Higher Bile Acid Research Articles

Maternal and Fetal Outcome in Intrahepatic Cholestasis of Pregnancy in a Multicultural Society Conducted at a Tertiary Care Hospital in Dubai

Introduction: Intrahepatic cholestasis of pregnancy (ICP) has been sparsely studied especially in the Middle East. The incidence and outcome of ICP varies worldwide. Its incidence in the Middle East and primary maternal and fetal outcome must be evaluated to ascertain the burden so that appropriate preventive and intervention measures can be formulated and implemented. Objective: To assess the incidence, associations, and maternal-fetal outcomes in ICP. Design: Case-control study. Settings: tertiary care hospital settings affiliated with the academic center in the UAE. Patients and methods: a total of 150 patients were included from October 2016 to September 2018 in the study with 75 cases of ICP and 75 controls matched according to age and date of delivery. The maternal risk factors attributable to ICP were recorded. Biochemical profile of mothers was monitored. Maternal and fetal outcomes were compared in 2 groups. Main outcomes measured: incidence and associations of ICP were evaluated. Maternal and fetal outcomes were compared in cases and controls. Sample size: 150. Result: The incidence of ICP in our study in the UAE was 1.0%. ICP has significant association with past obstetric cholestasis history (p value <0.01, odds ratio [OR] 9.3, 95% CI: 2.1–41.8), gestational diabetes (p value <0.05, OR 2.0, 95% CI: 1.0–3.8), pre-eclampsia (p value <0.05, OR 7.2, 95% CI: 1.6–33.1), and undergoing induction of labor (p value <0.01, OR 8.1, 95% CI: 3.7–17.8). The maternal bile acid level above 40 μmol/L is ­associated with higher chances of preterm delivery (p value <0.01, OR 8.2, 95% CI: 3.0–22.5), intrauterine fetal demise (p value <0.01), low birth weight (p value <0.01, OR 13.6, 95% CI: 4.2–43.5), respiratory distress (p value <0.05, OR 15.5, 95% CI: 1.8–132.7), poor Apgar score (p value <0.05, OR 12.720, 95% CI: 1.5–111.4), and NICU admissions (p value <0.01, OR 9.0, 95% CI: 1.8–45.9). Conclusion: ICP mothers have low incidence in the UAE and significant association with gestational diabetes and pre-eclampsia. High maternal bile acids above 40 μmol/L have poor fetal outcomes.

A strain of Bacteroides thetaiotaomicron attenuates colonization of Clostridioides difficile and affects intestinal microbiota and bile acids profile in a mouse model

Clostridioides difficile infection (CDI) is a growing global public health threat. While fecal microbiota transplantation (FMT) is an effective therapy for CDI, a number of challenges limit its application. Studies suggest that probiotics may be a promising alternative therapy. In the current study, we evaluated whether Bacteroides thetaiotaomicron (B. thetaiotaomicron) would inhibit colonization of toxigenic BI/NAP1/027 C. difficile in a mouse model. We found that B. thetaiotaomicron administration decreased the copies of C. difficile and inhibited inflammation in the colon. 16S rRNA sequencing showed that B. thetaiotaomicron administration was associated with a significantly increased relative abundance of Bacteroidetes and decreased level of Proteobacteria, leading to the reversal of the effect of antibiotics treatment and C. difficile infection on microbiota. B. thetaiotaomicron administration was associated with increases in the concentrations of alpha-muricholic acid, beta-muricholic acid, 12 ketolithocholic acid, and deoxycholic acid which are known to inhibit the growth of C. difficile, as well as reductions in the level of taurocholic acid, which promotes germination of C. difficile. Altered profile of major high abundance bile acids by B. thetaiotaomicron administration was similar to that with FMT treatment. Based on these results, we proposed the concept of “the ratio of promotion/inhibition BAs” which would advance our understanding of the relation of C. difficile and BAs.

Association between Proliferative Diabetic Retinopathy and Serum Bile Acid Level in Patients with Type 2 Diabetes Mellitus.

