Chenodeoxycholic Acid Research Articles

Impact of lumacaftor/ivacaftor on nutrition and growth in modulator-naïve children over 24 weeks

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulators improve nutritional status and are of importance in achieving normal growth among younger children with CF. The study was designed to examine CFTR modulator-associated changes in nutrition status, including bile acids and fatty acids after lumacaftor/ivacaftor therapy for 24 weeks. MethodsChildren 2 to 5.9 years were recruited from US and Canadian CF Centers. Eligible children were lumacaftor/ivacaftor naïve and approved to initiate therapy. Anthropometrics, diet, energy expenditure, nutrition biomarkers, pancreatic status, serum and fecal calprotectin, serum bile acids and plasma fatty acids were measured. Changes from baseline at 12 and 24 weeks were examined using mixed effects linear regression modeling. ResultsWeight-for-age z-score (WAZ) increased at 12 (0.15 ± 0.1, p = 0.01) and 24 weeks (0.23 ± 0.1, p = 0.001) from baseline following modulator therapy. Head circumference-for-age (HCZ) increased at 12 weeks compared to baseline (0.22 ± 0.1, p = 0.03) and subscapular Z score increased from baseline at 24 weeks following therapy (0.33 ± 0.1, p = 0.02). There were no changes in energy expenditure. Serum total bile acids (6.7 ± 2.0, p = 0.001), chenodeoxycholic acid (CDCA) (2.4 ± 1.1, p = 0.001), and cholic acid (CA) (3.5 ± 0.8, p < 0.0001) increased at 24 weeks compared to baseline. Fecal calprotectin decreased at 12 and 24 weeks compared to baseline (-463 ± 310, p = 0.03 and 566 ± 347, p = 0.047). A number of plasma fatty acids changed over the course of 24 weeks of therapy. Noteably, alpha-linolenic acid (ALA) decreased at 12 and 24 weeks (-24 ± 10,p = 0.03 and -18 ± 10, p = 0.02, respectively). ConclusionsOverall, young children experienced favorable changes in nutritional and growth, with the exception of plasma ALA status in the first 24 weeks of lumacaftor/ivacaftor therapy.

Prebiotic Fucoidan Potentially Improves Gut Microbiota and Metabolism in Long-Cared Elderly People with Malnutrition

The gut-microbiota-targeted prebiotic intervention has been a hot topic in the study of health modulation. To examine the effect of fucoidan supplementation on the health of long-cared elderly subjects (88years ± 3.41) with malnutrition (MNA-SF score ≤ 7), an eight-week randomized, single-blind clinical trial was carried out in a community hospital. The subjects were divided into a test group (TG, n = 45), which received the fucoidan supplementation (1g/d) and a control group (CG, n = 20). Preliminary data on metagenomes, plasma metabolomes, prealbumin, twelve cytokines, and clinical records from six people were analyzed. The results showed that with prebiotic intervention, prealbumin, a sensitive nutrition marker slightly increased. Furthermore, in the test group, there were 42 significantly enriched gut microbial species (t-test, p &lt; 0.05), including multiple beneficial bacteria (Bifidobacterium breve, Roseburia hominis, and Lactobacillus acidipiscis), which positively correlated with Medium-Chain Fatty Acid (MCFA)-associated carnitines (octanoylcarnitine and decanoylcarnitine), and chenodeoxycholic acid. The defecation and neuropsychological activities of the participants in the test group also improved slightly. The preliminary data suggests that fucoidan has the potential to improve metabolism, gut function, and nutrition in elderly people by changing the gut microbiota and enriching beneficial bacteria. A larger sample size analysis is needed for a deeper understanding of the effects and mechanism.

Stereochemistry and dose of bile acids (BA) influence probiotic growth and barrier function in human colon T84 cells

