Higher Bile Acid Research Articles

Elucidating Bile Acid Tolerance in Saccharomyces cerevisiae: Effects on Sterol Biosynthesis and Transport Protein Expression

The tolerance of Saccharomyces cerevisiae to high concentrations of bile acids is intricately linked to its potential as a probiotic. While the survival of yeast under high concentrations of bile acids has been demonstrated, the specific mechanisms of tolerance remain inadequately elucidated. This study aims to elucidate the tolerance mechanisms of S. cerevisiae CEN.PK2-1C under conditions of elevated bile acid concentrations. Through growth curve analyses and scanning electron microscopy (SEM), we examined the impact of high bile acid concentrations on yeast growth and cellular morphology. Additionally, transcriptomic sequencing and molecular docking analyses were employed to explore differentially expressed genes under high bile acid conditions, with particular emphasis on ATP-binding cassette (ABC) transporters and steroid hormone biosynthesis. Our findings indicate that high concentrations of bile acids induce significant alterations in the sterol synthesis pathway and transporter protein expression in S. cerevisiae. These alterations primarily function to regulate sterol synthesis pathways to maintain cellular structure and sustain growth, while enhanced expression of transport proteins improves tolerance to elevated bile acid levels. This study elucidates the tolerance mechanisms of S. cerevisiae under high bile acid conditions and provides a theoretical foundation for optimizing fermentation processes and process control.

Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.

High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70-/- mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart. RNA sequencing was performed on hearts of 3-week-old Cyp2c70-/- mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70-/- pups with low or high plasma BAs, and Cyp2c70-/- pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA). We identified 1355 genes that were differentially expressed in hearts of Cyp2c70-/- mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease. Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life. Cyp2c70-/- mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed Elevated plasma bile acids in Cyp2c70-/- pups coincide with cardiac stress and inflammation Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70-/- pups.

Analysis of the etiology and clinical indicators of infantile cholestasis

Objective: To explore the disease spectrum and corresponding clinical indicators of infantile cholestasis so as to provide a basis for the diagnosis of this type of disease at an early stage. Methods: The clinical data was collected from 203 hospitalized children diagnosed with infantile cholestasis at the Department of Gastroenterology of Maternal and Child Health Care, Guiyang City, from January 2018 to March 2023, including 130 males and 73 females. Patients general condition, personal history, and blood biochemical test indicators, including liver and coagulation function, blood ammonia, blood lipid profile, blood sugar, TORCH, thyroid function, and others, were retrospectively analyzed after admission. Cholangiography and high-throughput gene sequencing were performed in certain patients. The etiology of the enrolled cases were analyzed. Children's clinical data were compared with distinct inherited metabolic liver diseases (Group A) and biliary atresia (Group B). The statistical analysis was conducted using the t-test, Mann-Whitney test, Kruskal-Wallis test, or χ2 test, according to different data. Results: In 33 cases, infectious factors-primarily CMV infection-were the etiology of cholestasis. Forty cases had aberrant bile duct development, primarily biliary atresia, choledochal cysts, and intrahepatic bile duct dysplasia. In 26 cases, genetic metabolic factors mainly included citrin protein deficiency, sodium-taurocholate co-transporting polypeptide deficiency, and Alagille syndrome. 11 cases had drug/poisoning factors (parenteral nutrition-associated cholestasis). 19 cases had idiopathic infantile cholestasis. Three cases had other factors; however, all of them had Kawasaki disease. 71 cases had an unclear diagnosis. There was no statistically significant difference in terms of gender and age between groups A and B (P>0.05). The alkaline phosphatase (ALP) and bile acid levels were significantly higher in Group A than Group B, with a P<0.05, while the gamma glutamyltransferase (GGT), direct bilirubin (DBil), and albumin levels were lower than those in Group B, with a P<0.05. The cytomegalovirus infection rate was higher in Group B (62.50%) than Group A (34.62%), and the difference between the two groups was statistically significant (χ2=3.89, P<0.05). The alanine aminotransferase, aspartate aminotransferase, GGT, DBil, and albumin were significantly lower in patients with citrin protein deficiency than those in patients with biliary atresia, while ALP, bile acid, and blood ammonia were higher than those in patients with biliary atresia. Patients with sodium-taurocholate co-transporting polypeptide deficiency had higher bile acid than patients with biliary atresia, while the DBil was lower than that in patients with biliary atresia, and the difference was statistically significant (P<0.05). Conclusion: Infantile cholestasis etiology is diverse. ALP, bile acids, GGT, DBil, and albumin levels can serve as simple indicators for early-stage differentiation between inherited metabolic liver disease and biliary atresia. The cholestasis etiology should be determined as early as possible following biliary atresia exclusion by actively completing genetic metabolic gene detection.