Diabetic retinopathy (DR) is one of the diabetic microvascular complications, which is also one of the important causes of blindness in adults. To investigate the association between proliferative retinopathy and serum bile acid level in patients with type 2 diabetes mellitus (T2DM). Three hundred and thirty-six patients with T2DM were included, of which, 229 had a history of more than 10 years without diabetic retinopathy (no diabetic retinopathy, NDR) and 107 had proliferative diabetic retinopathy (PDR). The baseline characteristics of the two groups were compared. According to the level of bile acid, the patients were divided into low, medium and high bile acid groups. The ratio of proliferative retinopathy in each group was compared. The presence of retinopathy was taken as the dependent variable, and the significant variables were analyzed by logistic regression. The level of total bilirubin and bile acid in the NDR group was significantly higher than that in the PDR group, while the levels of triglyceride, cholesterol and LDL-C were significantly lower than that in the PDR group (P<0.05). With the increase of bile acid level, the proportion of proliferative retinopathy decreased. Logistic regression analysis showed that bilirubin and bile acid were protective factors of diabetic retinopathy, while SBP, LDL-C and UAER were risk factors of diabetic retinopathy. Bile acid might be a protective factor for diabetic retinopathy in T2DM, which might be a potential therapeutic role in retinal disorders.

Taurocholic acid inhibits the response to interferon-\u03b1 therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.

Improvement of Postprandial Lipid Metabolism After Ileal Transposition in Non-obese Diabetic Rats.

Ileal transposition (IT) could reduce obesity and improve type 2 diabetes mellitus (T2DM). The main aim of our study was to investigate lipid metabolism changes in T2DM rats after IT without a weight reduction effect. Thirty male diabetic rats were randomly divided into IT, sham IT (SI), and control groups. The levels of plasma cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs), and bile acid were measured. After sacrifice, the white adipose tissue, brown adipose tissue and liver were weighed. IT induced significant improvement in glucose and lipid metabolism. There were no significant differences in the levels of cholesterol (P = 0.87), HDL (P = 0.70), LDL (P = 0.96), or TGs (P = 0.97) among the groups before surgery. After IT, the levels of cholesterol (P = 0.019), LDL (P = 0.004), and TGs (P < 0.001) were lower than those in the SI and control groups, while the level of HDL was not significantly different compared to those of the other groups (P = 0.437). Higher bile acid level (P = 0.001), lower white adipose tissue/total body weight ratio (P < 0.001), and lower liver/total body weight ratio (P = 0.003) were found in the IT group. The BAT/total body weight ratio in the IT group was higher than that in the SI or control groups (P = 0.002). IT could improve lipid metabolism in diabetic rats.

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy

ObjectiveIntrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy. Patients and methodsSixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically. ResultsThe mean serum bile acid level (n=69; 38.74±35.92μmol/L) in patients with intrahepatic cholestasis of pregnancy (n=69) was detected to be higher than healthy pregnant women (n=20; 5.05±1.88μmol/L) (p<0.001). Weak correlation was detected between serum bile acid level and itch intensity (p=0.014, r=0.295), while no relation was detected between Autotaxin and itch intensity (p=0.446, r=0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10±424.42pg/mL, control: 535.16±256.47pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p=0.157). ConclusionIn our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.

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.

High expression of endothelial progenitor cell-induced angiogenic markers is associated with bile acid levels in HCC.

Endothelial progenitor cell (EPC)-induced angiogenesis activity is enhanced in hepatocellular carcinoma (HCC); however, the contributing factors remain unknown. The present study aimed to investigate the factors influencing the number of EPCs and circulating progenitor cells (CPCs), as well as the expression levels of vascular endothelial growth factor receptor 2 (VEGFR-2) and CD34, in patients with HCC. The expression levels of VEGFR-2 and CD34 were assessed in 72 HCC tumor and matched adjacent tissue microarrays by immunohistochemistry. The associations between VEGFR-2 or CD34 expression in tumors, clinicopathological characteristics and overall survival rates were analyzed. The number of EPCs and CPCs were analyzed in the peripheral blood of patients with HCC. In this study, high expression levels of VEGFR-2 and CD34 were detected in the tumor tissues of 41 (56.9%) and 44 (61.1%) patients, respectively. VEGFR-2 expression was significantly associated with tumor size (P<0.001), bile acid level (P=0.014) and α-fetoprotein level (P=0.011). However, CD34 expression was associated with tumor size (P=0.009), recrudescence (P<0.001) and bile acid (P=0.009). Next, the expression levels of VEGFR-2 and CD34 in tumor and adjacent tissues were compared according to the bile acid level. VEGFR-2 and CD34 expression levels were both higher in the high bile acid group, whereas expression levels of the markers were higher in adjacent tissues compared with tumor tissues. Kaplan-Meier curve analysis identified that patients with low CD34 expression had a longer overall survival compared with patients with high CD34 expression (P=0.029). Multivariate analysis also indicated that both VEGFR-2 (P=0.020) and CD34 (P=0.035) were independent prognostic risk factors. Moreover, flow cytometry demonstrated that the number of EPCs and CPCs was negatively related with the bile acid levels in patients with HCC. In conclusion, in patients with HCC, bile acid promotes EPC-induced angiogenesis. Furthermore, EPCs and CPCs may be activated by bile acid in tumors but are more so in adjacent tissues.

