Administration Of Ursodeoxycholic Acid Research Articles

Association between ursodeoxycholic acid use and COVID-19 in individuals with chronic liver disease: a nationwide case-control study in South Korea

BackgroundConflicting evidence exists regarding the effects of ursodeoxycholic acid (UDCA) on coronavirus disease 2019 (COVID-19). This study investigates the association between UDCA administration and COVID-19 infection and its related outcomes in individuals with chronic liver disease (CLD).MethodsA customized COVID-19 research database (n = 3,485,376) was created by integrating data from the National Health Insurance Service (NHIS) and the Korea Disease Control and Prevention Agency’s COVID-19 databases. The study focused on patients diagnosed with COVID-19 in 2021, using the NHIS data from 365 days before diagnosis. To create comparable groups with and without UDCA administration before COVID-19, we used propensity score matching. The primary endpoint was the first confirmed positive result for severe acute respiratory syndrome coronavirus-2. In addition, we identified severe COVID-19-related outcomes. Subgroup analysis were conducted based on the dose of UDCA exposure.ResultsData from 74,074 individuals with CLD was analyzed. The participants’ average age was 57.5 years, and 52.1% (19,277) of those in each group were male. Those with prior UDCA exposure had a significantly lower risk of COVID-19 infection (adjusted OR: 0.80, 95% CI [0.76–0.85]) compared to the non-UDCA group. Additionally, the UDCA group had a lower risk of severe COVID-19 outcomes (adjusted OR: 0.67, 95% CI [0.46–0.98]). Subgroup analyses indicated that there was a decrease in COVID-19 infection and its related outcomes with increasing UDCA exposure dose.ConclusionsOur large observational study highlights the potential use of readily available UDCA as an adjunctive therapy for COVID-19 in individuals with CLD.

Long-term outcomes in patients with primary biliary cholangitis complicated with CREST syndrome

Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P < 0.05). The predicted 3/5-year LT-free survival rates based on the GLOBE score were significantly higher in the PBC-CREST group (93/88%) than in the PBC-alone group (88/81%) (P < 0.05). Patients with PBC-CREST may have better long-term outcomes than those with PBC alone.

Total bile acids levels as a stratification tool for screening portopulmonary hypertension in patients with decompensated cirrhosis.

Echocardiography is necessary for portopulmonary hypertension diagnosis, and identifying patients with cirrhosis who require it is challenging. In this study, we aimed to investigate the utility of the total bile acid (TBA) levels as a screening tool for identifying patients with decompensated cirrhosis who should undergo echocardiography for portopulmonary hypertension diagnosis. We evaluated 135 patients with decompensated cirrhosis who underwent liver transplantation. Subsequently, factors contributing to tricuspid regurgitation pressure gradient (TRPG) elevation (≥30mmHg) were analyzed using preoperative data, including the TBA levels. The median age of patients was 58years (61 women), and 45 and 90 patients had Child-Turcotte-Pugh grades of B and C, respectively. The median TRPG level was 21mmHg, and 17 patients (12.6%) showed TRPG elevation. Multiple logistic regression analysis revealed that elevated TBA (odds ratio 4.322; p=0.013) and main pulmonary artery diameter ≥33mm (odds ratio 4.333; p=0.016) were significantly associated with TRPG elevation. The TBA cut-off value (167.7μmol/L) showed a high diagnostic performance, with 70.6% sensitivity and 64.4% specificity. Ursodeoxycholic acid (UDCA) administration increased the TBA levels dose-dependently. Analysis stratified by UDCA use revealed that in patients not taking UDCA (n=59), elevated TBA levels and younger age significantly contributed to TRPG elevation. However, in those taking UDCA (n=76), this contribution disappeared, suggesting that UDCA consumption reduced TBA levels' efficiency in diagnosing TRPG elevation. The TBA levels may be a potential screening tool for TRPG elevation; however, caution is warranted when interpreting cases treated with UDCA.

