Serum Bile Acid Concentrations Research Articles

Rats with high aerobic capacity display enhanced transcriptional adaptability and upregulation of bile acid metabolism in response to an acute high-fat diet.

Rats selectively bred for the high intrinsic aerobic capacity runner (HCR) or low aerobic capacity runner (LCR) show pronounced differences in susceptibility for high‐fat/high sucrose (HFHS) diet‐induced hepatic steatosis and insulin resistance, replicating the protective effect of high aerobic capacity in humans. We have previously shown multiple systemic differences in energy and substrate metabolism that impacts steatosis between HCR and LCR rats. This study aimed to investigate hepatic‐specific mechanisms of action via changes in gene transcription. Livers of HCR rats had a greater number of genes that significantly changed in response to 3‐day HFHS compared with LCR rats (171 vs. 75 genes: >1.5‐fold, p < 0.05). HCR and LCR rats displayed numerous baseline differences in gene expression while on a low‐fat control diet (CON). A 3‐day HFHS diet resulted in greater expression of genes involved in the conversion of excess acetyl‐CoA to cholesterol and bile acid (BA) synthesis compared with the CON diet in HCR, but not LCR rats. These results were associated with higher fecal BA loss and lower serum BA concentrations in HCR rats. Exercise studies in rats and mice also revealed higher hepatic expression of cholesterol and BA synthesis genes. Overall, these results suggest that high aerobic capacity and exercise are associated with upregulated BA synthesis paired with greater fecal excretion of cholesterol and BA, an effect that may play a role in protection against hepatic steatosis in rodents.

Resting and postpradial serum cholecystokinin concentrations and evaluation of the effect of seeing and/or smelling food on serum cholecystokinin and bile acid concentrations in healthy dogs

Serum bile acids concentrations rise postprandially. However, some dogs show paradoxical serum bile acids results with higher pre-prandial than post-prandial concentrations. The aim of this study was to evaluate serum cholecystokinin (CCK) concentrations and determine whether they correspond to paradoxical serum bile acids concentrations. In addition, seeing and smelling food was investigated as a possible cause for paradoxical serum bile acids results. Eight healthy dogs owned by volunteers enrolled in this experimental study. Food was withheld from the dogs for 12 h with great care not to expose them to any sight or smell of food. Blood samples were collected at 0, 30, 60, 120, 180, 240, 480 and 720 min after feeding. Food was then withheld again for 24 h, and blood samples were collected at 0, 30, 60, 120, 180, 240, 480 and 720 min after seeing and smelling food. After feeding, serum CCK concentrations increased, but paradoxical serum CCK concentrations were observed in some of dogs, but only one of those had also paradoxical serum bile acids concentrations. After seeing and smelling food, serum CCK and serum bile acids concentrations did not significantly increase. In conclusion, paradoxical serum CCK concentrations can occur in some healthy dogs after feeding. However, no correlation with paradoxical serum bile acids concentrations was found. Seeing or smelling food are unlikely causes for paradoxical serum bile acids concentrations. Additional studies are warranted to further evaluate the relationship of serum CCK and bile acids concentrations in healthy dogs and dogs with gastrointestinal disease.

Anamnestic and biochemical predictors of obstetric and perinatal complications in intrahepatic cholestasis of pregnancy

Objective. To determine the anamnestic and biochemical predictors of obstetric and perinatal complications in women with intrahepatic cholestasis of pregnancy (ICP).Materials and methods. 59 women with ICP and 30 pregnant women included into the comparison group were examined. The characteristics of the reproductive history, anamnesis of the disease, complaints, biochemical parameters of liver function (syndromes of cholestasis and hepatocyte cytolysis, function of protein synthesis), features of the course and treatment of ICP were studied.Results. The main predictors of preterm birth in the women with ICP were: age (P(U)=0.027), multiple pregnancy (OR=17.5, p=0.033); alkaline phosphatase (ALP) blood level &gt; 499 U/l (AUC=0.801; p=0.008); De Ritis Ratio value ≤ 0.49 (AUC=0.757; p=0.005). The main prognostic markers for meconium staining of amniotic fluid (MSAF) in the patients with ICP were: ICP in previous pregnancies (OR=7.1; p=0.029); serum bile acid concentration &gt; 14 μmol/l (AUC=0.718; p=0.043); total bilirubin blood level &gt; 13 μmol/l (AUC=0.773; p=0.007); ALP activity &gt; 484 U/l (AUC=0.728; p=0.033); blood creatinine concentration ≤ 60 μmol/l (AUC=0.930; p=0.0001) in asymptomatic course. The development of respiratory disorders in children born to women with asymptomatic ICP was associated with a total protein concentration in the blood of 78 g/l or less (AUC=0.852; p=0.0001).Conclusion. The anamnesis of the disease and the determination of the levels of the biochemical parameters of liver function allows predicting obstetric and perinatal complications in ICP.

