High Concentrations Of Bile Acids Research Articles

Bile Acid Diarrhea is Associated with an Increased Incidence of Gastrointestinal Cancers.

Bile acid diarrhea (BAD) is an underrecognized and socially debilitating disease caused by high concentrations of bile acids in the colon. Bile acids directly and indirectly promote carcinogenesis. Here, we investigated if individuals with BAD have an increased risk of gastrointestinal (GI) cancers. By using the Danish health registries, adult individuals with BAD were identified by international classification of disease 10th revision (ICD10) code K90.8 or referral to the diagnostic ⁷⁵selenium-homotaurocholic acid test followed by prescription of a bile acid sequestrant within 365 days (n=5,245). Age and sex-matched individuals without BAD were included for comparison (n=52,450). We analyzed the cumulative incidence of GI cancers after BAD diagnosis and the odds ratios (ORs) of GI cancer eight and 15 years before BAD diagnosis/matching. Cumulative incidence of GI cancer six years after BAD diagnosis/matching was 1.6% in the BAD group and 1.1% in controls (p=0.01). The ORs of total GI cancer eight and 15 years before BAD diagnosis were 6.16 (5.08-7.48) and 5.19 (4.28-6.29), respectively. Furthermore, 47 individuals with BAD (0.9%) and 250 (0.5%) controls died of GI cancer. This nationwide cohort study indicates an association between BAD and GI cancers. We found both a higher incidence of GI cancer after BAD diagnosis compared with controls and increased OR of GI cancer before BAD diagnosis. Bearing in mind the underdiagnosis of BAD, the delay of BAD diagnosis, and the carcinogenic effect of bile acids, these findings warrant further investigations of the risk of GI cancer in individuals with BAD.

Meta-analyses in cholestatic pregnancy: The outstanding clinical questions

Reports of adverse pregnancy outcomes associated with maternal pruritus and liver impairment have circulated since the 1800s, yet the precise diagnosis and management of intrahepatic cholestasis of pregnancy have varied markedly. Recent evidence, including that from individual participant data meta-analyses, has provided an evidence that brings us closer to standardised, and optimal, management of the condition. Based upon increased adverse perinatal outcomes with higher bile acid concentrations, disease management should be according to severity (defined by peak bile acid concentration) in order to recommend appropriate gestation of birth. Similarly, the reduced spontaneous preterm birth rate for patients receiving ursodeoxycholic acid treatment suggests potential benefit for the treatment of patients with moderate-severe disease.

Reduced Hepatocyte Bicarbonate Output Accelerates Periductal Inflammation and Fibrosis in mdr2-/- Mouse Liver

Background/Aims: Mice deficient for the canalicular phospholipid transporter MDR2 (ABCB4) develop sclerosing cholangitis due to high biliary concentrations of monomeric bile acids. This study determines whether a selective reduction in biliary bicarbonate output, secondary to the deletion of the hepatocyte-expressed carbonic anhydrase CAXIV (Car14) aggravates the bile acid-induced damage observed in the mdr2-/- mouse model. Methods: Bile flow was measured gravimetrically and HCO3- output by microtitration before and during stimulation with intravenously applied tauroursodesoxycholic acid (TUDCA) in car14-/-mdr2-/- (abcb4-/-), car14-/-/mdr2+/+, car14+/+/mdr2-/- and wt mice. Cholangiocyte proliferation, hepatic inflammation and fibrosis was studied by gene and/or protein expression for proinflammatory and profibrotic cytokines, cholangiocyte proliferation markers, and by (immuno) histochemical assessment. The impact of Car14 deficiency was also assessed in a xenobiotic cholangitis model. Results: TUDCA stimulated HCO3-output was significantly increased in 6 week old mdr2-/- mice, and significantly decreased in both car14-/- as well as car14-/-/mdr2-/-mice, compared to wt, while bile flow was unaltered. Both bile flow and HCO3- output were significantly decreased in 11 week old mdr2-/-, and more so in car14-/-/mdr2-/- mice. Loss of Car14 significantly increased inflammatory liver injury and cholangiocyte proliferation, and aggravated liver fibrosis in car14-/-/mdr2-/- mice compared to mdr2-/- mice. In contrast, the absence of Car14 did not affect the hepatic functional and morphological alterations in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) fed mice. Conclusions: Car14 deletion reduced biliary HCO3- output and aggravated the functional, inflammatory and morphological alterations in the liver of mdr2-/-mice. These results demonstrate the importance of sufficient hepatocellular bicarbonate output in the protection of the hepatobiliary epithelium against toxic bile acids.

