and serum biomarkers was established in cross-validation set by deep learning and validated in an independent external cohort.
RESULTS
The results of proteomics analysis and clinical specimen verification showed that bile clusterin (CLU) was significantly higher in CCA body fluids. Based on 376 subjects in the cross-validation set, ROC analysis indicated that bile CLU had a satisfactory diagnostic power (AUC: 0.852, sensitivity: 73.6%, specificity: 90.1%). Building on bile CLU and 63 serum markers, deep learning established a diagnostic model incorporating seven factors (CLU, CA19-9, IBIL, GGT, LDL-C, TG, and TBA), which showed a high diagnostic utility (AUC: 0.947, sensitivity: 90.3%, specificity: 84.9%). External validation in an independent cohort (n = 259) resulted in a similar accuracy for the detection of CCA. Finally, for the convenience of operation, a user-friendly prediction platform was built online for CCA.
CONCLUSIONS
This is the largest and most comprehensive study combining bile and serum biomarkers to differentiate CCA. This diagnostic model may potentially be used to detect CCA.
Topics: Humans; Bile; Clusterin; Deep Learning; Biomarkers, Tumor; Bile Duct Neoplasms; Cholangiocarcinoma; Bile Ducts, Intrahepatic
PubMed: 37553571
DOI: 10.1186/s12916-023-02990-9 -
BMC Research Notes Jul 2022Bile and its individual components, mainly bile acids, are important for digestion and drive bacterial community dynamics in the upper gastrointestinal tract of...
OBJECTIVE
Bile and its individual components, mainly bile acids, are important for digestion and drive bacterial community dynamics in the upper gastrointestinal tract of chickens. However, specific responses to bile acids have been characterized in only a few commensal bacteria, and it is unclear how other members of the microbiota respond to biliary stress. Here, we used label-free LC-MS/MS to assess the proteomic response of a common inhabitant of the chicken small intestine, Turicibacter bilis MMM721, to 24 h of growth in anaerobic growth media supplemented with 0.1% whole chicken bile, 0.1% taurochenodeoxycholic acid (TCDCA), or 0.1% taurocholic acid (TCA).
RESULTS
Seventy, 46, and 10 differentially expressed proteins were identified in Turicibacter bilis MMM721 cultured with supplements of chicken bile, TCDCA, and TCA, respectively, when compared to unsupplemented controls. Many differentially expressed proteins were predicted to be involved in ribosomal processes, post-translational modifications and chaperones, and modifications to the cell surface. Ultimately, the T. bilis MMM721 response to whole bile and bile acids is complex and may relate to adaptations for small intestine colonization, with numerous proteins from a variety of functional categories being impacted.
Topics: Animals; Bile; Bile Acids and Salts; Chickens; Chromatography, Liquid; Proteomics; Tandem Mass Spectrometry
PubMed: 35780123
DOI: 10.1186/s13104-022-06127-8 -
Molecular Metabolism Dec 2021Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is...
OBJECTIVE
Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is stimulated by fats, bile, and duodenal acidification but the underlying molecular mechanisms of motilin secretion remain poorly understood. This study aimed to establish the key signaling pathways involved in the regulation of secretion from human motilin-expressing M-cells.
METHODS
Human duodenal organoids were CRISPR-Cas9 modified to express the fluorescent protein Venus or the Ca sensor GCaMP7s under control of the endogenous motilin promoter. This enabled the identification and purification of M-cells for bulk RNA sequencing, peptidomics, calcium imaging, and electrophysiology. Motilin secretion from 2D organoid-derived cultures was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), in parallel with other gut hormones.
RESULTS
Human duodenal M-cells synthesize active forms of motilin and acyl-ghrelin in organoid culture, and also co-express cholecystokinin (CCK). Activation of the bile acid receptor GPBAR1 stimulated a 3.4-fold increase in motilin secretion and increased action potential firing. Agonists of the long-chain fatty acid receptor FFA1 and monoacylglycerol receptor GPR119 stimulated secretion by 2.4-fold and 1.5-fold, respectively. Acidification (pH 5.0) was a potent stimulus of M-cell calcium elevation and electrical activity, an effect attributable to acid-sensing ion channels, and a modest inducer of motilin release.
CONCLUSIONS
This study presents the first in-depth transcriptomic and functional characterization of human duodenal motilin-expressing cells. We identify several receptors important for the postprandial and interdigestive regulation of motilin release.