Deep Learning Algorithm-Based Magnetic Resonance Imaging Feature-Guided Serum Bile Acid Profile and Perinatal Outcomes in Intrahepatic Cholestasis of Pregnancy.

This study was aimed to explore magnetic resonance imaging (MRI) based on deep learning belief network model in evaluating serum bile acid profile and adverse perinatal outcomes of intrahepatic cholestasis of pregnancy (ICP) patients. Fifty ICP pregnant women diagnosed in hospital were selected as the experimental group, 50 healthy pregnant women as the blank group, and 50 patients with cholelithiasis as the gallstone group. Deep learning belief network (DLBN) was built by stacking multiple restricted Boltzmann machines, which was compared with the recognition rate of convolutional neural network (CNN) and support vector machine (SVM), to determine the error rate of different recognition methods on the test set. It was found that the error rate of deep learning belief network (7.68%) was substantially lower than that of CNN (21.34%) and SVM (22.41%) (P < 0.05). The levels of glycoursodeoxycholic acid (GUDCA), glycochenodeoxycholic acid (GCDCA), and glycocholic acid (GCA) in the experimental group were dramatically superior to those in the blank group (P < 0.05). Both the experimental group and the blank group had notable clustering of serum bile acid profile, and the experimental group and the gallstone group could be better distinguished. In addition, the incidence of amniotic fluid contamination, asphyxia, and premature perinatal infants in the experimental group was dramatically superior to that in the blank group (P < 0.05). The deep learning confidence model had a low error rate, which can effectively extract the features of liver MRI images. In summary, the serum characteristic bile acid profiles of ICP were glycoursodeoxycholic acid, glycochenodeoxycholic acid, and glycocholic acid, which had a positive effect on clinical diagnosis. The toxic effects of high concentrations of serum bile acids were the main cause of adverse perinatal outcomes and sudden death.

Circulating Bile Acids and Adenoma Recurrence in the Context of Strict Adherence to a High-Fiber, High-Fruit and -Vegetable, and Low-Fat Dietary Intervention

ObjectivesDiet may affect BA metabolism and signaling, and, in turn, chronically higher bile acid (BA) concentrations may be associated with colorectal cancer risk. Further evidence regarding these interrelationships among human populations is needed. Therefore, we investigated 1) the effect of strict adherence to a high-fiber, high-fruit and -vegetable, low-fat dietary intervention on serum BA concentrations; and 2) associations of BA concentrations with adenoma recurrence. MethodsThe Polyp Prevention Trial is a 4-year randomized dietary intervention that investigated the effect of a high-fiber, high-fruit and vegetable, and low-fat diet on colorectal adenoma recurrence. We used targeted, quantitative liquid chromatography–tandem mass spectrometry panels to measure 13 BAs in serially collected serum at baseline, year-2, and year-3 of the trial among 170 intervention participants who strictly adhered to the intervention and 198 comparable control arm participants. We estimated the effect of the dietary intervention on mean year-2 and year-3 BA concentrations using repeated-measures linear mixed-effects models. We estimated associations of BA concentrations with adenoma recurrence 3–4 years after baseline using multivariable logistic regression. We estimated temporal variability of BA concentrations over 3 years using intraclass correlation coefficients (ICCs). ResultsWe found no effects of the high-fiber, high-fruit and -vegetable, low-fat diet intervention on serum BA concentrations; however, pre-trial dietary fiber intake was inversely associated with total BAs (Spearman = –0.15; PFDR = 0.03). Baseline total BA concentrations were positively associated with adenoma recurrence (ORQ3 vs. Q1 = 2.17; 95% CI = 1.19–4.04; P-trendFDR = 0.05). These findings were inconsistent when considering BA concentrations at year-2 and year-3, potentially reflecting our findings of moderate temporal stability of BAs over 3 years (ICC for total BAs = 0.53; 95% CI = 0.46–0.59) and underlying changes in adenoma status across the follow-up period. ConclusionsA high-fiber, high-fruit and -vegetable, low-fat diet may not modify serum BA concentrations; however, BAs concentrations may be positively associated with risk of adenoma recurrence. Funding SourcesIntramural Research Program, National Cancer Institute, NIH.