Exploring the effects of ursodeoxycholic acid-probiotic combination on Lactobacillus and liver enzyme levels for cholestasis management: An experimental study

Background: Cholestasis arises from compromised bile secretion due to hepatocyte dysfunction, leading to liver impairment. Available treatments show limited efficacy, with ursodeoxycholic acid (UDCA) being a primary option. Cholestatic conditions influence gut microbiota; therefore, probiotic therapy emerges as a potential approach. Objective: This investigation aimed to evaluate the impact of combined administration of probiotics and UDCA on Lactobacillus levels, as well as the levels of the enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in rats with restricted common bile ducts .Methods: A total of 35 male Sprague Dawley rats were randomly assigned to 7 groups, each comprising 5 members: K1 (healthy control), K2 (negative control with cholestasis), K3 (positive control with cholestasis given UDCA), K4 (cholestasis given 36 mg probiotics), K5 (cholestasis given 18 mg probiotics and UDCA), K6 (cholestasis given 36 mg probiotics and UDCA), and K7 (cholestasis given 54 mg probiotics and UDCA). The treatment duration was 21 days, during which blood samples were collected for AST and ALT analysis. Lactobacillus count was determined by quantitative polymerase chain reaction (PCR) analysis of fecal samples.Results: When UDCA and probiotics were given together in three different dosages, the Lactobacillus count significantly increased (p&lt;0.05) compared to the other groups. Furthermore, compared to the other treatment groups, the UDCA-probiotic combination group exhibited noticeably lower AST and ALT values.Conclusion: Combining UDCA and probiotics elevated Lactobacillus count and decreased AST and ALT levels in cases of cholestasis more effectively than single therapy.

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.

Gradual dosing of ursodeoxycholic acid in mothers with intrahepatic cholestasis of pregnancy may improve composite neonatal outcome

Introduction and ObjectivesIntrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. Materials and MethodsRetrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. ResultsNeonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). ConclusionsCompared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Human mesenchymal stem cell secretome increases hepatocyte growth factor expression and promotes liver regeneration in Wistar rats with cholestasis

Globally, the annual mortality rate due to liver cirrhosis is 2.2%, which ranks 12th as the cause of death in the United States. Human mesenchymal stem cell secretome (Hu-MSC-S) is known to reduce liver injury and inflammation. Thus, the present study aims to determine the effect of Hu-MSC-S on hepatocyte growth factor (HGF) expression and liver regeneration in cholestatic rats after choledochal duct ligation receiving standard ursodeoxycholic acid (UDCA) therapy. A randomized experimental study was conducted on 24 male Wistar rats. All rats were randomly assigned into four groups such as control, UDCA, Hu-MSC-S, and UDCA+Hu-MSC-S. The expression of HGF and mitotic index as markers of liver regeneration were evaluated using histopathologic examination. Both HGF expression and the mitotic index were significantly higher in the UDCA and Hu-MSC-S groups (P &lt; 0.05) compared to the control group. The combined administration of UDCA and Hu-MSC-S resulted in significantly higher HGF expression and mitotic index than the individual intervention (P &lt; 0.05). The additional administration of Hu-MSC-S increased HGF expression and mitotic index in rat model of hepatic cholestasis. In conclusion, HuMSC-S administration could be considered as a therapy in patients who received standard UDCA therapy for liver regeneration.

Ursodeoxycholic Acid Prophylaxis and the Reduction of Gallstone Formation After Bariatric Surgery: An Updated Meta-Analysis of Randomized Controlled Trials.

Gallstone formation following bariatric surgery poses a significant clinical concern, prompting various preventive strategies, including ursodeoxycholic acid (UDCA) prophylaxis. This systematic review and meta-analysis aimed to assess the efficacy of UDCA in preventing gallstone formation after bariatric surgery. A comprehensive literature search was conducted in major databases up to September 2023, identifying 12 randomized controlled trials (RCTs) meeting the inclusion criteria. The studies, spanning from 1993 to 2022, involved 2,767 patients who underwent diverse bariatric procedures. The primary outcome was the overall incidence of cholelithiasis, with secondary outcomes encompassing gallstone occurrences at three, six, and 12 months; symptomatic cholelithiasis; and rates of cholecystectomy. The Cochrane risk-of-bias tool was utilized for evaluating study quality, and statistical analyses were conducted using the RevMan software (Cochrane Collaboration, London, UK). Patients receiving UDCA demonstrated a significantly lower overall incidence of gallstones post-bariatric surgery (risk ratio [RR] 0.13; P < 0.0001). Subgroup analyses confirmed reduced gallstone incidence at three months (P = 0.04), six months (P < 0.00001), and one year (P < 0.00001) with UDCA prophylaxis. Symptomatic cholelithiasis incidence was also lower in the UDCA group (RR 5.70; P < 0.00001), and cholecystectomy rates were significantly reduced (RR 3.05; P = 0.002). This meta-analysis supports the efficacy of UDCA prophylaxis in preventing gallstone formation after bariatric surgery. The findings suggest that UDCA administration not only lowers overall gallstone incidence but also reduces the occurrence of symptomatic cholelithiasis and mitigates the need for cholecystectomy. However, caution is warranted due to heterogeneity, diverse surgical procedures, and limited long-term follow-up in the included studies. Further research with standardized protocols and extended observational periods is recommended to strengthen the evidence base and guide clinical practice.