Intrahepatic cholestasis of pregnancy: Introduction and overview 2024.

Considerable progress has been made to explain the aetiology of intrahepatic cholestasis of pregnancy (ICP) and of the adverse pregnancy outcomes associated with high maternal total serum bile acids (TSBAs). The reported thresholds for non-fasting TSBA associated with the risk of stillbirth and spontaneous preterm birth can be used to identify pregnancies at risk of these adverse outcomes to decide on appropriate interventions and to give reassurance to women with lower concentrations of TSBA. Data also support the use of ursodeoxycholic acid to protect against the risk of spontaneous preterm birth. A previous history of ICP may be associated with higher rates of subsequent hepatobiliary disease: if there is a suspicion of underlying susceptibility, clinicians caring for women with ICP should screen for associated disorders or for genetic susceptibility and, where appropriate, refer for ongoing hepatology review.

Assessment of Fetal Ventricular Size and Shape in Women With Intrahepatic Cholestasis of Pregnancy Using Speckle Tracking.

To examine the effect of intrahepatic cholestasis of pregnancy (ICP) on fetal heart morphology. This case-control study was conducted with 40 women with ICP and 54 pregnant controls. Fetal heart quantification based on speckle tracking technology was used to assess the morphology of the fetal right and left ventricles. Routine ventricular size parameters, global and 24-segment spherical indices (SIs) were measured and compared between groups. The routine fetal cardiac parameters, global and right-ventricular SIs did not differ between the ICP and control groups. The left-ventricular apical (segments 16-24) SIs were lower in the ICP group than in the control group (P < .05), with no significant difference in the other left-ventricular segments. Subclinical morphological changes were observed in the left ventricular apical segments of the fetal hearts in women with ICP, which indicates an intrauterine environment with high bile acid concentrations. Twenty-four-segment SIs can be used to effectively evaluate these changes.

The severity of intrahepatic cholestasis during pregnancy increases risks of adverse outcomes beyond stillbirth: evidence from 15,826 patients

BackgroundWhat kinds of fetal adverse outcomes beyond stillbirth directly correlate to the severity of intrahepatic cholestasis during pregnancy (ICP) remained tangled. Herein, we conducted a retrospective cohort study and a dose-response meta-analysis to speculate the association between the severity of ICP and its adverse outcomes.MethodsWe retrospectively collected a cohort of ICP patients from electronic records from Guangzhou Women and Children’s Medical Center between Jan 1st, 2018, and Dec 31st, 2022. Also, we searched PubMed, Cochrane, Embase, Scopus, and Web of Science to extract prior studies for meta-analysis. The Kruskal-Wallis test, a one-way or two-way variants analysis (ANOVA), and multi-variant regression are utilized for cohort study. One stage model, restricted cubic spline analysis, and fixed-effect model are applied for dose-response meta-analysis. The data analysis was performed using the R programme.ResultsOur cohort included 1,289 pregnant individuals, including 385 mild ICP cases, 601 low moderate ICP cases, 282 high moderate ICP cases, and 21 severe ICP cases. The high moderate bile acid levels were correlated to preterm birth [RR = 2.14, 95%CI 1.27 to 3.62), P < 0.01], and preterm premature rupture of membranes [RR = 0.34, 95%CI 0.19 to 0.62), P < 0.01]. We added our cases to cases reported by other studies included in the meta-analysis. There were 15,826 patients included in dose-response meta-analysis. The severity of ICP was associated with increased risks of stillbirth, spontaneous preterm birth, iatrogenic preterm birth, preterm birth, admission to neonatal intensive care unit, and meconium-stained fluid (P < 0.05).ConclusionsOur study shows the correlation between the severity of ICP and the ascending risks of stillbirth, preterm birth, and meconium-stained fluid, providing new threshold TBA levels.Prospero registration numberCRD42023472634.

Ex vivo metabolism kinetics of primary to secondary bile acids via a physiologically relevant human faecal microbiota model

Bile acids (BA) are synthesized in the human liver and undergo metabolism by host gut bacteria. In diseased states, gut microbial dysbiosis may lead to high primary unconjugated BA concentrations and significant perturbations to secondary BA. Hence, it is important to understand the microbial-mediated formation kinetics of secondary bile acids using physiologically relevant ex vivo human faecal microbiota models. Here, we optimized an ex vivo human faecal microbiota model to recapitulate the metabolic kinetics of primary unconjugated BA and applied it to investigate the formation kinetics of novel secondary BA metabolites and their sequential pathways. We demonstrated (1) first-order depletion of primary BA, cholic acid (CA) and chenodeoxycholic acid (CDCA), under non-saturable conditions and (2) saturable Michaelis-Menten kinetics for secondary BA metabolite formation with increasing substrate concentration. Notably, relatively lower Michaelis constants (Km) were associated with the formation of deoxycholic acid (DCA, 14.3 μM) and lithocholic acid (LCA, 140 μM) versus 3-oxo CA (>1000 μM), 7-keto DCA (443 μM) and 7-keto LCA (>1000 μM), thereby recapitulating clinically observed saturation of 7α-dehydroxylation relative to oxidation of primary BA. Congruently, metagenomics revealed higher relative abundance of functional genes related to the oxidation pathway as compared to the 7α-dehydroxylation pathway. In addition, we demonstrated gut microbial-mediated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) formation from CDCA. In conclusion, we optimized a physiologically relevant ex vivo human faecal microbiota model to investigate gut microbial-mediated metabolism of primary BA and present a novel gut microbial-catalysed two-step pathway from CDCA to HCA and, subsequently, HDCA.

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Albireo Pharma, an Ipsen company.

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.

In vitro safety and functional characterization of the novel Bacillus coagulans strain CGI314.

Bacillus coagulans species have garnered much interest in health-related functional food research owing to their desirable probiotic properties, including pathogen exclusion, antioxidant, antimicrobial, immunomodulatory and food fermentation capabilities coupled with their tolerance of extreme environments (pH, temperature, gastric and bile acid resistance) and stability due to their endosporulation ability. In this study, the novel strain Bacillus coagulans CGI314 was assessed for safety, and functional probiotic attributes including resistance to heat, gastric acid and bile salts, the ability to adhere to intestinal cells, aggregation properties, the ability to suppress the growth of human pathogens, enzymatic profile, antioxidant capacity using biochemical and cell-based methods, cholesterol assimilation, anti-inflammatory activity, and attenuation of hydrogen peroxide (H2O2)-induced disruption of the intestinal-epithelial barrier. B. coagulans CGI314 spores display resistance to high temperatures (40°C, 70°C, and 90°C), and gastric and bile acids [pH 3.0 and bile salt (0.3%)], demonstrating its ability to survive and remain viable under gastrointestinal conditions. Spores and the vegetative form of this strain were able to adhere to a mucous-producing intestinal cell line, demonstrated moderate auto-aggregation properties, and could co-aggregate with potentially pathogenic bacteria. Vegetative cells attenuated LPS-induced pro-inflammatory cytokine gene expression in HT-29 intestinal cell lines and demonstrated broad antagonistic activity toward numerous urinary tract, intestinal, oral, and skin pathogens. Metabolomic profiling demonstrated its ability to synthesize several amino acids, vitamins and short-chain fatty acids from the breakdown of complex molecules or by de novo synthesis. Additionally, B. coagulans CGI314's strong antioxidant capacity was demonstrated using enzyme-based methods and was further supported by its cytoprotective and antioxidant effects in HepG2 and HT-29 cell lines. Furthermore, B. coagulans CGI314 significantly increased the expression of tight junction proteins and partially ameliorated the detrimental effects of H2O2 induced intestinal-epithelial barrier integrity. Taken together these beneficial functional properties provide strong evidence for B. coagulans CGI314 as a promising potential probiotic candidate in food products.

Lacticaseibacillus chiayiensis mediate intestinal microbiome and microbiota-derived metabolites regulating the growth and immunity of chicks

Emerging evidence confirms beneficial properties of probiotics in promoting growth and immunity of farmed chicken. However, the molecular mechanisms underlying the host-microbiome interactions mediated by probiotics are not fully understood. In this study, the internal mechanisms of Lacticaseibacillus chiayiensis-mediated host-microbiome interactions and to elucidate how it promotes host growth were investigated by additional supplementation with L. chiayiensis. We conducted experiments, including intestinal cytokines, digestive enzymes test, intestinal microbiome, metabolome and transcriptome analysis. The results showed that chickens fed L. chiayiensis exhibited higher body weight gain and digestive enzyme activity, and lower pro-inflammatory cytokines, compared to controls. Microbiota sequencing analysis showed that the gut microbiota structure was reshaped with L. chiayiensis supplementation. Specifically, Lactobacillus and Escherichia increased in abundance and Enterococcus, Lactococcus, Corynebacterium, Weissella and Gallicola decreased. In addition, the bacterial community diversity was significantly increased compared to controls. Metabolomic and transcriptomic analyses revealed that higher bile acids and N-acyl amides concentrations and lower carbohydrates concentrations in L. chiayiensis-fed chickens. Meanwhile, the expression of genes related to nutrient transport and absorption in the intestine was upregulated, which reflected the enhanced digestion and absorption of nutrients in chickens supplemented with L. chiayiensis. Moreover, supplementation of L. chiayiensis down-regulated genes involved in inflammation-related, mainly involved in NF-κB signaling pathway and MHC-II mediated antigen presentation process. Cumulatively, these findings highlight that host-microbiota crosstalk enhances the host growth phenotype in two ways: by enhancing bile acid metabolism and digestive enzyme activity, and reducing the occurrence of intestinal inflammation to promote nutrient absorption and maintain intestinal health. This provides a basis for the application of LAB as an alternative to antibiotics in animal husbandry.

Characterization and expression analysis of seven lipid metabolism-related genes in yellow catfish Pelteobagrus fulvidraco fed high fat and bile acid diet

SREBPs, such as SREBP1 and SREBP2, were the key transcriptional factors regulating lipid metabolism. The processing of SREBPs involved many genes, such as scap, s1p, s2p, cideb. Here, we deciphered the full-length cDNA sequences of scap, srebp1, srebp2, s1p, s2p, cideb and cidec from yellow catfish Pelteobagrus fulvidraco. Their full-length cDNA sequences ranged from 1587 to 3884 bp, and their ORF length from 1191 to 2979 bp, encoding 396–992 amino acids. Some conservative domains were predicted, including the multiple transmembrane domains in SCAP, the bHLH-ZIP domain in SREBP1 and SREBP2, the ApoB binding region, ER targeting region and LD targeting region in CIDEb, the LD targeting region in the CIDEc, the conserved catalytic site and processing site in S1P, and the transmembrane helix domain in S2P. Their mRNA expression could be observed in the heart, spleen, liver, kidney, brain, muscle, intestine and adipose, but varied with tissues. The changes of their mRNA expression in responses to high-fat (HFD) and bile acid (BA) diets were also investigated in the brain, heart, intestine, kidney and spleen tissues. In the brain, HFD significantly increased the mRNA expression of seven genes (scap, srebp1, srebp2, s1p, s2p, cideb and cidec), and the BA attenuated the increase of scap, srebp1, srebp2, s1p, s2p, cideb and cidec mRNA expression induced by HFD. In the heart, HFD significantly increased the mRNA abundances of six genes (srebp1, srebp2, scap, s2p, cideb and cidec), and BA attenuated the increase of their mRNA abundances induced by HFD. In the intestine, HFD increased the cideb, s1p and s2p mRNA abundances, and BA attenuated the HFD-induced increment of their mRNA abundances. In the kidney, HFD significantly increased the scap, cidec and s1p mRNA expression, and BA diet attenuated the increment of their mRNA expression. In the spleen, HFD treatment increased the scap, srebp2, s1p and s2p mRNA expression, and BA diet attenuated HFD-induced increment of their mRNA expression. Taken together, our study elucidated the characterization, expression profiles and transcriptional response of seven lipid metabolic genes, which would serve as the good basis for the further exploration into their function and regulatory mechanism in fish.