Association of Serum and Fecal Bile Acid Patterns With Liver Fibrosis in Biopsy-Proven Nonalcoholic Fatty Liver Disease: An Observational Study.

No reports on both blood and fecal bile acids (BAs) in patients with nonalcoholic fatty liver disease (NAFLD) exist. We simultaneously assessed the serum and fecal BA patterns in healthy participants and those with NAFLD. We collected stool samples from 287 participants from 5 hospitals in Japan (healthy control [HC]: n = 88; mild fibrosis: n = 104; and advanced fibrosis group: n = 95). Blood samples were collected and analyzed for serum BAs and 7α-hydroxy-4-cholesten-3-one (C4)-a surrogate marker for BA synthesis ability-from 141 patients. Concentrations of BAs, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid (LCA), were measured using liquid chromatography-mass spectrometry. The total fecal BA concentration was significantly higher in the NAFLD group with worsening of fibrosis than in the HC group. Most of the fecal BAs were secondary and unconjugated. In the fecal BA fraction, CA, DCA, chenodeoxycholic acid, ursodeoxycholic acid, and LCA were significantly higher in the NAFLD than in the HC group. The total serum BA concentration was higher in the NAFLD group with worsening of fibrosis than in the HC group. In the serum BA fraction, CA, LCA, and C4 concentrations were significantly higher in the NAFLD than in the HC group. Fecal and serum BA and C4 concentrations were high in patients with NAFLD with worsening of fibrosis, suggesting involvement of abnormal BA metabolism in NAFLD with fibrosis progression. Abnormalities in BA metabolism may be a therapeutic target in NAFLD with fibrosis.

Case-control exercise challenge study on the pathogenesis of high serum gamma-glutamyl transferase activity in racehorses.

High serum γ-glutamyl-transferase (GGT) activity syndrome in racehorses has been associated with maladaption to exercise. Investigation of affected horses before and immediately after standard exercise may provide critical insight into the syndrome's pathophysiology. To investigate blood biomarker changes in actively competing racehorses with high GGT activity associated with an exercise challenge. Case-control study. High GGT case (age: 2-3 years) and normal GGT control (age: 2-7 years) pairs (3 Thoroughbred, 4 Standardbred pairs) at least 3months into their training/racing season were included. Horses with a recent history of high GGT activity (≥50 IU/L) without additional biochemical evidence of liver disease were identified by veterinarians. Horses were tested again in the week prior to a planned exercise challenge to confirm persistent increases in GGT activity. Controls from the same stable with similar training/racing intensity and serum GGT activity ≤36 IU/L were matched with each case. Blood samples were obtained immediately before, 15 and 120 min after exercise. Pre-exercise serum samples were analysed for baseline select serum chemistries, selenium and vitamin E concentrations. Cortisol concentration and markers of oxidative status were measured in serum or plasma for all time points. Individual serum bile acid and coenzyme Q10 concentrations, plasma lipid mediator (fatty acids, oxylipids, isoprostanes) concentrations and targeted metabolomics analyses were performed using liquid chromatography-mass spectrometry. Serum viral PCR for equine hepaci- and parvovirus was performed in each animal. Cases had higher baseline concentrations of total glutathione, taurocholic acid, cortisol and cholesterol concentrations and higher or lower concentrations of specific oxylipid and isoprostane mediators, but there were no case-dependent changes after exercise. Small sample size. Results indicated that glutathione metabolism was altered in high GGT horses. Enhanced glutathione recycling and mild cholestasis are possible explanations for the observed differences.

Intrahepatic cholestasis of pregnancy - Time to redefine the reference range of total serum bile acids: A cross-sectional study.