Effect of Ursodeoxycholic Acid for Sars-Cov-2 Prevention in Hematological Malignancies: An Observational Real-World Study

Introduction: Disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).After the adjustments and optimizations of Chinese control strategies and policies for COVID-19 on December of 2022, clinical exposure increased rapidly.There are greater concerns for patients with hematological malignancies, particularly those who have undergone hematopoietic stem cell transplantation (HSCT). One promising preventive measure that has recently gained attention is ursodeoxycholic acid (UDCA). This drug is mainly used to treat biliary tract disease and other hepatobiliary disorders, particularly primary biliary cholangitis (Hirschfield GM, et al. Gut 2018); and also has been widely used at a higher dosage to prevent sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) after HSCT in the clinical setting. Recently, Brevini et al. demonstrated that UDCA downregulated ACE2 expression by reducing farnesoid X receptor signaling, resulting in reduced SARS-Cov-2 infection (Brevini T, et al. Nature 2022), indicating that pharmacological prophylaxis using UDCA against COVID-19 in vulnerable groups was feasible, but the clinical data to support this practice is limited. Therefore, we aim to present epidemiological data for Chinese patients with hematological malignancies during this epidemic wave, and investigate the protection effects offered by UDCA against COVID-19 in these patients. Methods: This investigation was a single-center, observational real-world study, and was granted by the ethics committee of the Institute of Hematology &amp; Blood Diseases [No. QTJ2023012-EC-1]. The transplant patients were included in the “NICHE-SKIRT” project (Cao Y, et al. Am J Hematol 2023). Informed consent for the acquisition and the use of patient samples was obtained. Data for hospitalized patients at the Institute of Hematology &amp; Blood Diseases Hospital (Tianjin, China) was reviewed between December 2022 and January 2023. COVID 19 status was assessed using hospital-reported PCR and/or antigen tests for twice a week. We analyzed follow-up records up to 14th February 2023. The primary end-point was the rate of COVID -19 infection. Results: We enrolled 393 patients with a median age of 38 years old. At the cutoff date, 297 patients (75.6%) had confirmed COVID-19 infection (72.5% in the allo-HSCT cohort). Among the 273 evaluable patients, the majority (64.8%) had asymptomatic/mild disease. The severe/critical patients accounted for only 15.8%. Seven hospitalized patients had died from COVID-19 by the last follow-up date. The median period between COVID-19 diagnosis and death was 15 days (range: 2-32 days). Lower proportion of CD3+CD4+T cells associated with more severe COVID-19 clinical spectrum (Asymptomatic/mild [n = 97] moderate [n = 46], adjusted P = 0.001; Asymptomatic/mild vs. severe/critical [n = 25], adjusted P = 0.036). Among these patients, 163 received UDCA (UDCA group) while 230 did not (non-UDCA group). The COVID-19 infection rate was lower in the UDCA group (69.9% vs. 79.6%; P= 0.039). However, patients in the UDCA group had a higher ECOG score and Charlson Comorbidity Index (Table 1), suggesting that they were more likely to have underlying health conditions. To account for this potential bias, we performed PSM, which confirmed that the UDCA group had a significantly lower rate of COVID-19 infection compared to the non-UDCA group (69.0% vs. 81.0%; P = 0.049) in the validated cohort. Univariate logistic regression analysis showed that only UDCA administration was associated with COVID-19 infection (OR: 0.598; P = 0.029). To further investigate the effect of UDCA in specific populations, we carried out an exploratory analysis. Our results suggest that males, patients with a CCI ≥ 2, a history of smoking, and those with acute lymphoblastic leukemia (ALL) may benefit the most from the protective effect of UDCA against COVID-19. Conclusion: This study aimed to investigate the prevalence and clinical outcomes of SARS-CoV-2 infections in Chinese patients with hematologic disorders during the COVID-19 epidemic that began at the end of 2022. Our findings provide support for preclinical studies suggesting that UDCA may have marginal benefit in protecting against COVID-19. However, prospective studies with a higher dose of UDCA need to be performed.

