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• W2892372567 abstract "Bile acid (BA) secretion and circulation in chronic pancreatitis (CP) patients with exocrine pancreatic insufficiency (EPI) were investigated by simultaneously measuring postprandial levels of individual BAs in duodenal contents and blood plasma using LC-MS/MS. CP patients and healthy volunteers (HVs) were intubated with gastric and duodenal tubes prior to the administration of a test meal and continuous aspiration of duodenal contents. Pancreatic lipase outputs in CP patients were very low (0.7 ± 0.2 mg) versus HVs (116.7 ± 68.1 mg; P < 0.005), thus confirming the severity of EPI. Duodenal BA outputs were reduced in CP patients (1.00 ± 0.89 mmol; 0.47 ± 0.42 g) versus HVs (5.52 ± 4.53 mmol; 2.62 ± 2.14 g; P < 0.15). Primary to secondary BA ratio was considerably higher in CP patients (38.09 ± 48.1) than HVs (4.15 ± 2.37; P < 0.15), indicating an impaired transformation of BAs by gut microbiota. BA concentrations were found below the critical micellar concentration in CP patients, while a high BA concentration peak corresponding to gallbladder emptying was evidenced in HVs. Conversely, BA plasma concentration was increased in CP patients versus HVs suggesting a cholangiohepatic shunt of BA secretion. Alterations of BA circulation and levels may result from the main biliary duct stenosis observed in these CP patients and may aggravate the consequences of EPI on lipid malabsorption. Bile acid (BA) secretion and circulation in chronic pancreatitis (CP) patients with exocrine pancreatic insufficiency (EPI) were investigated by simultaneously measuring postprandial levels of individual BAs in duodenal contents and blood plasma using LC-MS/MS. CP patients and healthy volunteers (HVs) were intubated with gastric and duodenal tubes prior to the administration of a test meal and continuous aspiration of duodenal contents. Pancreatic lipase outputs in CP patients were very low (0.7 ± 0.2 mg) versus HVs (116.7 ± 68.1 mg; P < 0.005), thus confirming the severity of EPI. Duodenal BA outputs were reduced in CP patients (1.00 ± 0.89 mmol; 0.47 ± 0.42 g) versus HVs (5.52 ± 4.53 mmol; 2.62 ± 2.14 g; P < 0.15). Primary to secondary BA ratio was considerably higher in CP patients (38.09 ± 48.1) than HVs (4.15 ± 2.37; P < 0.15), indicating an impaired transformation of BAs by gut microbiota. BA concentrations were found below the critical micellar concentration in CP patients, while a high BA concentration peak corresponding to gallbladder emptying was evidenced in HVs. Conversely, BA plasma concentration was increased in CP patients versus HVs suggesting a cholangiohepatic shunt of BA secretion. Alterations of BA circulation and levels may result from the main biliary duct stenosis observed in these CP patients and may aggravate the consequences of EPI on lipid malabsorption. Chronic pancreatitis (CP) is an ongoing inflammatory disorder associated with the loss of exocrine and endocrine pancreatic parenchyma and its replacement by fibrotic tissue. It results in various nutritional deficits linked to maldigestion subsequent to exocrine pancreatic insufficiency (EPI) and diabetes mellitus subsequent to pancreatic endocrine insufficiency. CP is mainly induced by alcohol abuse in Western countries (1Samokhvalov A.V. Rehm J. Roerecke M. Alcohol consumption as a risk factor for acute and chronic pancreatitis: a systematic review and a series of meta-analyses.EBioMedicine. 2015; 2: 1996-2002Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Other toxic and/or metabolic agents and gene mutations regulating the pancreatic enzyme-activating cascades and their inhibitors are also factors associated with a hereditary form of the disease (2Büchler M.W. Friess H. Uhl W. Malfertheiner P. Blackwell Wissenschafts-Verlag.Berlin. 2002; Google Scholar, 3Etemad B. Whitcomb D. Chronic pancreatitis: diagnosis classification, and new genetic developments.Gastroenterology. 