BA-associated diarrhea (BAD) occurs in ~1% of the population, where high [BA] alter the gut microbiota and epithelial barrier function. Probiotics are used to help restore the microbiome and alleviate diarrheal symptoms in these patients. Using T84 cells, we showed that the primary BA, chenodeoxycholic acid (CDCA; 500μM) increased apoptosis, oxidative stress (ROS) and proinflammatory cytokine IL-8 to disrupt tight junctions while its secondary BA, lithocholic acid (LCA), did not. We also showed that probiotics reversed the effects of CDCA in T84 cells (Physiol. 2023, 38, S1). In this study, we examined the dose-dependent effects of di-hydroxy (OH) BAs, CDCA, its 7-OH epimer ursodeoxycholic acid (UDCA) and its mono-OH BA, LCA, on microbial and epithelial cell function. We hypothesize that the differences in the -OH position (3, 7, or 12) and stereochemistry (α or β) will result in varied dose-dependent effects of these BAs. Probiotic strains in Up &amp; Up supplement (30 billion CFUs of 10 strains) were grown in T84 cell culture media ± BA (50 - 500μM) in anaerobic conditions (37°C, 48h). The effect of BAs (50-500μM, 0–18h) on barrier function was studied in confluent T84 cells (TransEpithelial Resistance, TER &gt;1000 Ω.cm2) as follows: i) apoptosis (Annexin-V, flow cytometry); ii. mitochondrial and nuclear ROS production (CellRox, flow cytometry) and iii) paracellular permeability (TER and FITC-10kD dextran fluxes (F10D)). The predominant bacterial species (Control media, CFU x 108: 7.5 ± 1) was Lactobacillus fermentum (L f) (16S rRNA sequencing). CDCA caused a dose-dependent (μM) reduction in growth rate (50: 0.6±0.2; 250: 0.06±0.04; 500: 0.05±0.01; p&lt;0.01, n=3) and changed the predominant species to L. plantarum (L p). UDCA and LCA (50-500μM) alone had no effect but reversed the actions of CDCA on bacterial growth (only 50 LCA/UDCA ± 500 CDCA are shown; CFU x 108: LCA: 7±1; CDCA+LCA: 6.7±0.8; UDCA: 6.2±0.5; UDCA + CDCA: 6.5±1, n=3) and changed the predominant species to L f. In T84 cells, apical exposure of CDCA caused a dose-dependent increase in apoptosis while UDCA or LCA at any dose had no effect (% Annexin V+ cells, 18 H: DMSO: 10±1; CDCA 50: 14±2; CDCA 250: 20±2; CDCA 500: 25±2; UDCA 500: 13±4; LCA 500: 9±2; n=3). CDCA increased ROS starting at 50μM (% CellRox+ cells: DMSO: 12±0.5; CDCA 50: 25±0.1; CDCA 250: 30±0.1; CDCA 500: 36±2). UDCA and LCA (50-500μM) had no effect. Time- and dose-dependent studies show that CDCA decreased TER (% decrease: CDCA 50: 50±5, CDCA 250: 63±7; CDCA 500: 71±8) and increased F10D fluxes (apparent permeability (x 10−9) cm/sec: Control: 8±1; CDCA 50: 35±5; CDCA 250: 78±10; CDCA 500: 90±20). In contrast, UDCA and LCA alone (50-500μM) had no effect on paracellular permeability but restored CDCA-induced barrier dysfunction (apparent permeability (x 10−9) cm/sec: Control: 8±1; CDCA 50: 35±5; CDCA 250: 78±10; CDCA 500: 90±20; UDCA 500: 13±2; CDCA 500+UDCA: 41±12; LCA 500: 15±2; CDCA 500+LCA: 38±2, n&gt;3). Comparing the effects of hydrophobic CDCA with that of its hydrophilic 7-b isomer, UDCA, highlighted the importance of stereochemistry of -OH groups in BA action. CDCA’s deleterious effects on microbiota and epithelia started as low as 50μM, while UDCA, like LCA, restores the microbiota and barrier function. Understanding and targeting the interplay of BA, microbiota and epithelia may open up new therapeutic avenues for the treatment of diarrheal diseases. Supported by Funds from UGSRF, APS to ZF, NSSRP Funds, BenU to ER, AL, MN, MP and JS, UIC Funds to MR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Secondary Bile acid, Lithocholic Acid, Inhibits Cl− Secretion Across Colonic Epithelial Cells in Vitro