1I. Vitamin D receptor-like receptors in GtoPdb v.2023.1

Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [50, 1]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [50].

Influence of dietary supplementation with new Lactobacillus strains on hematology, serum biochemistry, nutritional status, digestibility, enzyme activities, and immunity in dogs.

The use of antibiotics is associated with many side effects, with the development of bacterial resistance being particularly important. It has been found that dogs and their owners host similar resistant bacteria. This contributes to increased concurrent bacterial resistance and a possible trend of increased bacterial resistance in humans. Thus, using probiotics in dogs is an alternative option for preventing and reducing the transmission of bacterial resistance from dogs to humans. Probiotics are characterized by their potential to endure low pH levels and high concentrations of bile acids in the gastrointestinal tract. Lactobacilli are more acid-tolerant and resistant to bile acid, so they are ideal probiotics to be added to the canine diet. According to the previous studies, the benefits of Lactobacillus are a stable nutritional status and greater digestibility, along with improved fecal scores and reduced ammonia in dogs. However, no studies have been conducted with Lactobacillus plantarum CM20-8 (TISTR 2676), Lactobacillus acidophilus Im10 (TISTR 2734), Lactobacillus rhamnosus L12-2 (TISTR 2716), Lactobacillus paracasei KT-5 (TISTR 2688), and Lactobacillus fermentum CM14-8 (TISTR 2720), or their use in combination. Hence, the aim of this study was to examine the possible effects of the aforementioned Lactobacillus on hematological indices, nutritional status, digestibility, enzyme activities, and immunity in dogs. From the results, a new and safe strain of Lactobacillus may emerge for use as a probiotic in the future. In this study, 35 dogs were allocated equally into seven groups: Group 1 received a basal diet (control), while Groups 2-7 received the same diet further supplemented with L. plantarum CM20-8 (TISTR 2676), L. acidophilus Im10 (TISTR 2734), L. rhamnosus L12-2 (TISTR 2716), L. paracasei KT-5 (TISTR 2688), L. fermentum CM14-8 (TISTR 2720), or a mixture of probiotics (L. plantarum, L. acidophilus, L. rhamnosus, L. paracasei, and L. fermentum), respectively. All probiotics were administered at a dose of 109 colony-forming unit/dog for 28 days. Nutritional status, hematology, serum biochemistry, digestibility, enzyme activities, and immunity parameters were assessed. There were no differences among the groups in body weight, feed intake, body condition score, fecal score, and fecal dry matter on the different sampling days. The hematology and serum biochemical analyses showed a difference only in creatinine activity (p < 0.001), with higher values in group L. fermentum CM14-8 (TISTR 2720) and lower values in group L. paracasei KT-5 (TISTR 2688) than in controls. However, all measurements were within the normal laboratory reference ranges. Fecal characteristics (fecal ammonia and fecal pH), fecal digestive enzyme activities, serum immunoglobulin (IgG), and fecal IgA did not differ significantly among the groups (p > 0.05). Lactobacillus plantarum CM20-8 (TISTR 2676), L. acidophilus Im10 (TISTR 2734), L. rhamnosus L12-2 (TISTR 2716), L. paracasei KT-5 (TISTR 2688), and L. fermentum CM14-8 (TISTR 2720), along with their mixture are safe and non-pathogenic additives for use as new probiotic strains of Lactobacillus in dogs. Although the new Lactobacillus strains had no effect on hematology, serum biochemistry, nutritional status, digestive enzyme activities, immunity, body weight, feed intake, or body condition scores in dogs, further studies should investigate the intestinal microbiota and the development of clinical treatments.