Fetal PR Interval in Pregnancies with Intrahepatic Cholestasis of Pregnancy: A Case-Control Study.

This study had three purposes: first, to explore differences in fetal cardiac function in patients with and without intrahepatic cholestasis of pregnancy (ICP) based on PR interval (the interval between the beginning of the atrial contraction and the beginning of the ventricular contraction). Second, to explore a potential correlation between PR interval and bile acid levels in pregnant women with ICP. Third, to study changes in PR interval of fetuses from pregnant women with ICP after administration of ursodeoxycholic acid (UDCA). This was a prospective observational case-control study. ICP was defined as palmar plantar pruritus of nocturnal predominance for more than 1 week associated with a total bile acid level >10 μmol/L. Control cases were women with pregnancies scheduled for induction or elective cesarean section at term. One hundred and ten women with ICP and 72 controls were included in the study. Median gestational age at inclusion was 35.9 weeks. Median PR interval was significantly longer in fetuses of women with ICP (122 vs. 102 ms, p < 0.001). There was a significant correlation between bile acid levels and PR interval (rho = 0.723, p < 0.001). In 22 fetuses, the median PR interval decreased significantly following UDCA administration (134 vs. 118 ms, p = 0.004). PR interval is longer in fetuses of women with ICP. PR interval was significantly correlated with bile acid levels, and administration of UDCA significantly reduced PR interval. · Differences in fetal cardiac function in patients with and without intrahepatic cholestasis.. · PR interval and bile acid levels in pregnant women with intrahepatic cholestasis.. · Changes in PR interval of fetuses from pregnant women with ICP after use of UDCA..

Synergistic effect of Euphorbia kansui stir-fried with vinegar and bile acids on malignant ascites effusion through modulation of gut microbiota.

Background: Toxic Euphorbia kansui (EK) is employed to treat malignant ascites effusion (MAE). EK stir-fried with vinegar (VEK) has been demonstrated to reduce toxicity due to its preserved water-expelling effect. This was demonstrated to be correlated with gut microbiota. Therein, bile acids (BAs) have a bidirectional relationship with the gut microbiota. Therefore, the aim of this study is to explore whether BA-mediated gut microbiota influences the water-expelling effect of VEK against MAE. Methods: The MAE rat model was established by intraperitoneal injection of Walker-256 tumor cells. A reliable simultaneous method for the determination of 15 bile acids in rat feces using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established and applied to analyze the fecal BAs in rats treated with VEK. The screened BA was then administered to VEK-treated MAE rats. The water-expelling effect was evaluated using histopathological analysis, biochemical examination, inflammatory factors in ascites, urine volume, ascites amount, and intestinal aquaporin expression. The microbial composition was determined using 16S rRNA sequencing, and the contents of bile acids were finally measured. Results: VEK decreased the content of fecal deoxycholic acid (DCA), lithocholic acid (LCA), and taurocholic acid (TCA) while increasing the content of ursodeoxycholic acid (UDCA). VEK alleviated liver, stomach, and intestinal injuries; oxidative damage; and inflammation, which were further ameliorated with UDCA intervention. VEK alleviated MAE by increasing the fecal water content, urine volume, and AQP3 protein expression and decreasing the urine levels of Na+, K+, and Cl-. This was retained with the intervention of UDCA. UDCA and VEK regulated the BA metabolism disorder to a certain extent. Analysis of gut microbiota showed that VEK increased the abundance of Lactobacillus and decreased that of Prevotella_9 in MAE rats. The combined administration of UDCA and VEK showed a better modulation of the microbiota structure than that of VEK alone, and the effect of this administration reached closer to the reference state. Conclusion: The water-expelling effect of VEK did not directly depend on the BA-mediated gut microbiota. However, VEK and BAs had a synergistic effect on malignant ascites effusion through the regulation of the gut microbiota. These results provided a scientific basis for the reasonable usage of VEK and the novel combination treatment strategy of VEK and UDCA.