Cloning and characterization of MID1 interacting protein 1 (mid1ip1) from tiger puffer (Takifugu rubripes), and its gene expression in response to dietary bile acid and lipid levels

Mid1ip1 plays important roles in lipogenesis and microtubule stabilization, but little relevant information has been reported in fish. In the present study, mid1ip1 cDNA of tiger puffer was cloned and characterized, and its expression in response to dietary bile acid and lipid levels was investigated following a feeding trial. Experimental diets with suitable (8.5 %) or high lipid level (12.5 %), with or without bile acid supplementation (0.02 % and 0.10 % in the suitable-lipid diet; 0.02 % in the high-lipid diet) were used in the feeding trial. The tiger puffer Mid1ip1, which is putative Mid1ip1 subtype B, shared moderate identity to its known orthologs of other teleost and much lower identity to human Mid1ip1. Mid1ip1 had high transcription in the muscle, skin, eye, and brain, but low expression levels in the liver, intestine, and spleen. The high dietary bile acid level (0.1 %) significantly (P < 0.05) reduced the hepatic mRNA expression of mid1ip1, but unexpectedly the dietary lipid level did not significantly (P > 0.05) affect the gene expression. Significantly positive correlation (R2 = 0.812, P = 0.000) was observed between hepatic mRNA expression of mid1ip1 and tubulin-α, but not between the gene expression of mid1ip1 and acetyl-CoA carboxylase β (R2 = -0.434, P = 0.106), in response to dietary treatments, indicating the potential roles of this Mid1ip1 subtype in microtubule stabilization rather than in lipogenesis. To our knowledge, this is the first study investigating the regulation of fish mid1ip1 expression by dietary nutrients.

Cholesterol Induces Nrf-2- and HIF-1α-Dependent Hepatocyte Proliferation and Liver Regeneration to Ameliorate Bile Acid Toxicity in Mouse Models of NASH and Fibrosis.

Nonalcoholic steatohepatitis (NASH) is currently one of the most common liver diseases worldwide. The toxic effects of lipids and bile acids contribute to NASH. The regenerative pathway in response to damage to the liver includes activation of the inflammatory process and priming of hepatocytes to proliferate to restore tissue homeostasis. However, the effects of cholesterol on bile acid toxicity, inflammation, and fibrosis remain unknown. We have used two mouse models of bile acid toxicity to induce liver inflammation and fibrosis. A three-week study was conducted using wild-type mice receiving an atherogenic diet (1% (w/w) cholesterol and 0.5% (w/w) cholic acid) and its separate constituents. Mdr2-/- mice were fed a high-cholesterol-enriched diet or standard AIN-93 diet for 6 weeks. We measured serum transaminase levels to assess liver tissue necrosis and fibrosis; iNOS, SAA1, SAA2, and F4/80 levels to determine liver inflammation; PCNA and HGF levels to evaluate proliferative response; and Nrf-2, HIF-1α, and downstream gene expression to establish protective responses. In both studies, high bile acid levels increased serum transaminases and liver fibrosis, whereas cholesterol supplementation attenuated these effects. Cholesterol supplementation activated survival and the robustness of HIF-1α and Nrf-2 gene expression in hepatocytes, induced liver inflammation and hepatocyte proliferation, and inhibited stellate cell hyperplasia and fibrosis. In conclusion, our data show for the first time that cholesterol intake protects against bile acid liver toxicity. The balance between hepatic cholesterol and bile acid levels may be of prognostic value in liver disease progression and trajectory.

Surgical Choice for Different Types of Gallbladder Adenomyomatosis: An Initial Experience of 20 Years Laparoscopic Cholecystectomy.