Pathological bile acid concentrations in chronic cholestasis cause adipose mitochondrial defects

Although fat loss is observed in patients with cholestasis, how chronically elevated bile acids (BAs) impact white and brown fat depots remains obscure. To determine the direct effect of pathological levels of BAs on lipid accumulation and mitochondrial function, primary white and brown adipocyte cultures along with fat depots from two separate mouse models of cholestatic liver diseases, namely (i) genetic deletion of farnesoid X receptor (Fxr); small heterodimer (Shp) double knockout (DKO) and (ii) injury by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), were used. As expected, cholestatic mice accumulate high systemic BA levels and exhibit fat loss. Here, we demonstrate that chronic exposure to pathological BA levels results in mitochondrial dysfunction and defective thermogenesis. Consistently, both DKO and DDC-fed mice exhibit lower body temperature. Importantly, thermoneutral (30°C) housing of the cholestatic DKO mice rescues the decrease in brown fat mass, and the expression of genes responsible for lipogenesis and regulation of mitochondrial function. To overcome systemic effects, primary adipocyte cultures were treated with pathological BA concentrations. Mitochondrial permeability and respiration analysis revealed that BA overload is sufficient to reduce mitochondrial function in primary adipocytes, which is not as a result of cytotoxicity. Instead, we found robust reductions in uncoupling protein 1 (Ucp1), PR domain containing 16 (Prdm16), and deiodinase, iodothyronine, type II (Dio2) transcripts in brown adipocytes upon treatment with chenodeoxycholic acid, whereas taurocholic acid led to the suppression of Dio2 transcript. This BA-mediated decrease in transcripts was alleviated by pharmacological activation of UCP1. High concentrations of BAs cause defective thermogenesis by reducing the expression of crucial regulators of mitochondrial function, including UCP1, which may explain the clinical features of hypothermia and fat loss observed in patients with cholestatic liver diseases. We uncover a detrimental effect of chronic bile acid overload on adipose mitochondrial function. Pathological concentration of different BAs reduces the expression of distinct genes involved in energy expenditure, which can be mitigated with pharmacological UCP1 activation.

The impact of bariatric surgery on colorectal cancer risk.

Obesity is considered a risk factor for different types of cancer, including colorectal cancer (CRC). Bariatric surgery has been associated with improvements in obesity-related co-morbidities and reductions in overall cancer risk. However, given the contradictory outcomes of several cohort studies, the impact of bariatric surgery on CRC risk appears controversial. Furthermore, measurement of CRC biomarkers following Roux-en-Y gastric bypass (RYGB) has revealed hyperproliferation and increased pro-inflammatory gene expression in the rectal mucosa. The proposed mechanisms leading to increased CRC risk are alterations of the gut microbiota and exposure of the colorectum to high concentrations of bile acids, both of which are caused by RYGB-induced anatomical rearrangements. Studies in animals and humans have highlighted the similarities between RYGB-induced microbial profiles and the gut microbiota documented in CRC. Microbial alterations common to post-RYGB cases and CRC include the enrichment of pro-inflammatory microbes and reduction in butyrate-producing bacteria. Lower concentrations of butyrate following RYGB may also contribute to an increased risk of CRC, given the anti-inflammatory and anticarcinogenic properties of this molecule. Laparoscopic sleeve gastrectomy appears to have a more moderate impact than RYGB; however, relatively few animal and human studies have investigated its effects on CRC risk. Moreover, evidence regarding the impact of anastomosis gastric bypass on one is even more limited. Therefore, further studies are required to establish whether the potential increase in CRC risk is restricted to RYGB or may also be associated with other bariatric procedures.

Elevated GABRP expression is correlated to the excessive autophagy in intrahepatic cholestasis of pregnancy

In intrahepatic cholestasis of pregnancy (ICP) patients, high concentrations of bile acids altered the normal maternal-fetal-unit physiological condition and could bring negative influence on placenta functionality. GABRP is the pi subunit of the gamma-aminobutyric acid type A receptor (GABAA) and plays pivotal role in regulating GABAA receptor's physiological function. Here we presented evidence that increased expression of GABRP in parallel with autophagic biomarkers, LC3 and ATG14, in patients with ICP. Methods: A total of 27 participants, including 18 ICP patients and 9 healthy pregnancies were recruited according to strict inclusion criteria. Placentas of ICP patients and controls were collected immediately after cesarean section before labor onset. GABRP and autophagic markers expression in placenta were investigated by immunohistochemistry (IHC), RT-qPCR, and Western blot. Results: The neonatal birthweight and gestational weeks were significantly lower in severe ICP group, while the hepatic enzymes were elevated in ICP group. Semiquantitative analysis of IHC revealed the AOD of GABRP in severe ICP patients was higher than that in mild ICP patients and control pregnancies. Western blot and RT-qPCR analysis both indicated that the expression of GABRP and ATG14 were significantly elevated in severe ICP patients. Moreover, GABRP was correlated with TBA (r = 0.64, p < 0.05), ATG14 (r = 0.87, p < 0.05), direct bilirubin (r = 0.54, p < 0.05), ALT (r = 0.72, p < 0.05), and AST (r = 0.67, p < 0.05). Conclusion: There were elevated expression of GABRP, ATG14 and LC3 in ICP placentas compared with uncomplicated pregnancies. The expression of GABRP was associated with autophagy and was correlated with the TBA levels.