Biliary sludge syndrome induced by cephalosporins in children: clinical and diagnostic markers, management

Biliary sludge can occur when taking medicines (oral contraceptives, cephalosporins, octreotide, furosemide, clofibrate, morphine, calcium preparations, etc.). In particular, 30–40 % of ceftriaxone, which is widely used in pediatric inpatient practice, is excreted with bile, 5–15 % of all side effects of the drug are due to biliary sludge. The mechanism of ceftriaxone-associated biliary sludge is due to the fact that ceftriaxone competes with bilirubin for albumin, which induces an increase in unconjugated bilirubin in the blood. The drug enters the bile in the form of a divalent anion, binds to calcium in ceftriaxone-calcium complexes with inclusions of cholesterol monohydrate crystals and bilirubinate granules. In patients taking cephalosporins, when complaints from the gastrointestinal tract appear, ultrasound screening is mandatory. Children with a family history of gallstone disease and risk factors should undergo ultrasound screening on the 10th day and 1 month after treatment with cephalosporins, even in the absence of complaints. The administration of ursodeoxycholic acid leads to a significant regression of clinical symptoms of biliary sludge and objective ultrasound signs in 2/3 of children after 2 months.

Evaluating the effect of ursodeoxycholic acid (UDCA) in comparison with dexamethasone and diclofenac in a rat model of rheumatoid arthritis.

Ursodeoxycholic acid (UDCA) is known for its major effects on the liver, but its impact on autoimmune diseases is not well understood. This study aimed to assess the effectiveness of UDCA in controlling rheumatoid arthritis (RA) in an in vivo setting. Experimental RA was induced in rats using Freund's complete adjuvant, and the effects of UDCA (50,100 mg/kg) were compared to those of dexamethasone and diclofenac by measuring changes in paw size, IL-17, pro-inflammatory cytokines, oxidative stress (GSH, MDA), and radiological changes. The administration of UDCA resulted in decreased cartilage damage, reduced paw edema, and a decrease in the release of pro-inflammatory cytokines and oxidative stress. Additionally, X-ray joint alterations were observed in the UDCA-treated group compared to the dexamethasone and diclofenac groups. These results suggest that UDCA has anti-rheumatoid arthritis properties due to its ability to minimize oxidative stress and inflammation in arthritis-affected rats.

Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism.

Depression is a mental disorder with high morbidity, disability and relapse rates. Ginkgo biloba extract (GBE), a traditional Chinese medicine, has a long history of clinical application in the treatment of cerebral and mental disorders, but the key mechanism remains incompletely understood. Here we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial metabolism. GBE protected against unpredictable mild stress (UMS)-induced despair, anxiety-like and social avoidance behavior in mice without sufficient brain distribution. Fecal microbiome transplantation transmitted, while antibiotic cocktail abrogated the protective effect of GBE. Spatiotemporal bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid (UDCA) in the effect of GBE. UDCA administration induced depression-like behavior in mice. Together, these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.

Akut lösemili çocukların idame tedavisinde kemoterapiye bağlı hepatotoksisite tedavisinde ursodeoksikolik asitin rolü

Introduction: Chemotherapeutic agents used in the treatment of leukemia patients may cause toxic effects in the liver where they are metabolized. Ursodeoxycholic acid (UDCA) is used because of its hepatoprotective effect in the treatment of drug-induced liver toxicity. This study investigated the efficacy of UDCA use, despite the effect of UDCA on tumor cells being unknown, in the treatment of liver toxicity in pediatric patients on chemotherapy for leukemia. Methods: Data from pediatric leukemia patients, who were on maintenance therapy and developed liver toxicity, were retrospectively analyzed. Patients were divided into three groups and the results were compared regarding development of liver toxicity. Patients who were not given UDCA and whose chemotherapy (CT) treatment was interrupted were defined as Group 1, patients who were given UDCA and whose CT was interrupted were defined as Group 2, and patients who were given UDCA and continued CT were defined as Group 3. Results: The study cohort numbered 119 patients, of whom 64 were included in Group 1, 26 patients were in Group 2 and 29 patients were included in Group 3. The mean age of the patients was 6.29±3.03 years and 57.1% of them were male. In Group 1, alanine aminotransferase (ALT) decreased to &amp;lt;100 IU/L so UDCA was interrupted, and CT could be rechallenged in 85.9%, in Group 2 this proportion was 100%, and in 69.2% of patients in Group 3, respectively. While there was no significant difference between Group 1 versus Group 2 and Group 1 versus Group 3, a significant difference was found between Group 2 and Group 3 (p=0.005). There were no patients in any group with a bilirubin level of &amp;gt;3 mg/dL. Duration for normalization of ALT and aspartate aminotransferase levels were similar. Conclusions: The most effective treatment for chemotherapy-induced liver toxicity in pediatric patients with leukemia seems to be to interrupt CT. It was noteworthy that UDCA administration without interruption of CT treatment, the source of the liver toxicity, was effective in 69.2% of patients. Further and comprehensive studies are needed to evaluate the role of UDCA in hepatoprotection in these patients. Keywords: Ursodeoxycholic acid; leukemia; chemotherapy; hepatotoxicity