Lithocholic acid (LCA) is a secondary bile acid formed in the colon by bacterial metabolism of chenodeoxycholic acid. Our previous studies have shown the bile acid to be protective under conditions of colonic inflammation. Here, we sought to determine if LCA might also play a role in regulating fluid and electrolyte transport. T84 cell monolayers were mounted in Ussing chambers for measurements of Cl− secretion, the primary driving force for fluid secretion into the colon. qRT-PCR and Western blotting were used to analyze mRNA and protein expression. Results were expressed as mean ± SEM and data were analyzed by one way ANOVA and Tukey’s post hoc test or by mixed-effects analysis and Dunnett's post hoc test. To assess the effects of LCA on CFTR promoter activity, we used a luciferase promoter/reporter system, where HEK293 cells were transfected with a plasmid containing the firefly luciferase gene under control of the CFTR promoter. Co-transfections were carried out with 2 additional plasmids expressing either the nuclear bile acid receptor, FXR, or its dimerization partner, RXR. Pretreatment of T84 cell monolayers with LCA inhibited subsequent Cl− secretory responses to the cAMP-dependent agonist, forskolin (FSK; 10 μM), in a concentration (1 – 10 μM) and time-dependent (3 - 24 hrs) manner. Maximal effects of LCA were observed at a concentration of 10 μM after treatment for 24 hrs, when responses to FSK were reduced to 50.9 ± 8.5% of those in controls (n = 6; p &lt; 0.01). LCA (10 μM; 24 hrs) also inhibited responses to the Ca2+-dependent secretagogues, thapsigargin (2 μM) and histamine (100 μM), by 59.4 ± 2.4% (n = 4; p &lt; 0.001) and 52.2 ± 1.9% (n = 5; p &lt; 0.001), respectively. In further experiments, using nystatin-permeabilized T84 monolayers to isolate apical Cl− conductances, LCA (10 μM; 24 hrs) reduced FSK-stimulated responses to 72.7 ± 6.6% (n = 17; p &lt; 0.001) of those in control cells. Analysis of CFTR expression, the primary exit pathway for Cl− in colonic epithelial cells, revealed that LCA treatment reduced mRNA and protein expression of the channel to 0.65 ± 0.05 fold (n = 7; p &lt; 0.01) and 0.43 ± 0.06 fold (n = 6; p &lt; 0.001), respectively. In CFTR promoter assays, LCA (10 μM) reduced CFTR promoter activity to 0.7 ± 0.02 fold of that in control cells (n = 5; p &lt; 0.01), with co-expression of FXR being required for this effect to be observed. Finally, while LCA activated both FXR and the vitamin D receptor (VDR) in T84 cells, its effects in downregulating CFTR expression and Cl− conductances were mimicked by the FXR agonist, GW4064, but not by the VDR agonist, calcitriol. In conclusion, LCA, at physiologically relevant concentrations, inhibits Cl− secretion across colonic epithelial cells, likely through a mechanism involving FXR activation and inhibition of CFTR expression. These data add to the growing pool of knowledge regarding important regulatory actions of LCA in the colon and highlight its potential role as a target for the treatment of intestinal disorders. This work was supported by a grant from Science Foundation Ireland. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ferrocene Appended D-π-A chromophores for Dye-Sensitized Solar Cells: Synthesis, Photophysical, Effect of Co-adsorbent on Photovoltaic Efficiencies and DFT studies

A new ferrocene conjugated donor–π–acceptor type of dyes 1 and 2 were synthesized and characterized using different spectroscopic techniques (FT-IR, NMR, and ESI-mass). The intramolecular charge transfer process of both the dyes were analysed using the solvatochromic method, which reveals positive solvatochromism due to its well stabilization in the excited states than in the ground states. The electrochemical behavior of the dyes 1 and 2 were carried out by the cyclic voltammetric technique, which shows quasi-reversible in nature, and the potentials were further utilized for the band gap calculation with UV–visible data [2.99 eV (1) and 2.88 eV (2)]. The photovoltaic attainments of the dyes 1 and 2 were studied through the dye-sensitized solar cells (DSSCs) in the presence and absence of co-adsorbent like chenodeoxycholic acid (CDCA), which act as an anti-dye aggregation material. The photovoltaic parameters like short circuit current density (Jsc) = 0.067 mA cm2, open circuit voltage (Voc) = 0.444 V, fill factor (FF) = 0.447, and the cell displayed an overall conversion efficiency of 0.013 % for dye 2. In contrast, the power conversion efficiency (PCE) was found to be enhanced to 0.177 % (Jsc = 0.389 mA/cm2, Voc = 0.577 V, FF =0.790), in the presence of chenodeoxycholic acid (CDCA) co-adsorbent. This enhancement in efficiency is due to reduced dye aggregation and increased electron injection in the presence of CDCA. In addition, chromophore 2 has 1.4 times higher efficiencies than 1, attributing to the presence of an additional phenyl group making an efficient intramolecular process of 2. Furthermore, the incident photon to current efficiency (IPCE) and electrochemical impedance spectroscopy (EIS) studies reveal the dye efficiencies were directly proportional to that of the power conversion efficiency (PCE), respectively. Moreover, the electronic structure and electron density distribution analysis were analysed for both dyes 1 and 2 to confirm the intramolecular charge transfer properties using density-functional theory (DFT) and time-dependent density-functional theory (TD-DFT) calculations using the B3LYP/ 6–31+G** level of theory.