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.

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

Impact of encapsulation of probiotics in oil-in-water high internal phase emulsions on their thermostability and gastrointestinal survival

Probiotics have many beneficial physiological effects, such as enhancing immunity and regulating intestinal microflora. However, the highly acidic conditions in the stomach and the high bile acid concentration in the small intestine pose challenges to the maintenance of probiotic activity after ingestion. In this study, we examined the possibility of increasing the viability of probiotics under gastrointestinal conditions by encapsulating them within oil-in-water high internal phase emulsions (HIPEs). These emulsions were prepared using whey protein isolate (WPI) and pectin, which were gelled by adding GDL and calcium to form double network HIPE gels. The gel strength, stability, and shear viscosity of the gelled HIPEs increased as the pectin concentration was raised from 0 to 2%. Cryo-SEM analysis showed that the pectin formed a dense hydrogel network in the aqueous phase surrounding the oil droplets in the HIPEs. Probiotics were encapsulated within the gelled HIPEs by dispersing a probiotic powder in the oil phase. Confocal microscopy indicated that the probiotics were mostly distributed in the water, and interfacial phases, with only a few of the probiotics remaining in the oil phase. Encapsulation of the probiotics in the HIPEs increased the number of live cells remaining after a heat treatment and after passage through a simulated gastrointestinal model. The incorporation of pectin into the HIPEs increased the viability of the probiotics, especially after exposure to the gastric phase. This study highlights the potential of HIPEs in preserving probiotic activity, which may be useful for the development of more effective functional foods.

Association of Maternal Thyroid Function with Gestational Hypercholanemia.

Background: High bile acid concentration is associated with adverse perinatal outcomes (i.e., stillbirth and preterm birth) and experimental studies indicate that thyroid hormone regulates bile acid metabolism, but this has not yet been translated to clinical data in pregnant women. We aim to explore the association of thyroid function with bile acid concentrations and the risk of gestational hypercholanemia. Methods: This study comprised 68,016 singleton pregnancies without known thyroid or hepatobiliary diseases before pregnancy and thyroid medication based on a prospective cohort. Thyroid function and serum total bile acid (TBA) were routinely screened in both early (9-13 weeks) and late pregnancy (32-36 weeks). Hypercholanemia was defined as serum TBA concentration ≥10 μmol/L. Multiple linear regression models and multiple logistic regression models were performed. Results: A higher free thyroxine (fT4) during both early or late pregnancy was associated with a higher TBA concentration and a higher risk of hypercholanemia (all p < 0.01). A higher thyrotropin (TSH) in early pregnancy was associated with a higher TBA concentration in early pregnancy (p = 0.0155), but with a lower TBA concentration during later pregnancy (p < 0.0001), and there was no association of TSH with hypercholanemia. Overt hyperthyroidism in late pregnancy was associated with a 2.12-fold higher risk of hypercholanemia ([confidence interval; CI 1.12-4.03], p = 0.021) and subclinical hyperthyroidism during later pregnancy was associated with a 1.5-fold higher risk of hypercholanemia ([CI 1.14-1.97], p = 0.0034). Sensitivity analyses indicated that a high fT4 throughout pregnancy was associated with a higher risk of hypercholanemia rather than only in early or late pregnancy. Conclusions: A higher fT4 concentration during either early or late pregnancy, but not the TSH concentration, is associated with higher TBA and a higher risk of gestational hypercholanemia. Furthermore, hyperthyroidism during pregnancy could be a novel risk factor for hypercholanemia.

Concentrations of Fecal Bile Acids in Participants with Functional Gut Disorders and Healthy Controls.