Ursodeoxycholic acid administration did not reduce susceptibility to SARS-CoV-2 infection in children.

A recent study suggested that administration of ursodeoxycholic acid (UDCA) at dosages usually employed clinically may reduce rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A recent surge of SARS-CoV-2 omicron infection in China allowed study of whether UDCA administration reduced susceptibility to SARS-CoV-2 infection in children with liver disease. Through WeChat groups, a questionnaire was distributed to families (n = 300) in which a child had been admitted to our liver service in the past 5 years. Among the families/households in which someone was infected with SARS-CoV-2, the proportion in which a child taking UDCA was infected was compared with the proportion in which a child not taking UDCA was infected. Of the 300 questionnaire answers, 280 (93.3%) were valid. SARS-CoV-2 infection was confirmed in 226 families (80.7%): 146 children were taking UDCA (10-20 mg/kg/day) and 80 children were not taking UDCA. SARS-CoV-2 infection was confirmed in 95 children taking UDCA (65.1%) and in 51 children not taking UDCA (63.8%) (p = 0.843); SARS-CoV-2 infection was suspected in 23 children taking UDCA (15.8%) and in 11 children not taking UDCA (13.8%) (p = 0.687). These results indicate that UDCA administration does not reduce susceptibility to SARS-CoV-2 infection in children with liver disease.

Characterization of Metabolic Correlations of Ursodeoxycholic Acid with Other Bile Acid Species through In Vitro Sequential Metabolism and Isomer-Focused Identification.

As a first-line agent for cholestasis treatment in a clinic, ursodeoxycholic acid rectifies the perturbed bile acids (BAs) submetabolome in a holistic manner. Considering the endogenous distribution of ursodeoxycholic acid and extensive occurrences of isomeric metabolites, it is challenging to point out whether a given bile acid species is impacted by ursodeoxycholic acid in a direct or indirect manner, thus hindering the therapeutic mechanism clarification. Here, an in-depth exploration of the metabolism pattern of ursodeoxycholic acid was attempted. Sequential metabolism in vitro with enzyme-enriched liver microsomes was implemented to simulate the step-wise metabolism and to capture the metabolically labile intermediates in the absence of endogenous BAs. Squared energy-resolved mass spectrometry (ER2-MS) was utilized to achieve isomeric identification of the conjugated metabolites. As a result, 20 metabolites (M1-M20) in total were observed and confirmatively identified. Of those, eight metabolites were generated by hydroxylation, oxidation, and epimerization, which were further metabolized to nine glucuronides and three sulfates by uridine diphosphate-glycosyltransferases and sulfotransferases, respectively. Regarding a given phase II metabolite, the conjugation sites were correlated with first-generation breakdown graphs corresponding to the linkage fission mediated by collision-induced dissociation, and the structural nuclei were identified by matching second-generation breakdown graphs with the known structures. Together, except for intestinal-bacteria-involved biotransformation, the current study characterized BA species directly influenced by ursodeoxycholic acid administration. Moreover, sequential metabolism in vitro should be a meaningful way of characterizing the metabolic pathways of endogenous substances, and squared energy-resolved mass spectrometry is a legitimate tool for structurally identifying phase II metabolites.

Protective effects of dioscin against Parkinson's disease via regulating bile acid metabolism through remodeling gut microbiome/GLP-1 signaling

It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.

Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

BackgroundSkeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms.MethodsWe assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber’s diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy.ResultsUDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber’s diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux.ConclusionsOur results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.