Microbial Community and Metabolome Analysis of the Porcine Intestinal Damage Model Induced by the IPEC-J2 Cell Culture-Adapted Porcine Deltacoronavirus (PDCoV) Infection.

This study was conducted to elucidate the intestinal damage induced by the IPEC-J2 cell culture-passaged PDCoV. The results showed that PDCoV disrupted the intestinal structure and increased intestinal permeability, causing abnormalities in mucosal pathology. Additionally, PDCoV induced an imbalance in the intestinal flora and disturbed its stability. Microbial community profiling revealed bacterial enrichment (e.g., Proteobacteria) and reduction (e.g., Firmicutes and Bacteroidetes) in the PDCoV-inoculated piglet model. In addition, metabolomics analysis indicated that 82 named differential metabolites were successfully quantified, including 37 up-regulated and 45 down-regulated metabolites. Chenodeoxycholic acid, sphingosine, and oleanolic aldehyde levels were reduced in PDCoV-inoculated piglets, while phenylacetylglycine and geranylgeranyl-PP levels were elevated. Correlation analysis indicated a negative correlation between Escherichia-Shigella and choline, succinic acid, creatine, phenyllactate, and hippuric acid. Meanwhile, Escherichia-Shigella was positively correlated with acetylcholine, L-Glutamicacid, and N-Acetylmuramate. Roseburia, Lachnospiraceae_UCG-010, Blautia, and Limosilactobacillus were negatively and positively correlated with sphingosine, respectively. These data suggested PDCoV-inoculated piglets exhibited significant taxonomic perturbations in the gut microbiome, which may result in a significantly altered metabolomic profile.

Characteristics and diagnostic value of serum bile acids profile in pregnant women with intrahepatic cholestasis of pregnancy and asymptomatic hypercholanemia of pregnancy

Objective: To analyze serum bile acid profiles in pregnant women with normal pregnancy, intrahepatic cholestasis of pregnancy (ICP) and asymptomatic hypercholanemia of pregnancy (AHP), and to evaluate the application value of serum bile acid profiles in the diagnosis of ICP and AHP. Methods: The clinical data of 122 pregnant women who underwent prenatal examination in Xuzhou Maternal and Child Health Care Hospital from June 2022 to May 2023 were collected, including 54 cases of normal pregnancy group, 28 cases of ICP group and 40 cases of AHP group. Ultraperformance liquid chromatography-tandem mass spectrometry was used to measure the levels of 15 serum bile acids in each group, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), glycolcholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA) and tauroursodeoxycholic acid (TUDCA). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to screen differential bile acids. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of differential bile acids and combined indicators between groups. Results: (1) Compared with normal pregnancy group, the serum levels of LCA, GCA, GCDCA, GDCA, GLCA, UDCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in ICP group were significantly different (all P<0.05), while the levels of LCA, DCA, GCA, GCDCA, GDCA, GLCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). Compared with ICP group, the serum levels of CDCA, DCA, UDCA, TDCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). (2) In the OPLS-DA model, the differential bile acids between ICP group and AHP group were TUDCA, TCA, UDCA, GUDCA and GCA, and their variable importance in projection (VIP) were 1.489, 1.345, 1.344, 1.184 and 1.111, respectively. TCA, GCDCA, GCA, TDCA, GDCA and TCDCA were the differentially expressed bile acids between AHP group and normal pregnancy group, and their VIP values were 1.236, 1.229, 1.197, 1.145, 1.139 and 1.138, respectively. (3) ROC analysis showed that the area under the curve (AUC) of TUDCA, TCA, UDCA, GUDCA and GCA in the differential diagnosis of ICP and AHP was 0.860, and the sensitivity and specificity were 67.9% and 95.0%, respectively. The AUC of TCA, GCDCA, GCA, TDCA, GDCA and TCDCA in the diagnosis of AHP was 0.964, and the sensitivity and specificity were 95.0% and 93.1%, respectively. Conclusions: There are differences in serum bile acid profiles among normal pregnant women, ICP and AHP. The serum bile acid profiles of pregnant women have potential application value in the differential diagnosis of ICP and AHP and the diagnosis of AHP.