ObjectiveTo establish pregnancy‐specific reference ranges for fasting and postprandial total serum bile acid (TSBA) concentrations.DesignCross‐sectional study.SettingTertiary‐care university hospital.PopulationHealthy pregnant women at term admitted to the Obstetrics Department over a period of 1 year. Exclusion criteria were an established diagnosis of intrahepatic cholestasis of pregnancy (ICP) or any coexisting condition of increased risk for ICP.MethodsBoth fasting (after 8–14 h of fasting) and postprandial (2 h after meal) TSBA concentrations were measured in 612 women (with 528 fasting samples and 377 postprandial samples) by automated enzymatic spectrophotometric assay.Main outcome measuresFasting and postprandial TSBA concentrations in 612 women.ResultsReference intervals of 4.4–14.1 μmol/L for fasting TSBA and 4.7–20.2 μmol/L for postprandial TSBA were established. The postprandial values were significantly higher than the fasting values, with a median increase of 1.0 μmol/L (p < 0.0001). A correlation between fasting TSBA concentrations and postprandial concentrations was found, as well as correlations with fetal sex, parity and assisted reproductive technologies. A seasonal pattern was noticed for both fasting and postprandial TSBA, with the highest values measured in the winter season (p < 0.01 and 0.02, respectively)ConclusionsNormal pregnancy is associated with mild hypercholanaemia, and therefore a higher threshold should be considered for the diagnosis of ICP. We suggest using the upper reference limits observed in our healthy pregnant population (14 μmol/L for fasting TSBA and 20 μmol/L for postprandial TSBA). As the fasting measurement is more specific for the diagnosis, and the postprandial measurement is essential for the assessment of severity, it is recommended to measure both values rather than use random sampling.Tweetable abstractNormal pregnancy is associated with mild hypercholanaemia, a higher threshold should be considered for the diagnosis of ICP.

Prospective Associations of Circulating Bile Acids and Short-Chain Fatty Acids With Incident Colorectal Cancer.

Human studies investigating the prospective relationship between microbial metabolites and colorectal cancer (CRC) risk are lacking. We tested whether higher serum bile acids (BAs) and lower short-chain fatty acids (SCFAs) were associated with CRC risk. In baseline serum collected more than 30 years before a CRC diagnosis, we quantified concentrations of 15 BAs and 6 SCFAs using targeted liquid chromatography with tandem mass spectrometry assays in 1:1 matched cases and controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (men: n = 262 cases; women: n = 233 cases) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (men: n = 598 cases). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for BA and SCFA quartiles and summary measures with CRC overall and by anatomic location using multivariable conditional logistic regression models. PLCO analyses were stratified by sex. All statistical tests were 2-sided. In PLCO women, 7 BAs were strongly associated with increased CRC risk, including the secondary BAs, deoxycholic (ORQ4 v Q1 = 2.85, 95% CI = 1.45 to 5.60, Qtrend = 0.011), glycodeoxycholic (OR Q4 v Q1 = 3.45, 95% CI = 1.79 to 6.64, Qtrend = 0.006), taurodeoxycholic (OR Q4 v Q1 = 2.36, 95% CI = 1.22 to 4.55, Qtrend = 0.023), and glycolithocholic acid (ORQ4 v Q1 = 2.71, 95% CI = 1.41 to 5.22, Qtrend = 0.015). Women in the highest compared with lowest quartile of total SCFAs had a 45% lower risk of CRC (OR = 0.55, 95% CI = 0.31 to 0.98, Ptrend = .03). Associations for total BAs and SCFAs were strongest among women with proximal colon cancer. No statistically significant associations were observed for BA or SCFA measures among men. Serum concentrations of BAs, particularly downstream microbial metabolites of cholic acid, were strongly associated with increased risk of CRC among women.

Impact of elobixibat on serum and fecal bile acid levels and constipation symptoms in patients with chronic constipation.

Background and AimElobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group.MethodsHealthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once‐daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms.ResultsFecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation‐related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects.ConclusionsDespite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.

A high bile acid environment promotes apoptosis and inhibits migration in pancreatic cancer

ABSTRACT Bile acids, the main organic solutes in bile, have been established to play an important role at physiological concentrations in gastrointestinal metabolism. However, under pathological conditions, such as cholestatic disease, cholestasis can damage hepatocytes/biliary epithelial cells leading to apoptosis or necrosis. Clinically, pancreatic head cancer usually presents with obstructive jaundice and increased serum bile acid levels, suggesting that pancreatic cancer is intricately correlated with a high bile acid environment in the human body. An increasing body of evidence suggests that bile acids are toxic to normal human and colon cancer cells. Nonetheless, the effect of bile acids on the occurrence and development of pancreatic cancer remains a matter of debate. In the present study, to explore the direct effects of high serum concentrations of bile acids on pancreatic cancer and the possible related mechanisms, human pancreatic cancer (PANC-1) cells were subject to different concentrations of bile acid mixtures to assess cell viability and the migration and invasion ability. Besides, we found that a high bile acid environment could inhibit the proliferation and migration of pancreatic cancer cells through ROS(Reactive oxygen species) induction and the EMT(epithelial-mesenchymal transition) pathway, thereby promoting the apoptosis of pancreatic cancer cells. Abbreviations BAs: Bile Acids; EMT: epithelial-mesenchymal transition; FBS: fatal bovine serum;CCK-8: Cell-Counting-Kit-8; ROS: reactive oxygen species; CA: cholic acid; CDCA: chenodeoxycholic acid; GCDCA: Glycochenodeoxycholic acid; PVDF: Poly vinylidene fluoride