2001; 120: 682-707Abstract Full Text Full Text PDF PubMed Scopus (1015) Google Scholar). The first symptom is commonly the abdominal pain. Over the first 5 years of the course of the disease, complications such as pseudocysts or bile duct stenosis can occur. Occurrence of pancreatic calcifications is a lately observed diagnostic key. Because the clinical symptoms remain vague and nonspecific in many CP patients, biological tests are required (4Duggan S.N. Ni Chonchubhair H.M. Lawal O. O'Connor D.B. Conlon K.C. Chronic pancreatitis: A diagnostic dilemma.World J. Gastroenterol. 2016; 22: 2304-2313Crossref PubMed Scopus (53) Google Scholar) for the diagnosis as well as the follow up. In CP patients, fat digestion is more severely impaired than carbohydrate and protein digestion, and steatorrhea is usually a major symptom. The decrease in fat absorption is explained by a decrease in human pancreatic lipase (HPL) secretion and duodenal pH due to the reduced pancreatic bicarbonate secretion (5Carrière F. Grandval P. Renou C. Palomba A. Prieri F. Giallo J. Henniges F. Sander-Struckmeier S. Laugier R. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis.Clin. Gastroenterol. Hepatol. 2005; 3: 28-38Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 6Youngberg C.A. Berardi R.R. Howatt W.F. Hyneck M.L. Amidon G.L. Meyer J.H. Dressman J.B. Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects.Dig. Dis. Sci. 1987; 32: 472-480Crossref PubMed Scopus (96) Google Scholar). The decrease in duodenal pH impairs the activity and stability of residual HPL. It also promotes the precipitation of bile acids (BAs) and, thus, a further deterioration of intestinal lipid absorption (7Zentler-Munro P.L. Fine D.R. Fitzpatrick W.J. Northfield T.C. Effect of intrajejunal acidity on lipid digestion and aqueous solubilisation of bile acids and lipids in health, using a new simple method of lipase inactivation.Gut. 1984; 25: 491-499Crossref PubMed Scopus (21) Google Scholar, 8Zentler-Munro P.L. Fitzpatrick W.J. Batten J.C. Northfield T.C. Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentrations in pancreatic steatorrhoea due to cystic fibrosis.Gut. 1984; 25: 500-507Crossref PubMed Scopus (64) Google Scholar). It was shown that human gastric lipase secretion and contribution to lipolysis are increased in CP patients, but not sufficiently to compensate for the loss of the prominent pancreatic lipase (5Carrière F. Grandval P. Renou C. Palomba A. Prieri F. Giallo J. Henniges F. Sander-Struckmeier S. Laugier R. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis.Clin. Gastroenterol. Hepatol. 2005; 3: 28-38Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). The current treatment of EPI is enzyme replacement with porcine pancreatic extracts. Fat absorption can be improved with enteric-coated formulations of these exogenous pancreatic enzymes, associated also with proton pump inhibitors to increase the duodenal pH and enhance enzyme stability and activity (9Sander-Struckmeier S. Beckmann K. Janssen-van Solingen G. Pollack P. Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin (CREON(R)) in patients with pancreatic exocrine insufficiency.Pancreas. 2013; 42: 983-989Crossref PubMed Scopus (24) Google Scholar, 10Vecht J. Symersky T. Lamers C.B. Masclee A.A. Efficacy of lower than standard doses of pancreatic enzyme supplementation therapy during acid inhibition in patients with pancreatic exocrine insufficiency.J. Clin. Gastroenterol. 2006; 40: 721-725Crossref PubMed Scopus (42) Google Scholar, 11DiMagno E.P. Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency.Best Pract. Res. Clin. Gastroenterol. 2001; 15: 477-486Crossref PubMed Scopus (38) Google Scholar). In some patients with severe EPI, pancreatic enzyme replacement therapy may not lead to the reduction of steatorrhea, suggesting that other mechanisms interplay with the reduced lipase secretion. Although exogenous lipases act correctly in the small intestine, it can be suspected that other factors affecting the absorption of lipolysis products are limiting. BA levels, for instance, were rarely addressed in CP patients (12Regan P.T. Malagelada J.R. Dimagno E.P. Go V.L. Reduced intraluminal bile acid concentrations and fat maldigestion in pancreatic insufficiency: correction by treatment.Gastroenterology. 