The objective of this study was to compare the difference of clinical biochemical statistics in different types of gallbladder adenomyomatosis (GA). To investigate the different effects of patients between the 3 different types of GA. Retrospective analysis of the clinical data of the adenomyomatosis patients that come from our hospital between 2010 to 2018. According to the preoperative image (all cases are performed as elective surgery), it could be divided into 3 groups: group A: fundal (localized) type; group B: segmental type; group C: diffuse type. The number of each group is 136, 27, 17. We analyze the biochemical statistics (total bilirubin, direct bilirubin, serum bile acid, alanine aminotransferase, aspartate aminotransferase, cholinesterase, etc.) of the 3 groups to explore the difference in operative mode, operative time and prognosis between these 3 groups. (1) In the liver function statistics, aspartate aminotransferase has the statistical significance (F=4.974, P=0.012); (2) And the diffuse adenomyomatosis might have a higher bile acid (F=6.048, P=0.005); (3) The segmental and diffuse adenomyomatosis is easier to be combined with stones (F=19.226, P<0.001); (4) The fundal adenomyomatosis seems to have a better prognosis: fewer hospital stay (F=4.519, P=0.018), fewer drainage time (F=6.575, P=0.004) and fewer complications (χ=29.429, P<0.001). GA is a disease characterized by epithelial proliferation and hypertrophy of the muscles of the gallbladder wall with an outpouching of the mucosa into or through the thickened muscular layer and cannot be regarded as a precancerous lesion based on available evidence. As for asymptomatic GA, conservative treatment is recommended with ultrasound examinations twice a year. The fundal type GA can be treated by partial laparoscopic cholecystectomy. The segmental and diffuse-type should undergo a total laparoscopic cholecystectomy.

Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study.

Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans. Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations. Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95%CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk. This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.

Valorizing cabbage (Brassica oleracea L. var. capitata) and capsicum (Capsicum annuum L.) wastes: in vitro health-promoting activities.

The capsicum seed core and cabbage outer leaves are common wastes generated in the vegetable processing industry. We explored the in vitro health-promoting activity of these waste products for valorization. Freeze-dried and pulverized cabbage wastes had a high bile acid binding capacity and the capsicum wastes inhibited glucose dialysis more effectively. Methanolic extracts prepared with conventional solvent extraction and ultrasound-assisted extraction were analyzed to determine their 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity, in vitro α-amylase inhibitory, in vitro lipase inhibitory, and prebiotic activity. Crude extracts of cabbage and capsicum wastes were screened using GC-MS analysis. The cabbage waste extracts showed high antioxidant activities but did not inhibit α-amylase. The capsicum waste extracts inhibited both lipase and α-amylase activities and supported the growth of the probiotic bacterium, Lactobacilli brevis. Volatile compounds of the vegetables consisted mainly of phenols and fatty acid esters. In all assays except the α-amylase inhibition assay, the extracts prepared with ultrasound-assisted solvent extraction showed higher activity than those prepared using the conventional method. The capsicum seed core and cabbage outer leaves are potential sources of phytochemicals and antioxidant fibers. Capsicum waste extract supported probiotic bacterial growth without a lag phase. These waste products may be processed into high-value functional ingredients.

Bioassay Guided Isolation of Polysaccharide Rich Fraction from Myrmecodia Platytyrae and its Bile Acid Binder Property

Bioassay guided isolation was done on the Myrmecodia platytyrae (MyP) extracts in order to find the best extract that can bind with bile acid. The function of bile acid binder is to reduce the reabsorption of bile acid in the intestine so that it will cause the decrease of cholesterol in the blood circulation. The extraction process was started by using different organic solvent such as hexane, toluene, ethyl acetate, ethanol and water. All extracts were tested its bile acid binding properties and the extract gave out highest activity was selected to be fractionated. The result showed that water extract has highest bile acid binding property (75%). Then, fractionation process was performed in order to find the best fraction from water extract that have bile acid binding property. The sub-fractionation processes were continued and the process only focussed to the fraction that has highest bile acid binding property until a white powder with 97.02 % carbohydrate was obtained. The powder was subjected to FTIR and was found to have glycosidic bond as shown by bands at 1141 until 1018 cm-1 which is a character of polysaccharide. The polysaccharide rich fraction was hydrolysed and subjected to HPLC to identify its monosaccharide groups. The result showed the presence of glucose and fructose were found to be among the major monosaccharides. This result suggested that the polysaccharide from MyP water extract with high bile acid binding property was gluco-fructan.&#x0D;