656 Intra-hepatic cholestasis of pregnancy: treatment and obstetric outcomes

ObjectiveIntrahepatic cholestasis of pregnancy (ICP) is a reversible condition and the most common pregnancy related liver disorder. Defined by significant pruritus and elevated serum bile acid (BA) and/or liver enzymes (LE) levels, it represents an increased risk for adverse maternal and fetal outcomes. Therefore, early recognition and treatment are imperative for success. Recent data claims that use of ursodeoxycholic acid (UDCA) may not be effective in the improvement of maternal and fetal outcomes. We aim to study maternal profile, behaviour of the disease and obstetric outcomes in patients diagnosed with intra-hepatic cholestasis of pregnancy (IHCP) who received UDCA. Study design: A retrospective, descriptive and analytic study was performed, including all pregnant women diagnosed with IHCP in the second or third trimester of pregnancy and who had labor in our center, between January and December of 2019. SPSS.25 was used for statistical analysis. Results: In 2019, twenty eight pregnant women (mean age 32,7±5,9 years) were diagnosed with IHCP (pruritus and/or increased LE), of which 23 had serum BA elevation. Mean gestacional age (GA) at diagnosis was 33±6,2 weeks. Serum BA concentration at diagnosis and after 3 days of treatment was significantly diferent (29,4±42,5 vs 17,9±20,1 mg/dl; p<.05). Reduction of serum BA and LE was not diferent regarding UDCA dose (250 or 500 mg, 8/8h), neither was occurrance of preterm labor. We had no maternal deaths or complications directly associated with IHCP. Two women with preexisting liver disease are still being studied and did not deliver yet. Conclusions: Despite being a controversial thopic, use of UDCA showed to be effective in decreasing symptoms, bile acids and liver enzyme levels in our population. We had no stillbirths, neonatal adverse outcomes neither maternal liver insuficiency. Multicentric, case-control studies can be valuable in establishing new guideline treatments.

Serum Cholecystokinin and Bile Acid Concentrations in Response to Feeding And/Or Seeing and Smelling Food in Healthy Dogs

Serum Cholecystokinin and Bile Acid Concentrations in Response to Feeding And/Or Seeing and Smelling Food in Healthy Dogs

The comparison of total bile acid concentration and alcohol dehydrogenase activity as markers of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the liver disorder in the second or early third trimester of pregnancy. It is characterized by pruritus with increased serum bile acids concentration and other liver function tests. ICP is connected with increased risk of fetal mortality but is unfortunately detected quite late. Therefore, it is important to recognize the disease in its early stages. We aimed to investigate the serum alcohol dehydrogenase (ADH) activity and compare it with the concentration of total bile acid (TBA) in women with ICP. Serum samples were taken for routine investigation from 80 pregnancies with ICP in the second or third trimester of pregnancy and from 80 healthy pregnant women at the same time of pregnancy. For measurement of class I activity, we used the spectrofluorometric methods. The total ADH activity was measured by the photometric method. The analysis of results shows a statistically significant increase in the activity of ADH I and ADH total (about 60% and 41.3%, respectively). Activity of ADH I correlated well with aminotransferases (alanine ALT and aspartate AST) and total bile acids (TBA) concentration. The total ADH activity was also positively correlated with ALT, AST and total bile acids. We can state that the activity of class I alcohol dehydrogenase isoenzyme in the sera of patients with ICP is increased and seems to be a good indicator of liver cells destruction during this disease and is comparable with the value of other markers.

Circulating bile acids concentration is predictive of coronary artery disease in human

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.