1979; 77: 285-289Abstract Full Text PDF PubMed Scopus (75) Google Scholar). The BAs are critical for the digestion and absorption of fats (13Hofmann A.F. The function of bile salts in fat absorption. The solvent properties of dilute micellar solutions of conjugated bile salts.Biochem. J. 1963; 89: 57-68Crossref PubMed Scopus (199) Google Scholar, 14Hofmann A.F. Borgström B. The intraluminal phase of fat digestion in man: the lipid content of the micellar and oil phases of intestinal content obtained during fat digestion and absorption.J. Clin. Invest. 1964; 43: 247-257Crossref PubMed Scopus (246) Google Scholar). Due to their amphiphilic properties, they are found adsorbed at the surface of oil-in-water emulsions where they regulate the lipolytic activity of the pancreatic lipase-colipase complex. BAs are also found in the form of mixed micelles with other bile lipids (cholesterol, phosphatidylcholine) and lipolysis products (free fatty acids, 2-monoglycerides). The micellar cosolubilization of lipolysis products by BA is required for removing these products from the lipid-water interface and for ensuring their diffusion in the aqueous milieu of the gut toward the enterocytes. In the absence of bile secretion, fat absorption is impaired (15Hofmann A.F. Bile acids: the good, the bad, and the ugly.News Physiol. Sci. 1999; 14: 24-29PubMed Google Scholar). Apart from their function in fat absorption and regulation of cholesterol homeostasis, BAs are increasingly being appreciated as complex metabolic integrators and signaling factors. They have become attractive therapeutic targets for metabolic disorders and useful markers of hepatobiliary and intestinal diseases (16Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (928) Google Scholar). Individual BA molecular species from various biological samples (blood plasma, feces, urine) can now be separated and quantified in the clinical laboratory using LC-MS/MS. The BA profiles are used for a sensitive diagnosis of cholestasis (17Humbert L. Maubert M.A. Wolf C. Duboc H. Mahe M. Farabos D. Seksik P. Mallet J.M. Trugnan G. Masliah J. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2012; 899: 135-145Crossref PubMed Scopus (113) Google Scholar). BA levels and profiles in patients with EPI have not been fully investigated with the LC-MS/MS profiling method, whereas BA malabsorption in patients with CP was fully evidenced by the radiolabeled synthetic BA standard test (18Reid F. Peacock J. Coker B. McMillan V. Lewis C. Keevil S. Sherwood R. Vivian G. Logan R. Summers J. A multicenter prospective study to investigate the diagnostic accuracy of the SeHCAT test in measuring bile acid malabsorption: research protocol.JMIR Res. Protoc. 2016; 5: e13Crossref PubMed Scopus (8) Google Scholar). In the present study, we have detailed the postprandial individual BA level variations in both the duodenum and plasma of CP patients and healthy volunteers (HVs) after a standard test meal. The duodenal content and blood samples used in this study were collected in the framework of two clinical studies (mrtm02-01 for HVs and mrtm03-01 for CP patients; Principal Investigator: Prof. René Laugier, MD, PhD) that were not initially designed for the analysis reported here. The clinical study protocols were accepted on January 17, 2003 by the institutional board of the ethics committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale, Hôpital d'Adultes de la Timone, Marseille). Test meal experiments and sample collection were performed from March to July 2003 at “Centre de Pharmacologie Clinique et d'Etudes Thérapeutiques (Hôpital d'adultes de la Timone, Marseille, France)” after written informed consent was obtained from all CP patients and HVs. The study conformed to the standards set by the Declaration of Helsinki, except for registration in a database. Two groups of six HVs (mean age: 30 ± 3 years) with no history of pancreatic disease and six patients with severe CP (mean age: 53 ± 8 years) were selected for this study. The severity of each patient's pancreatic insufficiency was estimated from the medical record and steatorrhea level in the absence of treatment by pancreatic extracts (see supplemental Table S1). All selected CP patients had high levels of steatorrhea (8–45 g/day). All were documented with pancreatic calcification. Patients with common biliary duct stenosis had been treated by endoscopy within the 5 years preceding the study. Some patients were also treated for stenosis after the present study. Only one patient had highly elevated liver enzymes, presumably due to severe hepatic disease. The mixed solid/liquid meal used for the in vivo experiments contained 80 g string beans, 90 g beef meat, 70 g fried potatoes, 10 g butter, 15 ml olive oil, and water for a total volume of 700 ml. The string beans, beef meat, and fried potatoes were passed individually into a mincer with 2 mm holes before they were mixed. The total amount of neutral fat given as triglycerides in the meal was measured to 31.8 ± 2.9 g after extraction of total lipids with chloroform-methanol and triglyceride quantification using thin-layer chromatography coupled to flame ionization detection (19Cavalier J.F. Lafont D. Boullanger P. Houisse D. Giallo J. Ballester J.M. Carriere F. Validation of lipolysis product extraction from aqueous/biological samples, separation and quantification by thin-layer chromatography with flame ionization detection analysis using O-cholesteryl ethylene glycol as a new internal standard.J. Chromatogr. A. 2009; 1216: 6543-6548Crossref PubMed Scopus (19) Google Scholar). A nonabsorbable marker was added to the meal [5 g polyethylene glycol (PEG) 4000] to measure the gastric emptying rate and correct the duodenal volumes based on the PEG recovery rates (20Carrière F. Barrowman J.A. Verger R. Laugier R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans.Gastroenterology. 1993; 105: 876-888Abstract Full Text PDF PubMed Scopus (384) Google Scholar). After fasting overnight, the patients and volunteers were intubated with a double-lumen duodenal tube (outside diameter 5 mm) and a separate single-lumen gastric tube (outside diameter, 3 mm). The tubes were placed under fluoroscopy and their positions were checked by analyzing the pH of their contents. The distal end of the duodenal tube with the occluding balloon was located at the ligament of Treitz (see supplemental Fig. S1). During the sampling period, the subjects stayed in bed with continuous duodenal aspiration by connection of the duodenal tube to a vacuum (around −10 mbar). Aspiration was started a few minutes before the meal and the occluding balloon was inflated (10 ml air). After collecting basal gastric and duodenal samples, the test meal was introduced into the stomach via the gastric tube using a 50 ml syringe during a period of 5 min. The duodenal fluid was collected continuously for 15 min periods by aspiration upstream of the occluding balloon. The parameters measured in each sample were: i) volume and pH (to the nearest 0.5 ml and 0.1 pH unit, respectively); ii) PEG 4000 concentration; iii) pancreatic lipase activity; and iv) individual BA concentrations. In order to prevent the proteolytic inactivation of lipase before the assay, 1 ml of glycerol and 40 μl of protease inhibitors were added immediately to 1 ml of duodenal sample before storage at −20°C. The solution of protease inhibitors was prepared by dissolving a pellet of Complete™ protease inhibitor mix (Roche) in 2 ml of distillated water. All samples were kept at −80°C before they were analyzed. Blood samples were collected before and after the meal for a total duration of 240 min. All samples were kept at −80°C before they were analyzed. The PEG 4000 concentration was measured using the turbidimetric method developed by Hydén (21Hydén S. A turbidimetric method for determination of higher polyethyleneglycols in biological materials.Annals of the Royal Agricultural Coll. 1956; 22: 139-145Google Scholar) as modified by Malawer and Powell (22Malawer S.J. Powell D.W. An improved turbidimetric analysis of polyethylene glycol utilizing an emulsifier.Gastroenterology. 1967; 53: 250-256Abstract Full Text PDF Google Scholar). The enzyme activity of HPL in duodenal contents was measured by the pHstat technique as previously reported (20Carrière F. Barrowman J.A. Verger R. Laugier R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans.Gastroenterology. 