Hypoglycemic Activity of Rice Resistant-Starch Metabolites: A Mechanistic Network Pharmacology and In Vitro Approach.

Rice (Oryza sativa L.) is one of the primary sources of energy and nutrients needed by the body, and rice resistant starch (RRS) has been found to have hypoglycemic effects. However, its biological activity and specific mechanisms still need to be further elucidated. In the present study, 52 RRS differential metabolites were obtained from mouse liver, rat serum, canine feces, and human urine, and 246 potential targets were identified through a literature review and database analysis. A total of 151 common targets were identified by intersecting them with the targets of type 2 diabetes mellitus (T2DM). After network pharmacology analysis, 11 core metabolites were identified, including linolenic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, lithocholic acid, lithocholylglycine, glycoursodeoxycholic acid, phenylalanine, norepinephrine, cholic acid, and L-glutamic acid, and 16 core targets were identified, including MAPK3, MAPK1, EGFR, ESR1, PRKCA, FYN, LCK, DLG4, ITGB1, IL6, PTPN11, RARA, NR3C1, PTPN6, PPARA, and ITGAV. The core pathways included the neuroactive ligand-receptor interaction, cancer, and arachidonic acid metabolism pathways. The molecular docking results showed that bile acids such as glycoursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, deoxycholic acid, and cholic acid exhibited strong docking effects with EGFR, ITGAV, ITGB1, MAPK3, NR3C1, α-glucosidase, and α-amylase. In vitro hypoglycemic experiments further suggested that bile acids showed significant inhibitory effects on α-glucosidase and α-amylase, with CDCA and UDCA having the most prominent inhibitory effect. In summary, this study reveals a possible hypoglycemic pathway of RRS metabolites and provides new research perspectives to further explore the therapeutic mechanism of bile acids in T2DM.

Obeticholic Acid and Insulin Sensitivity in Overweight Patients with Prediabetes

BACKGROUND. Due to its role as a risk factor for the emergence of metabolic illnesses including type 2 diabetes, cardio-vascular disease, and certain cancers with pandemic evolution, obesity is a serious public health concern. Diabetes mellitus type 2 (T2DM) poses a major risk to human health. The byproducts of the breakdown of cholesterol are bile acids, which are crucial for preserving cholesterol homeostasis. Research indicates that bile acids might control insulin sensitivity, energy metabolism, and glucose tolerance. Farnesoid X receptors (FXRs) are crucial for controlling bile acid production and hepatic glucose metabolism. The ligand for FXR The semisynthetic derivative of chenodeoxycholic acid, a bile acid, is obeticholic acid (OCA). Research indicates that bile acids may be a viable therapeutic target for type 2 diabetes (T2DM) given that therapy with oleic acid (OCA) enhanced insulin sensitivity and decreased indicators of liver inflammation and fibrosis in individuals with T2DM and nonalcoholic steatohepatitis (NASH).AIM. To assess Obeticholic acid’s effectiveness in obese individuals with prediabetes.MATERIALS AND METHODS. Over the course of three months, we performed a randomized single blind placebo controlled trial on eighty-two overweight and obese patients with prediabetes in the outpatient clinic at Ain Shams University Hospital. Through block randomization, patients were split into two groups (Group A received daily oral tablets containing 5 mg of obeticholic acid, while Group B received non-sweet capsules as a placebo). Three follow-up visits were conducted to ensure adherence and monitor for any emergence of side effects.RESULTS. 82 patients of matched age and sex criteria who underwent block randomization into 2 equal groups, group (A) representing cases and group (B) the placebo controlled group, with 3 months’ regular follow up showed at end of treatment statistically significant difference in weight being lower in group (A) with p-value 0.004 with decreased parameters of glycemic profile (Fasting insulin, FPG, HOMA_IR, 2h PP, HbA1c) in group (A) with p-value &lt;0.001 except 2hpp which p-value is 0.006. Also ALT was much decreased in group(A) with p-value &lt;0.001. Lipid profile didn’t show significant difference between 2 groups except for TGs which deceased in follow up in group (A) with p-value &lt;0. 001. Additionally, it should be highlighted that there was no statistically significant difference between the control group’s baseline and post-treatment data.CONCLUSION. In individuals who are overweight or obese and have insulin resistance and prediabetes, activation of FXR by OCA results in enhanced insulin sensitivity. Patients who received OCA also lost weight.