Bile acids are metabolites involved in nutrient absorption and signaling with levels influenced by dietary intake, metabolic processes, and the gut microbiome. We aimed to quantify 23 bile acids in fecal samples to ascertain if concentrations differed between healthy participants and those with functional gut disorders. Fecal bile acids were measured using liquid chromatography-mass spectrometry (LC-MS) in the COMFORT (The Christchurch IBS cohort to investigate mechanisms for gut relief and improved transit) cohort of 250 participants with Rome IV IBS (IBS-constipation (C), IBS-diarrhea (D), IBS-mixed (M)), functional gut disorders (functional constipation (FC), functional diarrhea (FD)) and healthy controls (FC n = 35, FD n = 13, IBS-C n = 24, IBS-D n = 52, IBS-M n = 29, and control n = 97). Dietary information was recorded to ascertain three-day dietary intake before fecal samples were collected. Fecal bile acid concentrations, predominantly primary bile acids, were significantly different between all functional gut disorder participants and healthy controls (CDCA p = 0.011, CA p = 0.003) and between constipation (FC + IBS-C) and diarrhea (FD + IBS-D) groups (CDCA p = 0.001, CA p = 0.0002). Comparison of bile acids between all functional groups showed four metabolites were significantly different, although analysis of combined groups (FC + IBS-C vs. FD + IBS-D) showed that 10 metabolites were significantly different. The bile acid profiles of FD individuals were similar to those with IBS-D, and likewise, those with FC were similar to IBS-C. Individuals with a diarrhea phenotype (FD + IBS-D) had higher concentrations of bile acids compared to those with constipation (FC + IBS-C). Bile acid metabolites distinguish between individuals with functional gut disorders and healthy controls but are similar in constipation (or diarrhea) whether classified as IBS or not.

Fas, Caspase-8, and Caspase-9 pathway-mediated bile acid-induced fetal cardiomyocyte apoptosis in intrahepatic cholestasis pregnant rat models.

Intrahepatic cholestasis of pregnancy (ICP) is a specific complication in the middle and late pregnancy and has been recognized as one of the high-risk pregnancy for sudden fetal death. In this study, we aimed to investigate the role of Fas, Caspase-8, and Caspase-9 pathways in the internal relations of fetal myocardial apoptosis in ICP rat models, thus resulting in fetal intrauterine death. Furthermore, we researched whether ursodeoxycholic acid (UDCA) promoted benefits in fetal cardiomyocyte apoptosis. To establish ICP rat models, on the 15th day of pregnancy, rats were injected 17α-ethynyl estradiol (EE2). Meanwhile, in experimental group, pregnant rats were treated with EE2 + UDCA. All rats were sacrificed on the 21st day of pregnancy. The expression levels of Fas, Caspase-8, and Caspase-9 were examined by western blot and real-time polymerase chain reaction analysis. Fetal rat cardiac tissues were removed and stained for pathological evaluation. In addition, we observed fetal myocardial structure by using transmission electron microscopy. We detected high concentrations of bile acids and transaminase in the fetal circulation. And we found increased expression levels of Fas, Caspase-8, and Caspase-9 proteins and mRNA in the fetal cardiomyocyte in EE2-treated group but not in control- or EE2 + UDCA-treated groups. Furthermore, compared to controls, EE2-treated rats exhibited severe fetal myocardial structure damage and the apoptotic bodies by using transmission electron microscopy. UDCA reversed the impairment of fetal cardiomyocytes. Our study has led to research into the association between activation of Fas, Caspase-8, and Caspase-9 pathways and bile acid-induced fetal cardiomyocyte apoptosis, which may be one of the mechanisms on fetal cardiac death in ICP. More importantly, UDCA may improve the adverse outcome of fetus.

CAR directs T cell adaptation to bile acids in the small intestine.

Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mousesmall intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1-/- orRag2-/-mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.

Effect of bile acids on the expression of MRP3 and MRP4: An In vitro study in HepG2 cell line