CYP3A deficiency alters bile acid homeostasis and leads to changes in hepatic susceptibility in rats

Cytochrome P450 3A (CYP3A) as an important enzyme metabolizes many drugs and a variety of endogenous substances. Bile acids (BA) regulate physiological function by activating BA receptors. In this study, CYP3A1/2 gene knockout (KO) and wild-type (WT) rats were used to investigate the regulatory effects of CYP3A on BA homeostasis and liver function. Compared with WT rats, BA concentrations in serum, liver and small intestine of CYP3A1/2 KO rats increased significantly, which was due to the decrease of catabolism and the increase of synthesis. In particular, the composition of serum BA (overall hydrophobicity) presented an age- and CYP3A-dependent manner. With the aging of WT rats, the serum BA became more hydrophobic, while this trend was delayed in CYP3A1/2 KO rats. Moreover, the level of serum total cholesterol, the precursor of BA synthesis, decreased by about 20% in CYP3A1/2 KO rats, which is due to the low synthesis but high biotransformation rate. The increase of BA pool further led to the change of transcription level of BA receptor in liver (pregnane X receptor) and small intestine (Takeda G-protein receptor 5), and affected the function and morphology of CYP3A1/2 KO rat liver. In conclusion, CYP3A is a key regulator of BA homeostasis in rats, especially in regulating BA pool size, composition and balance of anabolism, and prevents susceptibility to hepatotoxicity under BA overload.

Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis.

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (−54%), and increased serum BA‐glucuronides (+2.1‐fold, P < 0.01) versus ursodiol monotherapy. The major serum BA‐glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid–6G (+3.7‐fold, P < 0.01), hyocholic acid–6G (+2.6‐fold, P < 0.05), chenodeoxycholic acid (CDCA)–3G (−36%), and lithocholic acid (LCA)–3G (−42%) versus ursodiol monotherapy. Fenofibrate also up‐regulated the expression of uridine 5′‐diphospho‐glucuronosyltransferases and multidrug resistance–associated protein 3 messenger RNA in primary human hepatocytes. Pearson’s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA‐3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)‐3G (r2 = 0.48, P < 0.0001), and LCA‐3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA‐glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA‐glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα‐mediated anti‐cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA‐glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.

Reproducibility, Temporal Variability, and Concordance of Serum and Fecal Bile Acids and Short Chain Fatty Acids in a Population-Based Study.

Bile acid (BA) and short chain fatty acid (SCFA) production is affected by diet and microbial metabolism. These metabolites may play important roles in human carcinogenesis. We used a fully quantitative targeted LC-MS/MS system to measure serum and fecal BA and SCFA concentrations in 136 Costa Rican adults at study baseline and 6-months. We randomly selected 50 participants and measured their baseline samples in duplicate. Our objective was to evaluate: Technical reproducibility; 6-month temporal variability; and concordance between sample type collected from the same individual at approximately the same time. Technical reproducibility was excellent, with intraclass correlation coefficients (ICC) ≥0.83 for all BAs except serum tauroursodeoxycholic acid (ICC = 0.72) and fecal glycolithocholic acid (ICC = 0.66) and ICCs ≥0.81 for all SCFAs except serum 2-methylbutyric acid (ICC = 0.56) and serum isobutyric acid (ICC = 0.64). Temporal variability ICCs were generally low, but several BAs (i.e., deoxycholic, glycoursodeoxycholic, lithocholic, taurocholic, and tauroursodeoxycholic acid) and SCFAs (i.e., 2-methylbutyric, butyric, propionic, and valeric acid) had 6-month ICCs ≥0.44. The highest degree of concordance was observed for secondary and tertiary BAs. Serum and fecal BAs and SCFAs were reproducibly measured. However, 6-month ICCs were generally low, indicating that serial biospecimen collections would increase statistical power in etiologic studies. The low concordance for most serum and fecal metabolites suggests that consideration should be paid to treating these as proxies. Our findings will inform the design and interpretation of future human studies on associations of BAs, SCFAs, and potentially other microbial metabolites, with disease risk.

Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a rare but potentially serious complication of pregnancy, the main symptom of which is intense pruritus with elevated serum levels of bile acids. The elevated serum bile acid concentration is regarded as a predictor for poor perinatal outcome including intrauterine death. Ursodeoxycholic acid (UDCA) has become established as the treatment of choice in clinical management to achieve a significant improvement in symptoms and reduce the cholestasis. Pregnant women with severe intrahepatic cholestasis should always be managed in a perinatal centre with close interdisciplinary monitoring and treatment involving perinatologists and hepatologists to minimise the markedly increased perinatal morbidity and mortality as well as maternal symptoms.

Serum bile acids in cystic fibrosis patients – glycodeoxycholic acid as a potential marker of liver disease

BackgroundCystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism. AimThis study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment. MethodsPrimary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS). ResultsBile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822–1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731–1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency. ConclusionsA CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF.