Bile Acid Concentrations Research Articles

Nigericin modifies the mechanism of the uncoupling action of bile acids in rat liver mitochondria by converting ΔpH into Δψ.

Cholestasis caused by impaired bile secretion in the liver is associated with the accumulation of primary bile acids (BA): cholic acid (CA) and chenodeoxycholic acid (CDCA) in the cells of this organ. The paper studies the uncoupling effect of the CA and CDCA on the succinate-fueled rat liver mitochondria under conditions of ΔpH to Δψ conversion by nigericin. It has been established that without nigericin, the dependence of the resting-state (state 4) respiration rate on the concentrations of these BA is nonlinear and is described by a parabolic equation. Under these conditions, the specific inhibitor of the ADP/ATP-antiporter - carboxyatractylate and the substrate of the aspartate/glutamate-antiporter - glutamate do not affect the state 4 respiration of mitochondria stimulated by these BA. It is suggested that without nigericin, the protonophore action of BA is due to the formation of a dimeric complex of their anion with the acid. In the presence of nigericin, the dependence of state 4 respiration rate on BA concentration is linear. Under these conditions, carboxyatractylate inhibits BA-stimulated respiration. Unlike the CDCA, the uncoupling action of CA is also suppressed by the substrates of the aspartate/glutamate-antiporter. The obtained results are considered as evidence that in the presence of nigericin, uncoupling action of CDCA is carried out primarily with the participation of ADP/ATP-antiporter. Both ADP/ATP-antiporter and aspartate/glutamate-antiporter are involved in the uncoupling action of CA. It is concluded that nigericin modifies the mechanism of the uncoupling action of BA in liver mitochondria by converting ΔpH to Δψ.

Hyperbilirubinemia and transaminitis in hepatitis A: case report on early remission through ayurveda interventions

Hepatitis A is a common cause for acute hepatitis and jaundice. It is mostly self-limiting requires no or suppurative treatment and very rare cases prolong jaundice, liver failure and death. Prolonged jaundice types of cases are mostly going to folk healers and herbalist. Ayurveda has no recordable evidence of course of treatment in Hepatitis A. Therefore, this case paper will be a notable evidence for Ayurveda in hepatitis A. A 43-year female came to hospital with an one week history of lethargy, anorexia, weight loss and yellow discoloration of urine. The patient has Hepatitis A (HAV) IgM antibody positive with other viral profile negative and elevated bilirubin(6.28mg/dl) and high transaminase (SGOT-824U/L and SGPT 1263 U/L). Arogyavardhini Vati, Liv 52Hb and Phalatrikadi Kwatha were administrated in its standard doses as these regimen have Agnideepak(Carminative), Srotosothaka (channel purifier), Mrudu virechana ( Mild purgative)properties, but no signicant change in liver function test . then ( Siddha Makardwaja Rasa) is added to reduce liver inflammation and possible involvement of cholangitis. The physical strength , appetite was normalised along with normalisation of bilirubin and liver transaminase within three weeks of the therapy. The combination of therapy may reduce the bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocyte. As Siddha Makardwaja special is in metallic oxide form (Au/HgO), it may be acts as an anti-inflammatory drug by reducing pro inflammatory cytokine expression, blocking leucocyte adhesion and decreasing oxidative stress due to infection. This case report is preliminary evidence for further stresses the significance of Siddha Makardwaja Rasayana along with other Ayurveda formulations in early remission of high bilirubin and liver transaminase in Hepatitis A infection. This treatment regimen can be used for local epidemic of Hepatitis A for appropriate Ayurveda management after randomised clinical trial.

Depletion of key gut bacteria predicts disrupted bile acid metabolism in inflammatory bowel disease.

The gut microbiome plays a key role in bile acid (BA) metabolism, where a diversity of metabolic products contribute to human health and disease. In particular, Inflammatory Bowel Disease (IBD) is characterized by a low concentration of secondary bile acids (SBAs), whose transformation from primary bile acids (PBAs) is an essential function performed solely by gut bacteria. BA-transformation activity mediated by the bile acid inducible (bai) operon has been functionally characterized in the genus Clostridium, and homologous bai gene sequences have been found in metagenome-assembled genomes (MAGs) belonging to other taxa in the human gut, but it is unclear which species of bai-carrying bacteria perform physiologically significant amounts of bile acid transformation in healthy and sick individuals. Here, we analyzed hundreds of stool samples with paired metagenomic and metabolomic data from IBD patients and controls and found that the abundance of the bai operon in metagenomic samples was highly predictive of that sample's high- or low-SBA metabolic state. We further found that bai genes from the Clostridium species best characterized as BA transformers were more prevalent in IBD patients than in non-IBD controls, while bai genes from uncharacterized taxa known only from MAGs were much more physiologically relevant in non-IBD samples. These un-isolated clades of BA-transforming bacteria merit further research; as beyond their prevalence in the human population, we found some cases in which they engrafted in IBD patients who had undergone fecal microbiota transplantation and experienced a clinical response.IMPORTANCEIn this paper, we identify specific bacteria that perform an important metabolic function in the human gut and demonstrate that in the guts of a large subset of patients with IBD, these bacteria are missing and the function is defective. This is a rare example where the correlation between the absence of specific bacteria and the dysfunction of metabolism is directly observed, not in mice nor in the lab, but in physiologic microbial communities in the human gut. Our results point to a path for studying how a small but important set of bacteria is affected by conditions in the IBD gut and perhaps to the development of interventions to mitigate the loss of these bacteria in IBD.

Bile duct ligation-induced cirrhosis does not alter the blood-brain barrier permeability to sucrose in rats

Contradictory results have been reported about the effects of liver diseases on the blood-brain barrier (BBB) permeability to markers. For instance, both an increase and no change in the BBB permeability to BBB markers sodium fluorescein and Evans blue have been reported in experimental cholestasis induced by bile duct ligation (BDL) in rats. These contradictory effects might be due to inherent limitations of these markers and/or methodological issues. Here, we investigated the time course of the impact of BDL in rats on BBB permeability using a recently developed stable isotope labeled marker [13C]sucrose, which is expected to be devoid of limitations of other markers, such as sodium fluorescein. At various times (five days, two weeks, and four weeks) after BDL or sham surgery, the brain uptake clearance (Kin) of [13C]sucrose was estimated using quantitation of the marker in plasma, blood, and brain by a specific LC-MS/MS analytical method. BDL caused substantial increases in the plasma concentrations of liver biochemical markers (bilirubin, total bile acids, ammonia, and cholesterol) and reduced liver cytochrome P450 content and metabolic activities. However, compared with the sham group, the plasma or blood AUC, brain concentrations, and Kin of [13C]sucrose in BDL animals remained unchanged at all the studied times. Additionally, we observed a negative correlation between the sucrose Kin and plasma total bile acids concentrations in the BDL animals. It is concluded that cholestatic liver disease, induced by BDL surgery in rats, does not significantly affect the BBB permeability to sucrose up to 4 weeks after the surgery.

Evaluation of bile acids and bilirubin in serum and abdominal fluid in dogs with abdominal effusion.

Determine the utility of abdominal fluid bile acids concentration to diagnose biliary tract rupture and the utility of abdominal fluid-to-serum bilirubin ratio as diagnostic tools in dogs. This was a prospective pilot study. Canine serum and abdominal fluid samples were collected and submitted for the determination of bilirubin and bile acids concentrations between 2020 and 2022. Samples were measured at the time of admission from dogs with acute onset of clinical signs and peritoneal fluid. A Mann-Whitney U test and ROC curves were used to compare serum and abdominal fluid bilirubin and bile acids concentration and fluid-to-serum bilirubin and bile acids ratio between patients with biliary tract rupture and non-biliary tract rupture. Ninety-four cases were included, of which seven were diagnosed with biliary tract rupture. Median abdominal fluid bile acids concentration was significantly higher in dogs with biliary tract rupture than non-biliary tract rupture (P-value <0.001). Abdominal fluid bile acids concentration had a sensitivity of 100% and specificity of 99% for the diagnosis of biliary tract rupture. Fluid-to-serum bilirubin ratio was also analysed and no statistically significant difference was seen between groups (P-value 0.925). Although the number of dogs with biliary tract rupture in this study population was small, abdominal fluid bile acids concentration may have a better accuracy than fluid-to-serum bilirubin ratio for the diagnosis of biliary tract rupture. The utility of fluid-to-serum bilirubin ratio for the diagnosis of biliary tract rupture, appears limited. Further studies with a larger number of biliary tract rupture cases are required to support these conclusions.