Dietary chenodeoxycholic acid attenuates high-fat diet-induced growth retardation, lipid accumulation and bile acid metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco.

This experiment was conducted to investigate whether dietary chenodeoxycholic acid (CDCA) could attenuate high-fat (HF) diet-induced growth retardation, lipid accumulation and bile acid (BA) metabolism disorder in the liver of yellow catfish Pelteobagrus fulvidraco. Yellow catfish (initial weight: 4·40 (sem 0·08) g) were fed four diets: the control (105·8 g/kg lipid), HF diet (HF group, 159·6 g/kg lipid), the control supplemented with 0·9 g/kg CDCA (CDCA group) and HF diet supplemented with 0·9 g/kg CDCA (HF + CDCA group). CDCA supplemented in the HF diet significantly improved growth performance and feed utilisation of yellow catfish (P < 0·05). CDCA alleviated HF-induced increment of hepatic lipid and cholesterol contents by down-regulating the expressions of lipogenesis-related genes and proteins and up-regulating the expressions of lipololysis-related genes and proteins. Compared with the control group, CDCA group significantly reduced cholesterol level (P < 0·05). CDCA significantly inhibited BA biosynthesis and changed BA profile by activating farnesoid X receptor (P < 0·05). The contents of CDCA, taurochenodeoxycholic acid and glycochenodeoxycholic acid were significantly increased with the supplementation of CDCA (P < 0·05). HF-induced elevation of cholic acid content was significantly attenuated by the supplementation of CDCA (P < 0·05). Supplementation of CDCA in the control and HF groups could improve the liver antioxidant capacity. This study proved that CDCA could improve growth retardation, lipid accumulation and BA metabolism disorder induced by HF diet, which provided new insight into understanding the physiological functions of BA in fish.

Revisited role of the placenta in bile acid homeostasis.

To date, the discussion concerning bile acids (BAs) during gestation is almost exclusively linked to pregnancy complications such as intrahepatic cholestasis of pregnancy (ICP) when maternal serum BA levels reach very high concentrations (>100μM). Generally, the placenta is believed to serve as a protective barrier avoiding exposure of the growing fetus to excessive amounts of maternal BAs that might cause detrimental effects (e.g., intrauterine growth restriction and/or increased vulnerability to metabolic diseases). However, little is known about the precise role of the placenta in BA biosynthesis, transport, and metabolism in healthy pregnancies when serum BAs are at physiological levels (i.e., low maternal and high fetal BA concentrations). It is well known that primary BAs are synthesized from cholesterol in the liver and are later modified to secondary BA species by colonic bacteria. Besides the liver, BA synthesis in extrahepatic sites such as the brain elicits neuroprotective actions through inhibition of apoptosis as well as oxidative and endoplasmic reticulum stress. Even though historically BAs were thought to be only "detergent molecules" required for intestinal absorption of dietary fats, they are nowadays acknowledged as full signaling molecules. They modulate a myriad of signaling pathways with functional consequences on essential processes such as gluconeogenesis -one of the principal energy sources of the fetus- and cellular proliferation. The current manuscript discusses the potential multipotent roles of physiologically circulating BAs on developmental processes during gestation and provides a novel perspective in terms of the importance of the placenta as a previously unknown source of BAs. Since the principle "not too much, not too little" applicable to other signaling molecules may be also true for BAs, the risks associated with fetal exposure to excessive levels of BAs are discussed.

Optimal glycated hemoglobin A1c value for prediabetes and diabetes in patients with pancreatic diseases.

