Hydrophobic Bile Acids Research Articles

Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients.

Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes.

Ursodeoxycholic Acid for Trans Intestinal Cholesterol Excretion Stimulation: A Randomized Placebo Controlled Crossover Study.

The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P=0.002) when compared with placebo. UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition.

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal FXR agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 weeks markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease.

Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPARα activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPARα activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.

Gly-β-MCA is a potent anti-cholestasis agent against “human-like” hydrophobic bile acid-induced biliary injury in mice

Cholestasis is a chronic liver disease with limited therapeutic options. Hydrophobic bile acid-induced hepatobiliary injury is a major pathological driver of cholestasis progression. This study investigates the anti-cholestasis efficacy and mechanisms of action of glycine-conjugated β-muricholic acid (Gly-β-MCA). We use female Cyp2c70 KO mice, a rodent cholestasis model that does not produce endogenous muricholic acid (MCA) and exhibits a “human-like” hydrophobic bile acid pool and female-dominant progressive hepatobiliary injury and portal fibrosis. The efficacy of Gly-β-MCA and ursodeoxycholic acid (UDCA), the first line drug for cholestasis, on cholangiopathy and portal fibrosis are compared. At a clinically relevant dose, Gly-β-MCA shows comparable efficacy as UDCA in reducing serum transaminase, portal inflammation and ductular reaction, and better efficacy than UDCA against portal fibrosis. Unlike endogenous bile acids, orally administered Gly-β-MCA is absorbed at low efficiency in the gut and enters the enterohepatic circulation mainly after microbiome-mediated deconjugation, which leads to taurine-conjugated MCA enrichment in bile that alters enterohepatic bile acid pool composition and reduces bile acid pool hydrophobicity. Gly-β-MCA also promotes fecal excretion of endogenous hydrophobic bile acids and decreases total bile acid pool size, while UDCA treatment does not alter total bile acid pool. Furthermore, Gly-β-MCA treatment leads to gut unconjugated MCA enrichment and reduces gut hydrophobic lithocholic acid (LCA) exposure. In contrast, UDCA treatment drives a marked increase of LCA flux through the large intestine. In conclusion, Gly-β-MCA is a potent anti-cholestasis agent with potential clinical application in treating human cholestasis.

Abcb4-defect cholangitis mouse model with hydrophobic bile acid composition by in vivo liver-specific gene deletion

Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with both human-like bile acid composition and Abcb4-defect exhibit severe cholestatic liver injury and are useful for studying human cholestatic diseases and developing new treatments.

Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice.

Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.

Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition.

Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause endemic and pandemic acute viral gastroenteritis. Previously, we reported that many HuNoV strains require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. BA was not essential for the replication of a pandemic-causing GII.4 HuNoV strain. We found the hydrophobic BA glycochenodeoxycholic acid (GCDCA) promotes the replication of the BA-dependent strain GII.3 in jejunal enteroids. Furthermore, we found that inhibition of the G-protein-coupled BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), by JTE-013, reduced GII.3 infection dose-dependently and inhibited GII.3 cellular uptake in enteroids. Herein, we sought to determine whether S1PR2 is required for other BA-dependent HuNoV strains, the BA-independent GII.4, and whether S1PR2 is required for BA-dependent HuNoV infection in HIEs from other small intestinal segments. We found a second S1PR2 inhibitor, GLPG2938, reduces GII.3 infection dose-dependently, and an S1PR2 agonist (CYM-5520) enhances GII.3 replication in the absence of GCDCA. GII.3 replication also is abrogated in the presence of JTE-013 and CYM-5520. JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not GII.4 Sydney (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. Finally, GII.3 infection of duodenal, jejunal, and ileal lines derived from the same individual is reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoVs exploit BA effects on S1PR2 to infect the entire small intestine.IMPORTANCEHuman noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA-independent strain, all require S1PR2 for infection. In addition, BA-dependent infection requires S1PR2 in multiple segments of the small intestine. Together, these results indicate that S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.

Mitochondria at the Crossroads of Cholestatic Liver Injury: Targeting Novel Therapeutic Avenues.