Novel Lipid Formulation Increases Absorption of Oral Cannabidiol (CBD)

Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice. Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging. Results: Plasma exposure (AUC0–48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0–48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification. Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome.

Comparative study on the effects of high dietary levels of pectin and soybean oil on liver health and bile acid homeostasis in grass carp (Ctenopharyngodon idellus)

Liver disease in farmed grass carp (Ctenopharyngodon idellus) is a major issue with unclear mechanisms. High dietary fiber and fat may contribute. This study employed pectin and soybean oil as dietary fiber and fat sources, respectively, to evaluate their effects on liver disease in grass carp. Three diets (33.0 % crude protein) were made: control (5 % lipid; CON), high pectin (24 % pectin; HPD), high fat (15 % lipid; HFD). Juvenile grass carp (initial weight 24.1 g) were fed for 8 weeks. The HPD diet reduced growth and feed efficiency, whereas the HFD diet enhanced these parameters (P < 0.05). Both HPD and HFD expanded the scope of green in liver and deepened the color of bile. HPD decreased hepatosomatic index and liver lipid content, with atrophy and fibrosis. In contrast, HFD caused hepatocellular hypertrophy and increased lipid deposition. Gallbladder somatic index (GBSI) in both HPD and HFD groups was lower than in the CON group after 6 hours of fasting (P < 0.05). GBSI increased across all groups after 24 hours of fasting (P < 0.05), with the lowest values in the HPD group. In midgut and hindgut digesta, HPD group had higher total bile acid (TBA) content than CON group; HFD group's midgut also had higher TBA content. (P < 0.05). Serum TBA significantly decreased in the HPD group but increased in the liver (P < 0.05). Intestinal transporters asbt and ostα mRNA expression decreased in the HPD group, while asbt expression increased in the HFD group. Liver gene expression of inflammatory markers il-1β and il-8 was upregulated in both HPD and HFD groups (P < 0.05). These findings indicated high level of both pectin and soybean oil induce green liver syndrome and tissue damage, though the mechanisms differ, with HPD primarily causing cholestasis and HFD promoting lipid deposition.

Industrial diet intervention modulates the interplay between gut microbiota and host in semi-stray dogs

BackgroundThe gut microbiota and derived metabolites play a key role in regulating host physiology. Diet is identified as a key regulatory factor of the microbiota composition and, potentially, of subsequent functionalities. Demonstrating the role of diet may be complex as most human studies are cross-sectional and dietary intervention is often accompanied by hygienic changes. The objective of the present study was to investigate the impact of an industrial diet on the modulation of the microbiota and targeted functionalities using a canine “natural” model.ResultsWe carried out a controlled dietary trial in a cohort of Tunisian semi-stray dogs. We made a transition from a natural diet to an industrial kibble diet and monitored the composition of the fecal microbiota, the concentration of short-chain fatty acids (SCFA) and bile acids (BAs), and protease activities. We demonstrated that dietary change significantly decreased fecal primary bile acids levels and protease activities. Interestingly, correlation analyses demonstrated that variation of specific microbial genera were associated with modulated physiological parameters.ConclusionsOur study reveals that an industrial diet induces beneficial changes in microbial composition and functions characterised by increased diversity, synthesis of SCFA and secondary bile acids production, stressing the key role of the diet-microbiota-dog crosstalk.