Topics: Bile; Cells, Cultured; Duodenum; Fatty Acids, Nonesterified; Humans; Hydrogen-Ion Concentration; Motilin; Organoids
PubMed: 34662713
DOI: 10.1016/j.molmet.2021.101356 -
Clinical and Translational... Dec 2021Bile reflux may cause for lung allograft rejection, yet there are no studies that determine (i) the relationship between gastric and lung bile concentrations, (ii)...
INTRODUCTION
Bile reflux may cause for lung allograft rejection, yet there are no studies that determine (i) the relationship between gastric and lung bile concentrations, (ii) whether bile is present in lungs of nontransplant patients, (iii) the relationship between gastric dysmotility and lung bile, (iv) the impact of reflux therapies on lung bile, and (v) whether lung bile worsens outcomes in nontransplant patients. This study will address these gaps in the literature.
METHODS
We prospectively recruited lung transplant (LTX) patients and nontransplant patients with respiratory symptoms (RP) and collected paired gastric and lung samples. Bile concentration and composition of samples was assessed using liquid chromatography-mass spectrometry. Bile results were compared with clinical parameters, including the presence of esophagitis, gastric dysmotility, and/or pathologic gastroesophageal reflux.
RESULTS
Seventy patients (48 RP and 22 LTX) were recruited. Overall, 100% of gastric and 98% of bronchoalveolar lavage samples contained bile. The mean gastric bile concentrations in RP and LTX patients were 280 ± 703 nmol/L and 1,004 ± 1721 nmol/L, respectively (P = 0.02). There was no difference in lung bile concentrations between RP (9 ± 30 nmol/L) and LTX (11 ± 15 nmol/L, P = 0.7). Patients with delayed gastric emptying had higher lung bile concentrations (15.5 ± 18.8 nmol/L) than patients with normal gastric emptying (4.8 ± 5.7 nmol/L, P = 0.05) independently of reflux burden. Proton pump inhibitor use increased the proportion of unconjugated gastric bile acids. High lung bile concentrations were associated with an increased risk of hospitalization and longer hospital stays in RP patients (P < 0.05).
DISCUSSION
Lung bile is almost universally present in symptomatic patients, and higher concentrations are associated with poorer respiratory outcomes.
Topics: Bile; Esophagitis, Peptic; Gastroesophageal Reflux; Humans; Lung Transplantation; Risk Factors
PubMed: 34978997
DOI: 10.14309/ctg.0000000000000434 -
International Journal of Molecular... May 2016Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative... (Review)
Review
Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20-22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs.
Topics: Bile; Biliary Tract Neoplasms; Biomarkers, Tumor; Diagnosis, Differential; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Plasma; Prognosis; Sensitivity and Specificity; Serum
PubMed: 27223281
DOI: 10.3390/ijms17050791 -
Hepatology (Baltimore, Md.) Feb 2016
Topics: ATP Binding Cassette Transporter, Subfamily B; Animals; Bile; Cholangitis, Sclerosing; Cyclic N-Oxides; Disease Progression; Female; Organic Anion Transporters, Sodium-Dependent; Symporters; Tropanes
PubMed: 26600416
DOI: 10.1002/hep.28363 -
ELife Sep 2023The seventh pandemic of the diarrheal cholera disease, which began in 1960, is caused by the Gram-negative bacterium . Its environmental persistence provoking recurring...
The seventh pandemic of the diarrheal cholera disease, which began in 1960, is caused by the Gram-negative bacterium . Its environmental persistence provoking recurring sudden outbreaks is enabled by rapid adaption to changing environments involving sensory proteins like ToxR and ToxS. Located at the inner membrane, ToxR and ToxS react to environmental stimuli like bile acid, thereby inducing survival strategies for example bile resistance and virulence regulation. The presented crystal structure of the sensory domains of ToxR and ToxS in combination with multiple bile acid interaction studies, reveals that a bile binding pocket of ToxS is only properly folded upon binding to ToxR. Our data proposes an interdependent functionality between ToxR transcriptional activity and ToxS sensory function. These findings support the previously suggested link between ToxRS and VtrAC-like co-component systems. Besides VtrAC, ToxRS is now the only experimentally determined structure within this recently defined superfamily, further emphasizing its significance. In-depth analysis of the ToxRS complex reveals its remarkable conservation across various species, underlining the significance of conserved residues in the ToxS barrel and the more diverse ToxR sensory domain. Unravelling the intricate mechanisms governing ToxRS's environmental sensing capabilities, provides a promising tool for disruption of this vital interaction, ultimately inhibiting survival and virulence. Our findings hold far-reaching implications for all strains that rely on the ToxRS system as a shared sensory cornerstone for adapting to their surroundings.