Bile acids are byproducts of cholesterol metabolism in the liver and constitute the primary components of bile. Disruption of bile flow leads to cholestasis, characterized by the accumulation of hydrophobic bile acids in the liver and bloodstream. Such accumulation can exacerbate liver impairment. This review discussed recent developments in understanding how bile acids contribute to liver damage, including disturbances in mitochondrial function, endoplasmic reticulum stress, inflammation, and autophagy dysfunction. Mitochondria play a pivotal role in cholestatic liver injury by influencing hepatocyte apoptosis and inflammation. Recent findings linking bile acids to liver damage highlight new potential treatment targets for cholestatic liver injury.

Recurrence of primary sclerosing cholangitis in the graft

Primary sclerosing cholangitis (PSC) is a disease characterized by inflammation, fibrosis and obliteration of both intra- and extrahepatic bile ducts, accompanied by cholestasis, with further outcome in biliary cirrhosis of the liver, cholangiocarcinoma. The pathogenesis of the disease is poorly understood, but, according to various sources, it involves genetic factors, innate and adaptive immunity mechanisms, the toxic effects of hydrophobic bile acids and, possibly, intestinal dysbiosis. The strong association with inflammatory bowel disease is associated with a significantly increased risk of colorectal cancer, which, along with cholangiocarcinoma, represents the most significant diagnostic challenge in the long-term management of PSC. The diagnosis of PSC is established based on the identification of typical cholangiographic lesions of the bile ducts and the exclusion of secondary causes of sclerosing cholangitis. Complex pathophysiology, heterogeneity of clinical features and the rare nature of the disease have led to the lack of effective therapy to date; there are no treatment algorithms, but a course of ursodeoxycholic acid in doses of 17–23 mg/kg/day can be prescribed for up to a year in order to monitor the dynamics of the decrease in levels serum alkaline phosphatase. A number of drugs are under investigation, including FXR (farnesoid X receptor) agonists with choleretic and antimicrobial properties. Clinically significant stenoses can be successfully treated with interventional endoscopy, but liver transplantation (LT) is currently the only curative treatment with a high survival rate. According to various literature data, 20–25% of patients develop disease relapse in the graft. Our case report of recurrent PSC in a patient 5 years after orthotopic LT provides an overview of management options from a practical, patient-centered perspective.

Gut microbiota-bile acid crosstalk contributes to intestinal damage after nitrate exposure in Bufo gargarizans tadpoles

Bile acids (BAs) are amphipathic steroid acids whose production and diversity depend on both host and microbial metabolism. Nitrate (NO3−) is a widespread pollutant in aquatic ecosystems, which can cause rapid changes in microbial community structure and function. However, the effect of gut microbiota reshaped by nitrate‑nitrogen (NO3-N) on BAs profiles remains unclarified. To test this, intestinal targeted BAs metabolomics and fecal metagenomic sequencing were performed on Bufo gargarizans tadpoles treated with different concentrations of NO3-N. NO3-N exposure induced a reduction in the abundance of microbiota with bile acid-inducible enzymes (BAIs) and/or hydroxysteroid dehydrogenases (HSDHs), thus inhibiting the conversion of primary BAs to secondary BAs. Inhibition of BAs biotransformation decreased protective hydrophilic BAs (UDCA) and increased toxic hydrophobic BAs (CA and CDCA), which may contribute to intestinal histopathological damage. Moreover, we found that NO3-N treatment increased microbial virulence factors and decreased Glycoside hydrolases, further highlighting the deleterious risk of NO3-N. Overall, this study shed light on the complex interactions of NO3-N, gut microbiota, and BAs, and emphasized the hazardous effects of NO3-N pollution on the health of amphibians.

Metal-Organic Cage Receptors for Encapsulation and Sensing of Bile Acids.

Developing synthetic supramolecular receptors to solubilize, scavenge, recognize, encapsulate, and sense steroids is challenging. Despite a limited number of receptors having affinity with steroids, none exists to bind steroidal bile acids selectively. Herein, we report a C2-symmetric metal-organic cage [Pd6L24]12+ and an expanded version of the Fujita cage [Pd6L14]12+, built with a conformationally flexible ligand L2, accessed through coordination-driven self-assembly. We examined both cages for steroid recognition in water: both have certain shared characteristics and distinctive features. [Pd6L14]12+ binds hydrophobic bile acids and other steroids by forming a 1:1 complex. In contrast, the expanded [Pd6L24]12+ cage exhibits an affinity for amphiphilic bile acids and selective steroids to encapsulate them as dimers, promoted by cooperative interguest hydrogen bonding. [Pd6L24]12+ has a 5 times stronger solubility enhancement ability for cholic acid compared to [Pd6L14]12+. Further, the expanded [Pd6L24]12+ cage can selectively sense bile acids in nanomolar detection limits through indicator displacement assay by employing sulforhodamine 101 (SR101).