Integrated Transcriptome and Metabolomics Analysis Reveals That Probiotics and Tea Polyphenols Synergetically Regulate Lipid Metabolism in Laying Hens

Tea polyphenols (TP) and probiotics (PB) have been recognized for their ability to improve lipid metabolism and regulate immune function. However, their specific impact on lipid metabolism in laying hens has not been thoroughly elucidated. Therefore, this study sought to examine the effect of TP and Bacillus subtilis on lipid metabolism in laying hens through transcriptome and metabolome analyses. Two hundred Hy-line Brown layers were randomly allocated into four groups with supplemental dietary TP and PB alone and their combination for 8 weeks. Each treatment had 10 replicates of five birds. Supplementation with a TP and PB combination (TP-PB) increased redness (a*) (p &lt; 0.05) compared to the control basal diet (CT). Dietary TP-PB decreased egg yolk and serum total cholesterol (TC) concentrations (p &lt; 0.05) without affecting the content of total bile acid (TBA). The combined use of TP and PB significantly improved hepatic fatty acid synthetase (FAS) activity (p &lt; 0.05) and reduced liver fat particles. Dietary TP-PB primarily influenced the transcript levels of genes involved in fat metabolic pathways. In particular, TP-PB supplementation reduced lipid storage by activating the Notch signaling pathway. Furthermore, the addition of TP-PB in the diet modulated the abundance of metabolic biomarkers associated with bile secretion and valine, leucine, and isoleucine degradation. An interaction network of mRNAs and metabolites was constructed associated with lipid metabolism, such as deoxycholic acid, TAG (14:3–14:3–20:5), PDK4, and HES4. Overall, these findings emphasized the potential health advantages of the TP and PB combination as a possible functional feed supplement in livestock nutrition.

Low feed intake at weaning reduces intestinal glutathione levels and promotes cysteine oxidation to taurine in pigs.

Weaning stress in pigs is associated with low feed intake and poor nutrient utilization. Cysteine is a sulfur amino acid with key roles in pig production, but how cysteine metabolism and requirements are affected by weaning stress should be better defined. The objective of this study was to determine the collective impact of weaning and feed restriction on tissue cysteine metabolism. Pigs were weaned at 21-d age without access to feed (W; 6.90 ± 0.81kg; n = 9; reflecting acute nutritional stress) or were not weaned and remained with the sow (NW; 6.81 ± 0.65kg; n = 8). At euthanasia (23-d age), blood, bile, and liver, jejunum, and ileum tissues were collected. Plasma, bile, and tissue amino acid and amino thiol concentrations were analyzed by HPLC. Activity of glutamate cysteine ligase (GCL) and glutathione synthetase (GSS), enzymes needed for glutathione (GSH) production, and cysteine dioxygenase 1 (CDO1) were determined with activity assays followed by HPLC analysis of reaction products. Plasma (271 versus 192 ± 19 µmol/L; P < 0.001) and liver (417 versus 298 ± 33 nmol/g; P < 0.05) Cys concentrations were increased in W compared to NW pigs. Despite greater plasma Cys, jejunum and ileum Cys content were not affected by weaning (P > 0.10), whereas γ-glutamylcysteine (γ-GlyCys), the immediate precursor of GSH, declined in both jejunum (14.3 versus 9.7 ± 1.4 nmol/g; P < 0.01) and ileum (11.2 versus 6.4 ± 0.8 nmol/g; P < 0.001) in W pigs. Glutathione content was lower in the jejunum (1379 versus 1720 ± 70 nmol/g; P < 0.05) and ileum (1497 versus 1740 ± 74 nmol/g; P < 0.05) in W pigs. In the jejunum, GCL activity tended to be greater (0.56 versus 0.39 ± 0.07 nmol γ-GluCys • mg-1 • min-1; P < 0.10), whereas GSS activity tended to be lower (1.11 versus 1.38 ± 0.10 nmol GSH • mg-1 • min-1; P < 0.10) in W compared to NW pigs. In the ileum, the activities of GCL and GSS were not affected by weaning (P > 0.10). Although liver CDO1 activity was not different between groups (P < 0.10), liver taurine was greater in W compared to NW pigs (5115 versus 2336 ± 912 nmol/g; P = 0.001). Bile concentrations of Cys (1203 versus 279 ± 103 µmol/L; P < 0.001) and cysteinylglycine (203 versus 117 ± 33 µmol/L; P < 0.10), the direct product of GSH degradation, were greater in W compared to NW pigs. Collectively, these results suggest that systemic Cys is not effectively utilized for gut GSH production in newly weaned pigs and is instead oxidized to taurine and eliminated in bile.