Ursodeoxycholic and chenodeoxycholic bile acids attenuate systemic and liver inflammation induced by lipopolysaccharide in rats.

Bacterial lipopolysaccharide (LPS) induces general inflammation, by activating pathways involving cytokine production, blood coagulation, complement system activation, and acute phase protein release. The key cellular players are leukocytes and endothelial cells, that lead to tissue injury and organ failure. The aim of this study was to explore the anti-inflammatory, antioxidant, and cytoprotective properties of two bile acids, ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in LPS-induced endotoxemia in rats. The experiment involved six distinct groups of Wistar rats, each subjected to different pretreatment conditions: control and LPS groups were pretreated with propylene glycol, as a bile acid solvent, while the other groups were pretreated with UDCA or CDCA for 10 days followed by an LPS injection on day 10. The results showed that both UDCA and CDCA reduced the production of pro-inflammatory cytokines: TNF-α, GM-CSF, IL-2, IFNγ, IL-6, and IL-1β and expression of nuclear factor-κB (NF-κB) induced by LPS. In addition, pretreatment with these bile acids showed a positive impact on lipid profiles, a decrease in ICAM levels, an increase in antioxidant activity (SOD, |CAT, GSH), and a decrease in prooxidant markers (H2O2 and O2-). Furthermore, both bile acids alleviated LPS-induced liver injury. While UDCA and CDCA pretreatment attenuated homocysteine levels in LPS-treated rats, only UDCA pretreatment showed reductions in other serum biochemical markers, including creatine kinase, lactate dehydrogenase, and high-sensitivity troponin I. It can be concluded that both, UDCA and CDCA, although exerted slightly different effects, can prevent the inflammatory responses induced by LPS, improve oxidative stress status, and attenuate LPS-induced liver injury.

Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns

Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.

Evaluation of chenodeoxycholic acid treatment in adult patients with cerebrotendinous xanthomatosis: A randomized, placebo-controlled Phase 3 study (RESTORE)

Evaluation of chenodeoxycholic acid treatment in adult patients with cerebrotendinous xanthomatosis: A randomized, placebo-controlled Phase 3 study (RESTORE)

Effect of Position of Donor Units and Alkyl Groups on Dye-Sensitized Solar Cell Device Performance: Indoline-Aniline Donor-Based Visible Light Active Unsymmetrical Squaraine Dyes.

Indoline (In) and aniline (An) donor-based visible light active unsymmetrical squaraine (SQ) dyes were synthesized for dye-sensitized solar cells (DSSCs), where the position of An and In units was changed with respect to the anchoring group (carboxylic acid) to have In-SQ-An-CO2H and An-SQ-In-CO2H sensitizers, AS1-AS5. Linear or branched alkyl groups were functionalized with the N atom of either In or An units to control the aggregation of the dyes on TiO2. AS1-AS5 exhibit an isomeric π-framework where the squaric acid unit is placed in the middle, where AS2 and AS5 dyes possess the anchoring group connected with the An donor, and AS1, AS3, and AS4 dyes having the anchoring group connected with the In donor. Hence, the conjugation between the middle squaric acid acceptor unit and the anchoring -CO2H group is short for AS2, AS5, and AK2 and longer for AS1, AS3, and AS4 dyes. AS dyes showed absorption between 501 and 535 nm with extinction coefficients of 1.46-1.61 × 105 M-1 cm-1. Further, the isomeric π-framework of An-SQ-In-CO2H and In-SQ-An-CO2H exhibited by means of changing the position of In and An units a bathochromic shift in the absorption properties of AS2 and AS5 compared to the AS1, AS3, and AS4 dyes. The DSSC device fabricated with the dyes contains short acceptor-anchoring group distance (AS2 and AS5) showed high photovoltaic performances compared to the dyes having longer distance (AS1, AS3, and AS4) with the iodolyte (I-/I3-) electrolyte. DSSC device efficiencies of 5.49, 6.34, 6.16, and 5.57% have been achieved for AS1, AS2, AS3, and AS4 dyes, respectively; without chenodeoxycholic acid (CDCA), small changes have been observed in the device performance of the AS dyes with CDCA. Significant changes have been noted in the DSSC parameters (open-circuit voltage VOC, short-circuit current JSC, fill factor ff, and efficiency η) for the AS5 dye while sensitized with CDCA and showed highest DSSC efficiency of 8.01% in the AS dye series. This study revealed the potential of shorter SQ acceptor-anchoring group distance over the longer one and the importance of alkyl groups on the overall DSSC device performance for the unsymmetrical squaraine dyes.