Characterization of individual bile acids in vivo utilizing a novel low bile acid mouse model.

Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.

Abstract 6682: Bile acid profiles and racial disparities in colorectal cancer: Exploring the protective role of secondary bile acid derivatives

Abstract Background: Colorectal cancer (CRC) is the third leading cause of cancer death in the United States, with diet and gut microbiota-derived bile acids implicated as long-term risk factors. The interplay between bile acids and immune cell differentiation, particularly of macrophages and T-cells, is a crucial aspect of the CRC microenvironment. Given the high-animal-fat diets' influence on the microbiome’s production of hydrophobic secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), this study investigates the potential immunomodulatory effects of their lower concentrations and their isomers in possibly fostering M2-like macrophage expansion. Methods: Clinical samples were obtained during colonoscopies with no tumor findings at Rush University Medical Center, Chicago. RNA was extracted from colonoscopy biopsies for NanoString RNA expression analysis, while bile acids were isolated from both lyophilized stool and frozen serum samples. To explore the immunological effects of secondary bile acids, the macrophage RAW 264.7 cell line, alongside peritoneal macrophages and bone marrow-derived macrophages (BMDMs) from C57BL/6J mice, were treated with LCA and LCA isomers. Following the bile acid treatment, LPS (100 ng/mL) or IL-4 (40 ng/ml) was added to elicit pro-inflammatory or anti-inflammatory states, respectively. After 48 hours, conditioned media were collected for enzyme-linked immunosorbent assay (ELISA), while cells were analyzed by flow cytometry and rt-qPCR. Results: Contrary to initial hypotheses, the levels of DCA and LCA levels were not significantly different between African American and non-Hispanic White subjects. Notably, allo-isomers and oxo-derivatives of these bile acids, which may promote Treg and M2-like macrophage expansion, were substantially lower in African American subjects. Ex vivo treatments with isoalloLCA and IsoLCA led to notable changes in the M2 macrophage differentiation and shifts in PGE2 production upon exposure to inflammatory or anti-inflammatory stimuli, suggesting a nuanced alteration in the macrophage-mediated inflammatory response. Conclusion: This study highlights a significant ethnic variation in bile acid profiles, with a potential impact on immune modulation and CRC risk. The reduced presence of certain bile acid isomers in African American subjects may influence the risk of CRC through altered macrophage differentiation and function. These findings emphasize the need for personalized dietary and therapeutic strategies to modulate the bile acid metabolome, potentially reducing CRC disparities. Citation Format: Hanchu Dai, Patricia G. Wolf, Lisa Tussing-Humphreys, Ece Mutlu, Jason M. Ridlon, Rex Gaskins. Bile acid profiles and racial disparities in colorectal cancer: Exploring the protective role of secondary bile acid derivatives [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6682.

Bile Acids as Signaling Molecules: Role of Ursodeoxycholic Acid in Cholestatic Liver Disease.

Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects still need to be clarified. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. This work aims to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in tissues other than the liver.

Bile Acid Application in Cell-Targeting for Molecular Receptors in Relation to Hearing: A Comprehensive Review.

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue.

Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection

Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection

Рак желчного пузыря: заболеваемость, факторы риска, диагностика

Aim. To analyze current data on the incidence, risk factors, diagnostic methods and prevention of gallbladder cancer (GBC). Key points. GBC is a malignant tumor arising from the epithelium of the gallbladder, characterized by local and vascular invasion, extensive regional lymphogenous and hematogenous metastasis. GBC is the most common malignant tumor of the biliary tract, characterized by high malignancy and low 5-year survival rate. In international recommendations, gastrointestinal tract is considered as a natural stage of the course of biliary pathology: dyskinesia — cholecystitis — cholelithiasis — GBC. Globally, the incidence of GBC varies significantly among different geographic regions, reaching 27 per 100,000 population in Chile. In Russia, according to the Federal State Statistics Service, the incidence of GBC in 2019 was 1.4 per 100 thousand among men, and 2.5 per 100 thousand among women. The incidence of GBC is associated with female gender and increasing age. In the pathogenesis of gallstones, decisive importance is attached to long-term inflammatory changes in the epithelium due to mechanical trauma to the mucous membrane of the gallbladder by stones and a probable increase in the proportion of secondary bile acids in the bile. In the diagnosis of GBC, the recommendations of the Japanese Society of Hepato-Biliary-Pancreatic Surgery, in the first step, particular importance is attached to ultrasound examination of the abdominal organs and biochemical blood test. For a more detailed study, computed tomography, magnetic resonance imaging, magnetic resonance cholangiopancreatography, endosonography, retrograde cholangiopancreatography, oral cholangioscopy and positron emission tomography are useful. Gallstone disease is one of the five most significant risk factors. The remaining 4 leading risk factors for GBC — ethnicity, genetic predisposition, lifestyle factors (excess weight) and biliary tract infections — are common risk factors for patients with cholelithiasis. The risk of developing GBC increases significantly in patients with stones larger than 2 cm and with the duration of the pathology for more than 5 years. Another significant risk factor for GBC is patients with gallbladder polyps, therefore the article presents the main recommendations of European associations for the management of patients with gallbladder polyps. Conclusion. GBC is currently considered as a possible and natural stage in the course of cholelithiasis. The risk of developing GBC increases significantly in patients with cholelithiasis and gallbladder polyps. Considering the above, diagnosis of possible complications in elderly patients with cholecystitis and gallstone disease should include a thorough clinical, laboratory and instrumental examination. Preventive measures for people with risk factors for GBC should include optimizing diet, weight loss, and, if possible, expanding the physical activity regime. Taking ursodeoxycholic acid preparations helps reduce the content of hydrophobic bile acids in bile and reduces the likelihood of complications of biliary pathology. Keywords: gallbladder cancer, cholelithiasis, gallbladder polyps, diagnosis, morbidity.

Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition.

Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70-/- mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70-/- mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70-/- mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (-99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70-/- mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70-/- mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70-/- mice. In conclusion, depletion of gut microbiota in Cyp2c70-/- mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.

Extracorporeal adsorption of protective and toxic bile acids and bilirubin in patients with cholestatic liver dysfunction: a prospective study

BackgroundThe release of toxic bile acids (BAs) in the blood of critically ill patients with cholestatic liver dysfunction might lead to the damage of various organs. Their extracorporeal elimination using the cytokine adsorber Cytosorb® (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data proving a potential adsorption are missing so far.MethodsThe prospective Cyto-SOVLE study (NCT04913298) included 20 intensive care patients with cholestatic liver dysfunction, continuous kidney replacement therapy, total bilirubin concentration > 10 mg/dl and the application of CS into the dialysis circuit. Bilirubin and different BAs were measured pre- and post-CS at defined timepoints (10 min, 1, 3, 6, and 12 h after initiation). Relative reduction (RR, %) was calculated with: 1-left(frac{mathrm{concentration} (mathrm{pre}-mathrm{post})}{mathrm{concentration} (mathrm{pre})}right)*100.ResultsThe median RR for total and conjugated bilirubin after initiation was − 31.8% and − 30.3%, respectively, and decreased to − 4.5% and − 4.8% after 6 h. A high initial RR was observed for the toxic BAs GCA (− 97.4%), TCA (− 94.9%), GCDCA (− 82.5%), and TCDCA (− 86.0%), decreasing after 6 h to − 32.9%, − 32.7%, − 12.8%, and − 14.3%, respectively. The protective hydrophilic BAs showed a comparable RR after initiation (UDCA: − 77.7%, GUDCA: − 83.0%, TUDCA: − 91.3%) dropping after 6 h to − 7.4%, − 8.5%, and − 12.5%, respectively.ConclusionsCytosorb® can adsorb bilirubin and toxic as well as protective BAs. However, a fast saturation of the adsorber resulting in a rapid decrease of the RR was observed. Furthermore, no relevant difference between hydrophobic toxic and hydrophilic protective BAs was detected regarding the adsorption amount. The clinical benefit or harm of the BA adsorption needs to be evaluated in the future.