Topics: Transcription Factors; DNA-Binding Proteins; Bacterial Proteins; Bile; Vibrio; Vibrio cholerae; Bile Acids and Salts; Gene Expression Regulation, Bacterial
PubMed: 37768326
DOI: 10.7554/eLife.88721 -
Scandinavian Journal of Surgery : SJS :... 2022The most common way of closing the cystic duct in laparoscopic cholecystectomy is by using metal clips (>80%). Nevertheless, bile leakage occurs in 0.4%-2.0% of cases,...
BACKGROUND AND OBJECTIVE
The most common way of closing the cystic duct in laparoscopic cholecystectomy is by using metal clips (>80%). Nevertheless, bile leakage occurs in 0.4%-2.0% of cases, and thus causes significant morbidity. However, the optimal number of clips needed to avoid bile leakage has not been determined. The primary aim of this study was to evaluate bile leakage and post-procedural adverse events after laparoscopic cholecystectomy concerning whether two or three clips were used to seal the cystic duct.
METHODS
Using a retrospective observational design, we gathered data from the Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (ERCP) (GallRiks). From 2006 until 2019, 124,818 patients were eligible for inclusion. These were nested to cohorts of 75,322 (60.3%) for uncomplicated gallstone disease and 49,496 (39.7%) with complicated gallstone disease. The cohorts were grouped by the number (i.e. two or three) of metal clips applied to the proximal cystic duct. The main outcome was 30-day bile leakage and post-procedural adverse events.
RESULTS
No significant differences surfaced in the rate of bile leakage (0.8% vs 0.8%; = .87) or post-procedural adverse events (three clips, 5.7% vs two clips, 5.4%; = .16) for uncomplicated gallstone disease. However, for complicated disease, bile leakage (1.4% vs 1.0%; < .001) and post-procedural adverse events (10.2% vs 8.6%; < .001) significantly increased when the cystic duct was sealed with three clips compared with two.
CONCLUSIONS
Because no differences in the rates of bile leakage or adverse events emerged in uncomplicated gallstone disease when a third clip was applied, a third clip for additional safety is not recommended in such cases. On the contrary, bile leakage and adverse events increased when a third clip was used in patients with complicated gallstone disease. This finding probably indicates a more difficult cholecystectomy rather than being caused by the third clip itself.
Topics: Bile; Cholangiopancreatography, Endoscopic Retrograde; Cholecystectomy, Laparoscopic; Cholelithiasis; Cystic Duct; Humans; Retrospective Studies; Surgical Instruments
PubMed: 35694737
DOI: 10.1177/14574969221102284 -
The Great ESKAPE: Exploring the Crossroads of Bile and Antibiotic Resistance in Bacterial Pathogens.Infection and Immunity Sep 2020Throughout the course of infection, many pathogens encounter bactericidal conditions that threaten the viability of the bacteria and impede the establishment of... (Review)
Review
Throughout the course of infection, many pathogens encounter bactericidal conditions that threaten the viability of the bacteria and impede the establishment of infection. Bile is one of the most innately bactericidal compounds present in humans, functioning to reduce the bacterial burden in the gastrointestinal tract while also aiding in digestion. It is becoming increasingly apparent that pathogens successfully resist the bactericidal conditions of bile, including bacteria that do not normally cause gastrointestinal infections. This review highlights the ability of , , , (ESKAPE), and other enteric pathogens to resist bile and how these interactions can impact the sensitivity of bacteria to various antimicrobial agents. Given that pathogen exposure to bile is an essential component to gastrointestinal transit that cannot be avoided, understanding how bile resistance mechanisms align with antimicrobial resistance is vital to our ability to develop new, successful therapeutics in an age of widespread and increasing antimicrobial resistance.
Topics: Anti-Bacterial Agents; Bacteria; Bile; Biofilms; Drug Resistance, Bacterial; Humans; Intestine, Small; Membrane Transport Proteins; Virulence
PubMed: 32661122
DOI: 10.1128/IAI.00865-19