Some articles suggest that using HbA1c alone for diabetes diagnosis is inappropriate. It requires considerable researches to explore the efficacy of HbA1c for diagnosing hyperglycemia in patients with pancreatic disease. This study analyzed 732 patients, comprising of 331 without pancreatic disease and 401 patients diagnosed with pancreatic diseases. All participants underwent the HbA1c assay and oral glucose tolerance test. Kappa coefficients were calculated to assess agreement between the HbA1c and glucose criteria. The receiver operating characteristic curve (ROC) was used to calculate the optimal HbA1c value. DeLong test was analyzed to compared the aera under curves (AUCs). There were 203 (61.3%) patients with NGT, 78 (23.6%) with prediabetes, and 50 (15.1%) with diabetes in patients without pancreatic diseases. In patients with pancreatic disease, 106 participants were diagnosed with NGT (36.4%), 125 with prediabetes (31.2%), and 130 with diabetes (32.4%). Patients with pancreatic disease exhibited elevated levels of bilirubin, transaminase enzymes, aspartate transaminase, high density lipoprotein cholesterol and total bile acid. The sensitivity and specificity of the HbA1c (6.5%) for diagnosing pancreatic diabetes were 60.8% (95% CI 52.3, 69.3) and 92.6% (95% CI 89.5, 95.7). In prediabetes, the sensitivity and specificity of HbA1c (5.7%) is 53.2% (44.3, 62.0) and 59.6 (51.5, 67.6). The optimal HbA1c value for diagnosing diabetes was 6.0% (AUC = 0.876, 95% CI 0.839, 0.906), with the sensitivity of 83.8% and the specificity of 76.8%. The optimal HbA1c value for the diagnosis of prediabetes was 5.8% (AUC = 0.617, 95% CI: 0.556, 0.675), with the corresponding sensitivity and specificity of 48.0% and 72.6% respectively. The combined tests (HbA1c, 6.0% or FPG, 7.0mmol/L) presented the sensitivity of 85.7% (95% CI 79.1, 91.3)and the specificity of 92.6% (95% CI 87.6, 97.3) in pancreatic diabetes. From our results, the recommended HbA1c by ADA criterion may not be sufficiently sensitive to diagnose hyperglycemia in pancreatic disease. The optimal value of 5.8% and 6.0% improved the accuracy for diagnosing prediabetes and diabetes and should be considered to be applied. Besides, we advocate the combination of HbA1c and FPG test for the diagnosis of diabetes in patients with pancreatic diseases.

Extraction and Characterization of β-Glucan from Kombucha Bacterial Cellulose and Concentrated Kombucha: Evaluating their Bile Acid Binding Capacity

β-glucan is a water-soluble polysaccharide present in natural products and has many health benefi ts such as its role as a dietary fi ber. This study aimed to extract and characterize β-glucan in kombucha bacterial cellulose (KBC) powder and concentrated kombucha. The extraction method used was ultrasound sonication combined with enzymatic treatment. The results showed that the content of β-glucan was 19.70% (w/w) in KBC extract and 8.34% (w/v) in concentrated kombucha extract, determined using β-glucan assay kit (Mixed linkage). Fourier-transform infrared (FTIR) spectroscopy analysis confi rmed the presence of β-glucan with β-(1→3) and β-(1→4) glucan linkages, as well as the presence of proteins, mannans, and other components in both KBC β-glucan and concentrated kombucha β-glucan extracts. Regarding bile acid binding potential, concentrated kombucha β-glucan exhibited a high bile acid binding capacity for up to 24 hours, while KBC β-glucan only retained this capacity for up to 4 hours. Altogether, these fi ndings highlight the presence and properties of β-glucan in kombucha, suggesting its potential as a functional ingredient with health benefi ts.

An observational study to assess the Helicobacter pylori infection rates in patients with cholelithiasis

Background: Cholelithiasis and chronic cholecystitis cholelithiasis is fairly common all around the world. Since chronic inflammation causes repeated trauma to the gallbladder mucosa and DNA damage led by high or abnormal bile acid exposure, gallstones are closely related to the development of hepatobiliary cancers. After cholecystectomy, some patients experience ongoing upper abdomen pain, which is distressing for the surgeons and raises the possibility of a concomitant upper gastrointestinal issue, which in most cases turned out to be peptic ulcer disease. Numerous studies have found various Helicobacter species in the gallbladder tissue, gallstones, and bile taken from the gallbladder. We conducted this study to assess the relationship between cholelithiasis and H. pylori infection in the stomach. Ascending infection of H. pylori from the stomach and duodenum to biliary tree may have function in development of gall stone production and hepatobiliary carcinomas. Methods: Hospital based cross sectional observational study on patients admitted in surgical wards of SMS Hospital Jaipur for laparoscopic cholecystectomy. All patients underwent UGI and gastric antral biopsy followed by laparoscopic cholecystectomy, gastric mucosa and GB mucosa were subjected to Warthin starry silver stain for detection of H. pylori. Results: Out of 116 patients who underwent upper GI endoscopy followed by laparoscopic cholecystectomy, 29 (25%) patients were positive for H. pylori infection. Conclusions: This study shows significant positive co-relation between H. pylori infection in stomach, gall bladder to chronic cholecystitis and cholelithiasis, which signifies gastric colonisation of H. pylori has it’s role in biliary pathologies through ascending infection, the effectiveness of H. pylori eradication therapy in preventing these pathologies need to be studied further.