Lactobacillus johnsonii CCFM1376 improves hypercholesterolemia in mice by regulating the composition of bile acids

Aim: Strains with high bile salt hydrolase (BSH) activity have the potential to regulate cholesterol metabolism. This study aimed to assess the alleviating effect of Lactobacillus johnsonii (L. johnsonii ) CCFM1376, a strain with high BSH activity, on mice with hypercholesterolemia and explore the mechanism of its effect through the modulation of bile acid metabolism. Methods: The BSH activity was measured using the ninhydrin method. C57BL/6J mice were given a high-cholesterol diet to induce hypercholesterolemia with simultaneous gavage of L. johnsonii CCFM1376 for 8 weeks. The biochemical parameters in the serum and liver of hypercholesterolemic mice were measured to assess the alleviating effect of L. johnsonii CCFM1376 on hypercholesterolemia. Bile acid content in the mouse liver, serum, distal ileum contents, and feces was determined using liquid chromatograph mass spectrometer (LC-MS). RNA was extracted from mouse ileum and liver, and the expression levels of relative genes implicated in bile acid metabolism were measured by quantitative real-time PCR (qPCR). Results: Compared to the model group, the group treated with L. johnsonii CCFM1376 exhibited significantly reduced levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), along with a significant increase in high density lipoproteins cholesterol (HDL-C) level. Moreover, hepatic levels of TC and LDL-C in the CCFM1376 group also decreased significantly. Furthermore, the content and amount of unconjugated bile acids in the hepatic-enteric circulation of the L. johnsonii CCFM1376 group significantly increased, and the total bile acid content in the feces also significantly increased. In the L. johnsonii CCFM1376 group, the relative expression levels of ileal farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were downregulated, while the relative expression level of CYP7A1 was upregulated. Conclusion: These results indicated L. johnsonii CCFM1376 improves hypercholesterolemia in mice by regulating the composition of bile acids. This provides a reference for probiotic strategy to regulate cholesterol metabolism.

Immunomodulatory metabolites in IgE-mediated food allergy and oral immunotherapy outcomes based on metabolomic profiling.

The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multiethnic cohorts and responses to OIT. Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N = 384), a Costa Rican cohort of children with asthma (N = 1040), and a peanut OIT trial (N = 20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterward). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q = 2.4 × 10-20) and linoleic acid derivatives (q = 3.8 × 10-5) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q = 4.1 × 10-8), eicosanoids (q = 7.9 × 10-7), and histidine pathways (q = .015). In particular, the bile acid lithocholate (4.97 [1.93, 16.14], p = .0027), the eicosanoid leukotriene B4 (3.21 [1.38, 8.38], p = .01), and the histidine metabolite urocanic acid (22.13 [3.98, 194.67], p = .0015) were higher in SU. We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy.

Apple Polyphenol Extracts Attenuated Depressive-Like Behaviors of High-Sucrose Diet Feeding Mice by Farnesoid X Receptor-Mediated Modulation of Bile Acid Circulation within the Liver-Gut-Brain Axis.