Carboxyl Ester Lipase May Not Mediate Lipotoxic Injury during Severe Acute Pancreatitis

Acute lipolysis of visceral fat or circulating triglycerides may worsen acute pancreatitis (AP)-associated local and systemic injury. The pancreas expresses pancreatic triacylglycerol lipase (PNLIP), pancreatic lipase-related protein 2 (PNLIPRP2), and carboxyl ester lipase (CEL), which may leak into the visceral fat or systemic circulation during pancreatitis. We, thus, aimed to determine the pancreatic lipase(s) regulating lipotoxicity during AP. For this AP, associated fat necrosis was analyzed using Western blot analysis. Bile acid (using liquid chromatography-tandem mass spectrometry) and fatty acid (using gas chromatography) concentrations were measured in human fat necrosis. The fat necrosis milieu was simulated invitro using glyceryl trilinoleate because linoleic acid is increased in fat necrosis. Bile acid requirements to effectively hydrolyze glyceryl trilinoleate were studied using exogenous or overexpressed lipases. The renal cell line (HEK 293) was used to study lipotoxic injury. Because dual pancreatic lipase knockouts are lethal, exocrine parotid acini lacking lipases were used to verify the results. PNLIP, PNLIPRP2, and CEL were increased in fat necrosis. Although PNLIP and PNLIPRP2 were equipotent in inducing lipolysis and lipotoxic injury, CEL required bile acid concentrations higher than in human fat necrosis. The high bile acid requirements for effective lipolysis make CEL an unlikely mediator of lipotoxic injury in AP. It remains to be explored whether PNLIP or PNLIPRP2 worsens AP severity invivo.

Umbilical Cord Ulcer and Intrauterine Death in Fetal Intestinal Atresia

Objective: To examine the incidence of umbilical cord ulcer (UCU) that causes intrauterine fetal death (IUFD) in fetal duodenal or jejunoileal atresia and the association between UCU and bile acid concentrations in amniotic fluid. Methods: Perinatal outcomes were evaluated in cases of fetal intestinal atresia between 2003 and 2017. A pathological examination of the umbilical cord was performed, and bile acid concentrations in the amniotic fluid were measured. Results: Among the 46 cases included in this study, there were 27 with duodenal atresia and 19 with jejunoileal atresia. There were 4 cases (8.7%) of IUFD and 1 (2.2%) neonatal death with multiple structural anomalies. UCUs were found in 37.5% (15/40) of cases, and severe UCUs with exposed vessels were significantly more common in IUFD (3/4) than in livebirth (0/42) cases (p < 0.01). The incidences of chromosomal abnormality and structural anomalies were not markedly different between livebirth (9/30 and 11/42, respectively) and IUFD (1/3 and 1/4, respectively) cases. Bile acid concentrations in amniotic fluid were significantly higher in cases of UCUs than in those without (p < 0.01). Conclusion: UCUs were not rare in fetal intestinal atresia and were associated with high bile acid concentrations in amniotic fluid. UCUs with exposed vessels were associated with IUFD in intestinal atresia.

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis.

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg-/- mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg-/- mice displayed high hepatic cholesterol 7 α-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg-/- mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr-/- mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.

In vitro effects of four polysaccharides containing β-D-Glup on intestinal function

ABSTRACTPlant polysaccharides exert a wide range of biological effects on the intestinal function. In this study, four polysaccharides containing β-D-Glup, including Dendrobium officinale polysaccharide (DOP), Dendrobium aphyllum polysaccharide (DAP), and glucans from yeast (G-Y) and barley (G-B), were investigated in vitro for their intestinal-promoting functions such as inhibition of digestive enzymes, effect of blood glucose and blood lipid levels by using ultraviolet spectrophotometry, as well as the relationship of their structures to those functions. The results indicated that all polysaccharides significantly slowed glucose diffusion rate, decreased protease, and pancreatic lipase activities. Increased branching degrees had a deleterious effect on the α-amylase activity but increased bile acid binding. Increased calcium concentration in glucans (G-Y and G-B) and increased mannose molar ratio in Dendrobium polysaccharides (DOP and DAP) were correlated with increased pancreatic lipase inhibition. The polysaccharides with higher glucose content and branching degrees had higher bile acid binding and disruption of cholesterol micelle formation. These polysaccharides exerted a variety of potential health-promoting effects attributed to their different structures, which should be further investigated in vivo.