FXR/Menin-mediated epigenetic regulation of E2F3 expression controls β-cell proliferation and is increased in islets from diabetic GK rats after RYGB

Farnesoid X receptor (FXR) improves the function of islets, especially in the setting of Roux-en-Y gastric bypass (RYGB). Here we investigated how FXR activation regulates β-cell proliferation and explored the potential link between FXR signaling and the menin pathway in controlling E2F3 expression, a key transcription factor for controlling adult β-cell proliferation. Stimulation with the FXR agonist GW4064 or chenodeoxycholic acid (CDCA) increased E2F3 expression and β-cell proliferation. Consistently, E2F3 knockdown abolished GW4064-induced proliferation. Treatment with GW4064 increased E2F3 expression in β-cells via enhancing Steroid receptor coactivator-1 (SRC1) recruitment, increasing the pro-transcriptional acetylation of histone H3 at the E2f3 promoter. GW4064 treatment also decreased the association between FXR and menin, leading to the induction of FXR-mediated SRC1 recruitment. Mimicking the impact of FXR agonists, RYGB also increased E2F3 expression and β-cell proliferation in GK rats and SD rats. These findings unravel the crucial role of the FXR/menin signaling in epigenetically controlling E2F3 expression and β-cell proliferation, a mechanism possibly underlying RYGB-induced β-cell proliferation.

Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways.

Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-β-muricholic acid (T-β-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression.

Investigating the mechanism of cornel iridoid glycosides on type 2 diabetes mellitus using serum and urine metabolites in rats

Ethnopharmacological relevanceCornel iridoid glycosides (CIG) are extracted from Corni fructus, a herbal medicine used in traditional Chinese medicine to treat diabetes. However, the antidiabetic effects of CIG and the underlying metabolic mechanisms require further exploration. Aim of the studyThis study aimed to assess the antidiabetic effects and metabolic mechanism of CIG by performing metabolomic analyses of serum and urine samples of rats. Materials and methodsA rat model of type 2 diabetes mellitus (T2DM) was established by administering a low dose of streptozotocin (30 mg/kg) intraperitoneally after 4 weeks of feeding a high-fat diet. The model was evaluated based on several parameters, including fasting blood glucose (FBG), random blood glucose (RBG), urine volume, liver index, body weight, histopathological sections, and serum biochemical parameters. Subsequently, serum and urine metabolomics were analyzed using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS). Data were analyzed using unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA). Differential metabolites were examined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways to explore the underlying mechanisms. ResultsAfter 4 weeks of treatment with different doses of CIG, varying degrees of antidiabetic effects were observed, along with reduced liver and pancreatic injury, and improved oxidative stress levels. Compared with the T2DM group, 19 and 23 differential metabolites were detected in the serum and urine of the CIG treatment group, respectively. The key metabolites involved in pathway regulation include taurine, chenodeoxycholic acid, glycocholic acid, and L-tyrosine in the serum and glycine, hippuric acid, phenylacetylglycine, citric acid, and D-glucuronic acid in the urine, which are related to lipid, amino acid, energy, and carbohydrate metabolism. ConclusionsThis study confirmed the antidiabetic effects of CIG and revealed that CIG effectively controlled metabolic disorders in T2DM rats. This seems to be meaningful for the clinical application of CIG, and can benefit further studies on CIG mechanism.

Goreisan‐induced modulation of fecal bile acid composition and gut microbiota in mice

AbstractAimBile acids are suggested to be involved in the antidiarrhetic effect of Goreisan (GRS). This study aimed to investigate the effect of GRS on fecal bile acid levels and composition of the gut microbiota in mice. Correlation analysis was employed to identify the potential gut microbiota associated with the alterations in fecal bile acid levels induced by GRS.MethodsMale C57BL/6 mice were fed a diet supplemented with GRS water extract for 4 weeks. Feces and cecal contents were collected from the mice to determine bile acid levels and analyze bacterial composition.ResultsGRS administration significantly increased the levels of fecal secondary bile acids, including ω‐muricholic acid (MCA), hyodeoxycholic acid (HDCA), and lithocholic acid (LCA). In contrast, the levels of primary bile acids, such as β‐MCA, cholic acid (CA), and chenodeoxycholic acid (CDCA) showed a marked decrease. Further analysis revealed a positive correlation between the relative abundance of Alloprevotella, Dehalobacterium PAC001221, and Eubacterium g23 and fecal levels of ωMCA, HDCA, and LCA.ConclusionsGRS was suggested to promote the formation of fecal secondary bile acids in mice, possibly through the enhancement of bacterial 7β‐dehydroxylation and 6β‐epimerization activities. These changes may be involved in the antidiarrhetic action of GRS. Concurrent evaluation of fecal bile acids and gut microbiota presents a promising approach for elucidating the novel mechanisms underlying the effects of kampo formulations, particularly in modulating the microbial metabolism of intestinal bile acids.