Introduction and objectivesFree and conjugated bile acids (BA's) cannot cross cell membranes; therefore, a particular transport system is required by the cell. Members of the family of ABC (ATP-binding proteins) transporters transfer bile acids in and out of the cell, preventing their accumulation. High intracellular concentrations of bile acids, such as those observed in cholestasis, have been related to oxidative stress and apoptosis, which in many cases are the leading causes of hepatocyte damage. MRP3 and MRP4 (multidrug resistance-associated protein 3 and 4) proteins belong to the ABC subfamily C, and are transporters of the hepatocyte's basolateral membrane with a compensatory role. Both transporters’ increased expression constitutes an essential role in the protective and adaptive responses of bile acid overload, such as cholestasis. This work aimed to analyze both transporters’ mRNA and protein expression in an in vitro model of cholestasis using HepG2 cell line treated with main bile acids. MethodsThe expression of transporters was investigated through confocal microscopy immunofluorescence, Western Blot, and RT-qPCR after the main bile acids in HepG2 line cells. ResultsThe results showed the relation between confluence and expression of both transporters in the plasma membrane. MRP3 showed atypical and heterogeneous distribution in this cell line. CDCA (chenodeoxycholic acid) at low concentrations induced the expression of mRNA of both transporters. In contrast, protein expression was induced by CA (cholic acid) at high concentrations. ConclusionPrimary bile acids (CDCA and CA) induce overexpression of the MRP4 and MRP3 transporters in the HepG2 cell line.

Overview of bile acid signaling in the cardiovascular system.

Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.

Effects of patent ductus venosus on bile acid homeostasis in aryl hydrocarbon receptor (AhR)-null mice

The Aryl hydrocarbon receptor (AhR) is primarily known as one of the xenosensors and regulators of drug-metabolizing genes. Bile acids (BAs) are synthesized in the liver, and undergo several enterohepatic recirculations in which the liver removes BAs from the portal blood, minimizing the BAs that spill over into the systemic circulation. Previous studies revealed a lifelong patent ductus venosus (PDV) in AhR-null mice. Increased concentration of total BAs (Σ-BAs) in AhR-null mice is known; however, the impact of PDV on BA homeostasis in liver and bile remains unclear. This work investigated the consequences of PDV on BA homeostasis by comparing AhR-null and wild-type (WT) mice of both genders.In serum, Σ-BAs were markedly higher (64–85-fold) in AhR-null mice than in WT mice, especially due to the increase of tri-OH primary BAs (86–142-fold). Despite the extremely high concentration of serum BAs, the concentration of BAs in livers of AhR-null mice remained similar to WT mice. AhR-null livers were protected against increased BA influx by downregulation of uptake transporters and BA synthetic enzymes in the alternative pathway. Although livers of AhR-null mice are 20–25% smaller than WT mice, biliary excretion of BAs was maintained in the AhR-null mice, and even tended to increase. Surprisingly, intestinal Fgf15 expression was not increased, even though there was a marked increase in serum BA concentrations. Although PDV resulted in extremely high BA concentrations in serum of AhR-null mice, they maintained a concentration of BAs in liver and biliary excretion of BAs similar to control mice.

1I. Vitamin D receptor-like receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [47]) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [47].

Ingestion of difructose anhydride III partially suppresses the deconjugation and 7α-dehydroxylation of bile acids in rats fed with a cholic acid-supplemented diet.

Difructose anhydride III (DFAIII) is a prebiotic involved in the reduction of secondary bile acids (BAs). We investigated whether DFAIII modulates BA metabolism, including enterohepatic circulation, in the rats fed with a diet supplemented with cholic acid (CA), one of the 12α-hydroxylated BAs. After acclimation, the rats were fed with a control diet or a diet supplemented with DFAIII. After 2weeks, each group was further divided into two groups and was fed diet with or without CA supplementation at 0.5g/kg diet. BA levels were analyzed in aortic and portal plasma, liver, intestinal content, and feces. As a result, DFAIII ingestion reduced the fecal deoxycholic acid level via the partial suppression of deconjugation and 7α-dehydroxylation of BAs following CA supplementation. These results suggest that DFAIII suppresses production of deoxycholic acid in conditions of high concentrations of 12α-hydroxylated BAs in enterohepatic circulation, such as obesity or excess energy intake. Abbreviation: BA: bile acid; BSH: bile salt hydrolase; CA: cholic acid; DCA: deoxycholic acid; DFAIII: difructose anhydride III; MCA: muricholic acid; MS: mass spectrometry; NCDs: non-communicable diseases; LC: liquid chromatography; SCFA: short-chain fatty acid; TCA: taurocholic acid; TCDCA: taurochenodeoxycholic acid; TDCA: taurodeoxycholic acid; TUDCA: tauroursodeoxychlic acid; TαMCA: tauro-α-muricholic acid; TβMCA: tauro-β-muricholic acid; TωMCA: tauro-ω-muricholic acid.