1993; 105: 876-888Abstract Full Text PDF PubMed Scopus (384) Google Scholar, 23Erlanson C. Borgström B. Tributyrin as a substrate for determination of lipase activity of pancreatic juice and small intestinal content.Scand. J. Gastroenterol. 1970; 5: 293-295Crossref PubMed Google Scholar). Lipase levels were expressed in international units per milliliter (1 international unit = 1 μmol of fatty acid released per minute from the standard substrate, tributyrin). Lipase outputs were expressed either in total units or milligrams of active lipase based on the known specific activity (8,000 U/mg) of a pure HPL acting on tributyrin under similar conditions. A correction factor accounting for the partial recovery in duodenal aspirates of the nonabsorbable marker, PEG 4000, was calculated for the whole period of measurement by dividing the total amount of marker initially added in the meal by the recovered amount at the end of the experiment. The duodenal output of HPL was estimated from the assay of enzyme activity in duodenal samples, the volume of duodenal aspirates, and the correction factor based on the recovery of PEG. Concentrated BA calibration solutions were prepared in methanol (1 mg/ml) and stored in a sealed container at −20°C. These stock solutions were diluted to obtain calibration solutions ranging from 31.3 ng/ml to 31.3 μg/ml. Cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), lithocholic acid (LCA), hyocholic acid (HCA), and the corresponding glyco- and tauro-conjuguates were obtained from Sigma-Aldrich (Saint Quentin Fallavier, France). The 3-sulfate derivatives of the BAs were a generous gift from Dr. J. Goto (Niigita University of Pharmacy and Applied Life Science, Japan). The 23-nor-5μ-cholanoic acid-3α,12μ diol, muricholic acid derivatives, and glyco- and tauro-derivatives were purchased from Steraloids Inc. (Newport, RI). An internal standard solution (2 μl of 23-nor-5μ-cholanoic acid-3α,12μ diol at 1 mg/ml) was added to plasma samples (500–1,000 μl) and duodenal aspirates (100–200 μl). Proteins were precipitated by addition of ammonium carbonate 0.4 M for 30 min at 60°C (17Humbert L. Maubert M.A. Wolf C. Duboc H. Mahe M. Farabos D. Seksik P. Mallet J.M. Trugnan G. Masliah J. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2012; 899: 135-145Crossref PubMed Scopus (113) Google Scholar). The clean-up procedure was achieved by centrifugation (4,000 g for 10 min) followed by a solid-phase extraction. Reverse phase Chromabond C18 cartridges (100 mg; Macherey-Nagel, Düren, Germany) were prewashed with 5 ml of methanol and 5 ml of water, successively, before the sample was loaded onto the cartridge. The subsequent steps were processed on a vacuum manifold designed for solid-phase extraction. The cartridge was rinsed successively with 20 ml of water, 10 ml of hexane to discard neutral lipids, and again with 20 ml water. BAs were finally eluted by methanol. The eluates were dried under a nitrogen stream at 50°C and the residue dissolved in 150 μl of methanol. Five microliters were injected into the HPLC-MS/MS equipment. The chromatographic separation of BAs (see supplemental Fig. S2) was carried out on a reverse phase column [Restek C18 Pinnacle II (250 × 3.2 mm, 5 μm); Restek, Lisses, France] thermostated at 35°C (Agilent 1100 HPLC; Agilent Massy, France). The column was initially equilibrated with a 65/35 (v/v) mixture of solvent A (15 mM of aqueous ammonium acetate, pH 5.3) and solvent B (methanol). BA elution was achieved by increasing the proportion of solvent B from 65/35 to 95/5 (v/v). Simultaneously, the flow rate was increased from 0.3 to 0.5 ml/min for 30 min. The HPLC column eluates were infused into the ESI source of a triple quadrupole mass spectrometer (QTRAP 2000; Applied Biosystems-SCIEX, Concord, Ontario, Canada). Electrospray ionization was set in the negative mode. Nebulizer, curtain, and heater nitrogen gases were set at 40, 20, and 40 (arbitrary units), respectively. The temperature for the evaporation gas (nitrogen) was set at 400°C. The ion spray, declustering, and entrance potentials were set at −4,500, −60, and −10 V, respectively. The MS/MS detection was operated with a unit resolution in the multiple reaction monitoring mode. The dwell time for each transition was set at 70 ms. Multiple reaction monitoring was performed by examination of the transition reactions from precursor conjuguated BA to product fragment-ions after collision-induced dissociation: the sulfite (m/z 80, SO3 fragment-anion cleaved from taurine) and glycine moieties (m/z 74), respectively, for tauroconjugated and glycoconjugated BAs. Sulfo-conjuguates were identified by the sulfuric anion (m/z 97, HSO4). No specific fragment-ions were observed for unconjugated BAs, except those corresponding to loss of water, and those fragments were not reliable for quantification. Therefore, we used selected ion monitoring mode for quantifying unconjugated BAs, with mono-, di-, and tri-hydroxylated BAs scanned at m/z 375, 391, and 407, respectively. The 23-nor-5μ-cholanoic acid-3α,12μ diol (m/z 377) was used as the internal standard for normalization. The method for BA analysis was validated according to Humbert et al. (17Humbert L. Maubert M.A. Wolf C. Duboc H. Mahe M. Farabos D. Seksik P. Mallet J.M. Trugnan G. Masliah J. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2012; 899: 135-145Crossref PubMed Scopus (113) Google Scholar), who previously checked that similar values were obtained with three different internal standards (23-nor-5μ-cholanoic acid-3α,12 α diol, ursodeoxycholic-2,2,4,4-d4 acid, and lithocholic-2,2,4,4-d4 acid) with distinct hydrophobicity and retention times. All the data are expressed as mean ± SD unless stated otherwise. The data obtained in the various series of experiments were compared using paired and unpaired Student's t-tests. The data obtained at time 30 min after meal administration were also analyzed using principal component analysis and discriminant analysis (DA) using an orthogonal-partial least square (O-PLS) statistical model [SIMCA14 software package (Umetrics, Umeå, Sweden)]. In HVs, the duodenal pH values remained in the pH 4.1–7.4 range during the meal digestion, with a mean value of 6.10 ± 0.8 (Fig. 1A). In CP patients, the duodenal pH decreased rapidly after 30 min, and then remained very low with mean pH values ranging between pH 2 and pH 3.5 (Fig. 1A). The pH differences between CP patients and HVs were significant (P < 0.05) from 30 to 180 min. Pancreatic lipase outputs during the whole digestion period were estimated from the recovery of duodenal contents. The HPL activities recorded in HVs were in the 320–5,250 U/ml range (i.e., 40–656 μg/ml of active HPL), whereas HPL activity in CP patients was extremely low and never greater than 12 U/ml (1.5 μg/ml; Fig. 2B). From the cumulated outputs of HPL, it was observed that pancreatic lipase secretion was almost abolished in CP patients (0.7 ± 0.2 mg vs. 116.7 ± 68.1 mg in HVs; P < 0.005). In HVs, the BA concentration in duodenal contents was increased immediately after the meal intake and reached a maximum value (14.8 ± 12.7 mM) after 30 min (Fig. 2A). It then decreased and leveled off around 3–4 mM after 120 min. Except during the 75–90 min period, mean BA concentration found in human duodenal contents was above the average critical micellar concentration (CMC) of the main BAs found in human bile (24Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Abstract Full Text PDF PubMed Google Scholar) (around 4 mM; see supplemental Table S2). In CP patients, the BA concentration in the duodenum was much lower than in HVs. A maximum value of 3.9 ± 5.6 mM was observed at 45 min (Fig. 2A). Except at 30 and 45 min, the total BA concentration remained below the CMC. The ratio of primary BA (7α-hydroxylated in the liver) over secondary BA (produced from primary BA by the intestinal microbiota after 7α-dehydroxylation) was considerably higher in CP patients (38.09 ± 48.1) than in HVs (4.15 ± 2.37; P < 0.15) (Fig. 2B). The ratio ranged from 19.3 to 72.8 in CP patients as compared with 4.1 to 7.1 in HVs. Total BA outputs in duodenal contents over the postprandial period (Table 1) were much lower in CP patients (1.00 ± 0.89 mmol; 0.47 ± 0.42 g) versus HVs (5.52 ± 4.53 mmol; 2.62 ± 2.14 g). The ratio of primary to secondary BA was also much higher in CP patients (38.1 ± 39.4) than in HVs (4.2 ± 1.9). The examination of the detailed BA composition (expressed as total BA mole percent) revealed a significant decrease in taurochenodeoxycholic acid (TCDCA) (P < 0.015), taurodeoxycholic acid (TDCA) (P < 0.025), glycolithocholic acid 3-sulfate (GLCA-3S) (P < 0.02), taurolithocholic acid 3-sulfate (TLCA-3S) (P < 0.01), UDCA 3-sulfate (UDCA-3S) (P < 0.035), LCA 3-sulfate (P < 0.05), glycoursodeoxycholic acid 3-sulfate (GUDCA-3S) (P < 0.03), glycoursodeoxycholic acid (GUDCA) (P < 0.035), glycohyodeoxycholic acid (GHDCA) (P < 0.005), glycocholic acid (GCA) (P < 0.015), and taurolithocholic acid (TLCA) (P < 0.05) in CP patients versus HVs (Table 1). Only traces of glucuronated conjugates (<0.01% of total BAs) were detected and were not taken onto account for comparison of BA profiles between CP patients and HVs. For comparison, total sulfated BAs accounted for around 0.04% (CP patients) to 0.3% (HVs) of total BAs in duodenal contents.TABLE 1BA outputs and distribution in duodenal contents of HVs and patients with severe CP after intake of a liquid-solid test mealHVs (Controls) (n = 6)CP Patients (n = 6)BAsOutput (μmol)Total BA Percent (mol%)Output (μmol)Total BA Percent (mol%)Percent of ControlsTUDCA53.02 ± 58.930.78 ± 0.790.67 ± 0.530.07 ± 0.031.27THDCA10.04 ± 14.320.08 ± 0.120.54 ± 0.750.02 ± 0.045.42TCDCA777.22 ± 618.9714.56 ± 2.99101.68 ± 94.828.78 ± 3.1513.08TDCA522.95 ± 549.817.80 ± 4.9327.33 ± 32.811.71 ± 1.375.23THCA2.30 ± 1.790.05 ± 0.021.36 ± 1.370.16 ± 0.2159.35TCA827.88 ± 570.9819.13 ± 8.82229.80 ± 214.3022.76 ± 12.9227.76GLCA-3S4.43 ± 3.010.11 ± 0.060.43 ± 0.560.02 ± 0.039.62TLCA-3S5.81 ± 4.630.14 ± 0.080.27 ± 0.370.01 ± 0.024.62UDCA-3S0.03 ± 0.03<0.010.000.000.00CDCA-3S0.05 ± 0.04<0.010.01 ± 0.01<0.0115.33DCA-3S0.23 ± 0.24<0.010.02 ± 0.02<0.0110.16LCA-3S0.21 ± 0.10<0.010.02 ± 0.02<0.018.12CA-3S0.00−0.00−−TUDCA-3S0.42 ± 0.490.01 ± 0.010.01 ± 0.02<0.013.22GUDCA-3S1.92 ± 1.650.03 ± 0.020.09 ± 0.120.01 ± 0.014.86GLCA20.37 ± 13.310.43 ± 0.302.39 ± 3.060.15 ± 0.1811.76GUDCA181.35 ± 193.462.33 ± 1.525.38 ± 5.510.61 ± 0.452.97GHDCA29.32 ± 28.110.42 ± 0.151.40 ± 1.740.10 ± 0.084.77GCDCA1438.15 ± 1126.4526.19 ± 8.74278.11 ± 277.7729.35 ± 11.5819.34GDCA889.17 ± 867.8412.55 ± 5.1379.39 ± 99.125.71 ± 4.878.93GHCA1.74 ± 1.410.03 ± 0.020.90 ± 0.730.13 ± 0.1651.63GCA736.51 ± 559.0315.02 ± 4.34242.89 ± 184.2928.23 ± 8.8232.98TLCA13.83 ± 11.070.29 ± 0.221.02 ± 1.220.06 ± 0.057.40LCA0.02 ± 0.03<0.010.06 ± 0.10<0.01315.21UDCA0.11 ± 0.10<0.010.04 ± 0.07<0.0136.24HDCA0.00−0.00−−CDCA0.84 ± 0.660.02 ± 0.015.71 ± 9.100.41 ± 0.77680.48DCA0.28 ± 0.21<0.012.27 ± 3.720.15 ± 0.32804.00MCA0.01 ± 0.01<0.010.03 ± 0.05<0.01312.19HCA0.00−0.00−−CA1.77 ± 1.500.04 ± 0.0316.62 ± 22.531.54 ± 1.87937.62Total BA5,519.97 ± 4,534.78100.00998.46 ± 889.62100.0018.09BA outputs are expressed in micromoles and BA distributions are expressed as the mole percent of total BA. CA-3S, CA 3-sulfate; CDCA-3S, CDCA 3-sulfate; DCA-3S, DCA 3-sulfate; GHCA, glycohyocholic acid; GLCA, glycolithocholic acid; HDCA, hyodeoxycholic acid; LCA-3S, LCA 3-sulfate; MCA, muricholic acid; THCA, taurohyocholic acid; THDCA, taurohyodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; TUDCA-3S, tauroursodeoxycholic acid 3-sulfate. Open table in a new tab BA outputs are expressed in micromoles and BA distributions are expressed as the mole percent of total BA. CA-3S, CA 3-sulfate; CDCA-3S, CDCA 3-sulfate; DCA-3S, DCA 3-sulfate; GHCA, glycohyocholic acid; GLCA, glycolithocholic acid; HDCA, hyodeoxycholic acid; LCA-3S, LCA 3-sulfate; MCA, muricholic acid; THCA, taurohyocholic acid; THDCA, taurohyodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; TUDCA-3S, tauroursodeoxycholic acid 3-sulfate. The BA concentration in blood plasma was" @default.
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• W2892372567 date "2018-11-01" @default.
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• W2892372567 title "Postprandial bile acid levels in intestine and plasma reveal altered biliary circulation in chronic pancreatitis patients" @default.
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• W2892372567 doi "https://doi.org/10.1194/jlr.m084830" @default.
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