Bile acid profiles and mRNA abundance of bile acid-related genes in adipose tissue of dairy cows with high versus normal body condition

Besides their lipid-digestive role, bile acids (BA) influence overall energy homeostasis, such as glucose and lipid metabolism. We hypothesized that BA along with their receptors, regulatory enzymes, and transporters are present in subcutaneous adipose tissue (scAT). In addition, we hypothesized that their mRNA abundance varies with the body condition of dairy cows around calving. Therefore, we analyzed BA in serum and scAT as well as the mRNA abundance of BA-related enzymes, transporters, and receptors in scAT during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into either a high (HBCS; n = 19) or normal BCS (NBCS; n = 19) group based on their BCS and back-fat thickness (BFT). Cows were fed different diets to achieve the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off at 7 wk antepartum. During the dry period and subsequent lactation, both groups were fed the same diets according to their energy demands. Using a targeted metabolomics approach via liquid chromatography-electrospray ionization-MS /MS, BA were analyzed in serum and scAT at wk -7, 1, 3, and 12 relative to parturition. In serum, 15 BA were observed: cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid, deoxycholic acid (DCA), lithocholic acid, glycodeoxycholic acid (GDCA), glycolithocholic acid, taurodeoxycholic acid, taurolithocholic acid, β-muricholic acid, tauromuricholic acid (sum of α and β), and glycoursodeoxycholic acid, whereas in scAT 7 BA were detected: CA, GCA, TCA, GCDCA, taurochenodeoxycholic acid, GDCA, and taurodeoxycholic acid. In serum and scAT samples, the primary BA CA and its conjugate GCA were predominantly detected. Increasing serum concentrations of CA, CDCA, TCA, GCA, GCDCA, DCA, and β-muricholic acid with the onset of lactation might be related to the increasing DMI after parturition. Furthermore, serum concentrations of CA, CDCA, GCA, DCA, GCDCA, TCA, lithocholic acid, and GDCA were lower in HBCS cows compared with NBCS cows, concomitant with increased lipolysis in HBCS cows. The correlation between CA in serum and scAT may point to the transport of CA across cell membranes. Overall, the findings of the present study suggest a potential role of BA in lipid metabolism depending on the body condition of periparturient dairy cows.

BaiJ and BaiB are key enzymes in the chenodeoxycholic acid 7α-dehydroxylation pathway in the gut microbe Clostridium scindens ATCC 35704

ABSTRACT Bile acid transformation is a common gut microbiome activity that produces secondary bile acids, some of which are important for human health. One such process, 7α-dehydroxylation, converts the primary bile acids, cholic acid and chenodeoxycholic acid, to deoxycholic acid and lithocholic acid, respectively. This transformation requires a number of enzymes, generally encoded in a bile acid-inducible (bai) operon and consists of multiple steps. Some 7α-dehydroxylating bacteria also harbor additional genes that encode enzymes with potential roles in this pathway, but little is known about their functions. Here, we purified 11 enzymes originating either from the bai operon or encoded at other locations in the genome of Clostridium scindens strain ATCC 35704. Enzyme activity was probed in vitro under anoxic conditions to characterize the biochemical pathway of chenodeoxycholic acid 7α-dehydroxylation. We found that more than one combination of enzymes can support the process and that a set of five enzymes, including BaiJ that is encoded outside the bai operon, is sufficient to achieve the transformation. We found that BaiJ, an oxidoreductase, exhibits an activity that is not harbored by the homologous enzyme from another C. scindens strain. Furthermore, ligation of bile acids to coenzyme A (CoA) was shown to impact the product of the transformation. These results point to differences in the 7α-dehydroxylation pathway among microorganisms and the crucial role of CoA ligation in the process.