Although the association between high-sugar diets and depression has been verified, few studies have explored the antidepressant mechanisms of apple polyphenol extracts (APE). Therefore, fifty-four C57BL/6 male mice aged 5 weeks were randomly assigned into five groups: the control group with the standard diet (CON), the constant high-sucrose diet group (HSD), the "2 + 5" alternate diet group (A-HSD), and the 500 mg/(kg·bw) APE treatment for the HSD group (APE) and the A-HSD group (A-APE), respectively. The data of hypothalamic-pituitary-adrenal (HPA) axis function and behavioral experiments confirmed the success in the establishment of depression-like mouse models in both HSD and A-HSD groups, which were significantly alleviated after APE treatment. Meanwhile, APE reduced serum levels of corticosterone and adrenocorticotrophic hormone, alleviated histopathological damage of the liver, colon, and brain, respectively, elevated the protein expressions of Occludin, ZO-1, and MUC-2, and decreased Firmicutes/Bacteroidota ratio and Dubosiella abundance with the increased microbiota of Tannerellaceae_unclassified, Muribaculum, and Lachnospiraceae_unclassified. Moreover, APE treatment reduced Farnesoid X receptor (FXR) protein levels along with the increased expressions of CYP7A1 and TGR5, lowered the contents of serum and fecal total bile acids, and modulated fecal BA compositions, particularly glycocholic acid (GCA) and isolithocholic acid (ILCA). Thus, both the constant and alternate high-sucrose diets successfully induced depression-like behaviors in mice, and APE might be a potential nutraceutical to attenuate high-sucrose diet-induced depression by regulating BAs circulation within the liver-gut-brain axis mediated by FXR.

Novel Expression of Apical Bile Acid Transport (ASBT) More Proximally Than Distal Ileum Contributing to Enhanced Intestinal Bile Acid Absorption in Obesity.

Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1-S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and 3H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1-S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity.

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.

Metformin: Diverse molecular mechanisms, gastrointestinal effects and overcoming intolerance in type 2 Diabetes Mellitus: A review.

Metformin, the first line treatment for patients with type 2 diabetes mellitus, has alternative novel roles, including cancer and diabetes prevention. This narrative review aims to explore its diverse mechanisms, effects and intolerance, using sources obtained by searching Scopus, PubMed and Web of Science databases, and following Scale for the Assessment of Narrative Review Articles reporting guidelines. Metformin exerts it actions through duration influenced, and organ specific, diverse mechanisms. Its use is associated with inhibition of hepatic gluconeogenesis targeted by mitochondria and lysosomes, reduction of cholesterol levels involving brown adipose tissue, weight reduction influenced by growth differentiation factor 15 and novel commensal bacteria, in addition to counteraction of meta-inflammation alongside immuno-modulation. Interactions with the gastrointestinal tract include alteration of gut microbiota, enhancement of glucose uptake and glucagon like peptide 1 and reduction of bile acid absorption. Though beneficial, they may be linked to intolerance. Metformin related gastrointestinal adverse effects are associated with dose escalation, immediate release formulations, gut microbiota alteration, epigenetic predisposition, inhibition of organic cation transporters in addition to interactions with serotonin, histamine and the enterohepatic circulation. Potentially effective measures to overcome intolerance encompasses carefully objective targeted dose escalation, prescription of fixed dose combination, microbiome modulators and prebiotics, in addition to use of extended release formulations.

Ferulic Acid Alleviates Lipid and Bile Acid Metabolism Disorders by Targeting FASN and CYP7A1 in Iron Overload-Treated Mice.

Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid β-oxidation and bile acid export, as indicated by increased mRNA expression of PPARα, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.

Yeast β-glucan supplementation lowers insulin resistance without altering microbiota composition compared with placebo in subjects with type II diabetes: a phase I exploratory study.

The increased global prevalence of type II diabetes mellitus (T2DM) is associated with consumption of low fibre 'Western diets'. Characteristic metabolic parameters of these individuals include insulin resistance, high fasting and postprandial glucose, as well as low-grade systemic inflammation. Gut microbiota composition is altered significantly in these cohorts suggesting a causative link between diet, microbiota and disease. Dietary fibre consumption has been shown to alleviate these changes and improve glucose parameters in individuals with metabolic disease. We previously reported that yeast β-glucan (yeast beta-1,3/1,6-D-glucan; Wellmune) supplementation ameliorated hyperinsulinaemia and insulin resistance in a murine model. Here, we conducted a randomised, placebo-controlled, two-armed dietary fibre phase I exploratory intervention study in patients with T2DM. The primary outcome measure was alteration to microbiota composition, while the secondary outcome measures included markers of glycaemic control, inflammation as well as metabolomics. Patients were supplemented with 2·5g/day of maltodextrin (placebo) or yeast β-1,3/1,6-D-glucan (treatment). Yeast β-glucan (Wellmune) lowered insulin resistance compared with the placebo maltodextrin after 8 weeks of consumption. TNFα was significantly lower after 4 weeks of β-glucan supplementation. Significantly higher fecal concentrations of several bile acids were detected in the treatment group when compared with the placebo after 8 weeks. These included tauroursodeoxycholic acid, which was previously shown to improve glucose control and lower insulin resistance. Interestingly, the hypoglycaemic and anti-inflammatory effect of yeast β-glucan was independent of any changes in fecal microbiota composition or short-chain fatty acid levels. Our findings highlight the potential of yeast β-glucan to lower insulin resistance in patients with T2DM.

Fecal Bile Acids in Canine Chronic Liver Disease: Results from 46 Dogs.

The concentrations of fecal and serum bile acids (BAs) are known to be altered in human patients with chronic liver diseases (CLDs), especially those with biliary tract involvement (BTD). Scarce literature is available regarding fecal BA modifications during canine CLDs. This study aimed to evaluate fecal BAs in canine CLDs according to different clinical and clinicopathological variables. Forty-six dogs were enrolled. Canine feces were analyzed by HPLC. Cholic Acid (CA), Chenodeoxycholic Acid (CDCA), Ursodeoxycholic Acid (UDCA), Deoxycholic Acid (DCA), and Lithocholic Acid (LCA) were measured, and primary BAs (CA + CDCA), secondary BAs (UDCA + DCA + LCA), and the primary/secondary (P/S) ratio were calculated. Primary BAs (p < 0.0001), CA (p = 0.0003), CDCA (p = 0.003), the P/S ratio (p = 0.002), and total BAs (p = 0.005) were significatively higher in BTD dogs (n = 18) compared to in non-BTD dogs (n = 28). Fecal secondary BAs did not statistically differ between BTD and non-BTD dogs. Gastrointestinal clinical signs (p = 0.028) and diarrhea (p = 0.03) were significantly more prevalent in BTD dogs compared to in non-BTD dogs, supporting the hypothesis of some pathological mechanisms assimilable to bile acid diarrhea (BAD). Our results could reflect imbalances of the fecal BA metabolism in dogs with CLDs. Further studies involving gut microbiome and metabolomic assessment are needed to better understand the possible clinical implications of BA metabolism disruption and their potential role in canine CLDs.

Extraction Method Effects on Structural Properties and Functional Characteristics of Dietary Fiber Extracted from Ginseng Residue.

In this research, the dietary fibers (DFs) from ginseng residue were extracted by employing three different extraction methods (alkaline: AL, acidic: AC, enzymatic: EN). The extracted DFs were characterized in terms of their structural and functional properties. The results clearly showed that, regardless of the extraction methods, all DF samples exhibited representative infrared spectral features. The DF extracted by AC (citric acid) had more porous structures with a looser configuration, in conjunction with high apparent viscosity, whereas the DF extracted by EN (α-amylase and protease) exhibited higher thermal stability. Moreover, the monosaccharide composition of the DF samples was significantly influenced by the extraction method type. The DF from ginseng residue extracted by AC had the highest functional properties, such as water holding capacity (8.16 g/g), oil holding capacity (3.99 g/g), water swelling capacity (8.13 g/g), cholesterol-absorption capacity (12.85 mg/g), bile acid absorption capacity (91.51 mg/g), nitrite ion absorption capacity (124.38 ug/g at pH 2.0), glucose absorption capacity (52.67 mg/g at 150 mmol/L), as compared to those of DF extracted by the EN and AL (sodium hydroxide) methods. Hence, ginseng residue-derived DF extracted by the AC method may be potentially employed in the preparation of functional food ingredients.