Acute Kidney Injury May Not Be As Uncommon As Believed in Children With Advanced Chronic Liver Diseases.

The article by Berg et al is interesting, where they have directly measured the glomerular filtration rate (GFR) in children with chronic liver disease (CLD) and showed that many of these children had hyperfiltration (1). A novel, though unexplainable finding is the increased GFR and effective renal plasma flow in children with higher international normalized ratio, aspartate aminotransferase to platelet ratio index, high bile acid concentration, and lower albumin (1). A cross-sectional design is not an ideal choice for studying renal involvement in CLD, as acute kidney injury (AKI) can occur at various time points in the natural course, especially when the patient decompensates. In the present study, hypofiltration was present in 15.2% of children with CLD and only 1.5% of the control population. As the current definitions of AKI are based on an interval decrease in GFR, we can assume that the prevalence of renal dysfunction in this study was 15.2%. AKI had been shown to be present in 22.6% of children admitted with acute-on-chronic liver failure, 10.6% children with decompensated CLD and only 1.33% of children with compensated CLD (2). The frequency of AKI was 14.3% in children with CLD undergoing liver transplant (3). In addition, we have shown that presence of AKI leads to 7.7-fold higher risk of short-term mortality in advanced CLD (2). Hence, the conclusion by Berg et al that most children with CLD have well preserved renal functions may bring in a “false sense of security” to the readers and may delay the diagnosis as well as interventions. We believe that a high index of suspicion should be maintained for AKI, especially in decompensated CLD and an aggressive approach should be employed. It would be more informative if the authors could specify the percentage of patients with hyperfiltration/hypofiltration who fulfilled the current criteria for AKI/chronic kidney disease. Inclusion of heterogenous etiological groups and a fair number of noncirrhotic patients like glycogen storage disease who had high GFR could have decreased the significance of difference in GFR between CLD and controls. The authors have also included diseases like tyrosinemia and alagille's known to have primary renal involvement, which could lead to bias. The current emphasis while defining AKI in children as well as adults with CLD is on progressive rise in serum creatinine (4,5). In this study, eGFR overestimated lower mGFR and underestimated elevated mGFR. As lower body surface area in children leads to overestimation of GFR, absolute GFR gains significance. In fact, absolute mGFR correlated well with absolute eGFR (r = 0.82) in the present study (1). In current scenario, interval change in eGFR is easy and quick method to detect renal dysfunction and is best calculated by equations that employ a combination of creatinine, cystatin C, and growth parameters (6). With increasing evidence that hyperfiltration precedes end-stage kidney disease by several years, it would be interesting if the authors could monitor long-term renal functions of those who had initial hyperfiltration (7). To conclude, we need more studies in homogenous population to determine the true prevalence of AKI in CLD, but till then we need to maintain a high index of suspicion for early recognition of AKI as almost all modalities of treatment for AKI in CLD are effective if initiated early.

Bile Acid Metabolism is an Intermediary Factor between Non-Alcoholic Steatohepatitis and Ischemic Heart Disease in SHRSP5/Dmcr Rats

The non-alcoholic steatohepatitis (NASH) increases the cardiovascular risk regardless of risk factors in metabolic syndrome. The stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr), fed a high-fat and -cholesterol (HFC) diet and administered Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) presented NASH and cardiovascular disease. However, the intermediary factors between NASH and cardiovascular risk are still unknown. We investigated whether bile acids (BAs) play an intermediary role between NASH and cardiovascular disease in SHRSP5/Dmcr rats. SHRSP5/Dmcr rats divided into 2 groups were fed an SP (non-NASH group, n=7) or HFC diet (NASH group, n=10) for 8 weeks. L-NAME was administered intraperitoneally in the final 2 weeks. In the NASH group, total BA levels were increased in both serum and liver; they aggravated the endothelial dysfunction in aorta, which is the first step to atherosclerosis, and activated the gene expression levels of cell adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1) in coronary artery. In particular, the nuclear factor-kappa B (NFkB) was increased in the NASH group in the coronary endothelial cells activated by high BA levels. We demonstrated that liver BAs aggravated steatosis and fibrosis and serum BA accelerated arteriosclerosis and ischemic heart disease via the classical pathway of NFkB in the endothelial cells. BA metabolism disorder may be an intermediary factor between NASH and cardiovascular risk in SHRSP5/Dmcr rats.