Effect of Insoluble Dietary Fiber Extracted from Feijoa (Acca sellowiana (O. Berg) Burret.) Supplementation on Physicochemical and Functional Properties of Wheat Bread.

This study aimed to assess the effects of insoluble dietary fiber (IDF) from feijoa supplementation on the physicochemical and functional properties of wheat bread. The results showed that feijoa IDF (FJI) had the typical structures of hydrolysis fiber, polysaccharide functional groups, and crystal structure of cellulose. The gradual increase of FJI levels (from 2 to 8%) in wheat bread resulted in increased total DF, ash, and protein contents, accompanied by a reduction in moisture, carbohydrates, and energy value. The inclusion of FJI in the bread crumb caused a rise in both redness (a*) and yellowness (b*) values while decreasing the brightness (L*) relative to the control specimen. In addition, adding FJI up to 2% significantly increased total phenolic and flavonoid contents and antioxidant activity, as well as flavor score of supplemented bread samples, while additions above 2% resulted in undesirable taste and texture. FJI addition caused higher bile acid, NO2-, and cholesterol adsorption capacities. Moreover, FJI addition up to 4% significantly reduced glucose adsorption capacities at different in vitro starch digestion intervals. The findings revealed that FJI offers great potential as an ideal functional ingredient in food processing.

Socio-economic issues in the diagnostic approach and decision to treat of a child with familial cholestasis

Objectives. The diagnostic approach in familial cholestasis cases involves using expensive investigations. The need for complex therapeutic resources is predictable. Material and methods. We present the case of a 3 years 5 months old boy diagnosed with cholestasis and liver cirrhosis, admitted in the Pediatrics Department of “Grigore Alexandrescu” Children’s Hospital for evaluation in order to check the criteria for liver transplantation. Outcomes. The patient is known to our clinic since he was 1 year 3 months; he was admitted at that time for green jaundice. He comes from a family with nine children, low socio-economic status and low education. The first four children have a different father, two of them were stillborn. The next five come from a consanguineous union (the father is maternal uncle of the mother): three (the patient included) presented with the same symptoms, two of them died before 3 years of age with liver cirrhosis. In time, infectious causes, autoimmune, neoplastic and metabolic disease were excluded. The liver biopsy describes cholestasis and fibrosis. Alagille syndrome and progressive familial intrahepatic cholestasis are still debated, but the genetic testing necessary for a positive diagnosis are not financially available to the family. The patient presents with failure to thrive, developmental delay, intense jaundice and pruritus, hippocratic fingers, dyspnea, enlarged abdomen with visible collateral circulation, significant hepatosplenomegaly. The lab tests show anemia, thrombocytopenia, liver cytolysis, normal gamma-glutamyl transferase, low prothrombin activity, normal renal function, no inflammatory syndrome, increased ammonia level, very high bile acids level. The upper endoscopy describes first degree esophageal varices and portal hypertensive gastropathy. A PELD (Pediatric End-Stage Liver Disease) score is calculated – 13.6 (76.3% one year survival rate on the transplant list, 90.9% one year survival rate after liver transplantation). The patient is enrolled on the transplant waiting list provided we would expect suboptimal results considering the developmental delay and difficult post-transplant monitoring. Conclusions. The low education level of the family correlated with a postponed positive diagnosis due to financial reasons and the lack of genetic advice already lead to the demise of four brothers. In this setting, the prognosis of the patient is very likely to be poor.