Chenodeoxycholic Acid Research Articles

Cerebrotendinous Xanthomatosis (CTX) Disease Prevalance in Patients with Autism Spectrum Disorder (ASD): A Prospective Observational Study

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system.It has been demonstrated that many congenital metabolic diseases like CTX are associated with Autism Spectrum Disorder (ASD). The aim of this study is to identify the prevalence of CTX disease in patients with ASD. Method: The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A socio-demographic form and Gilliam Autism Rating Scale-2 were applied to all participants. Results: In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, four patients with mutations in the CYP27A1 gene, two homozygous variants and two different heterozygous mutations were identified. Most common symptom was diarrhea. 67.3% of all patients and 3 in 4 cases with CYP27A1 gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations.Moreover, all mutant cases had comorbid Oppositional Defiant Disorder (ODD). 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder. Conclusion: psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration and permanent disability through early initiation of chenodeoxycholic acid treatment.

An exploratory study of metabolomics in endogenous and cannabis-use-associated psychotic-like experiences in adolescence

In adolescence, psychotic-like experiences (PLE) may indicate potential prodromal symptoms preceding the onset of psychosis. Metabolomic studies have shown promise in providing valuable insights into predicting psychosis with enhanced precision compared to conventional clinical features. This study investigated metabolomic alterations associated with PLE in 76 depressed adolescents aged 14–20 years. Serum concentrations of 92 metabolites were analyzed with liquid chromatography–mass spectrometry. PLE were assessed using the Youth Experiences and Health (YEAH) questionnaire. The associations between PLE symptom dimensions (delusions, paranoia, hallucinations, negative symptoms, thought disorder, and dissociation) and metabolite concentrations were analyzed in linear regression models adjusted for different covariates. The symptom dimensions consistently correlated with the metabolome in different models, except those adjusted for cannabis use. Specifically, the hallucination dimension was associated with 13 metabolites (acetoacetic acid, allantoin, asparagine, decanoylcarnitine, D-glucuronic acid, guanidinoacetic acid, hexanoylcarnitine, homogentisic acid, leucine, NAD+, octanoylcarnitine, trimethylamine-N-oxide, and valine) in the various linear models. However, when adjusting for cannabis use, eight metabolites were associated with hallucinations (adenine, AMP, cAMP, chenodeoxycholic acid, cholic acid, L-kynurenine, neopterin, and D-ribose-5-phosphate). The results suggest diverse mechanisms underlying PLE in adolescence; hallucinatory experiences may be linked to inflammatory functions, while cannabis use may engage an alternative metabolic pathway related to increased energy demand and ketogenesis in inducing PLE. The limited sample of individuals with depression restricts the generalizability of these findings. Future research should explore whether various experiences and related metabolomic changes jointly predict the onset of psychoses and related disorders.

Altered bile acids profile is a risk factor for hyperandrogenism in lean women with PCOS: a case control study

The levels of fasting-state serum bile acids (BAs) in individuals with polycystic ovary syndrome (PCOS) differ from those of control subjects. However, there is a lack of research on the BAs profile in lean women with PCOS and whether these changes are linked to the host metabolism. Therefore, our objective was to investigate the synthesis and metabolism of serum BAs in lean women with PCOS and assess the correlation between BAs and clinical characteristics. This study employed a cross-sectional design of lean women with PCOS (n = 240) in comparison to a control group (n = 80) consisting of healthy lean women. The findings revealed significant increases in the levels of non-12-OH BAs and chenodeoxycholic acid (CDCA)% (both P < 0.05) in lean women with PCOS. Additionally, a positive correlation was observed between CDCA% and total testosterone (T) (r = 0.130, P = 0.044) and free androgen index (FAI) (r = 0.153, P = 0.019). Furthermore, a decreased ratio of cholic acid/chenodeoxycholic acid (CA/CDCA) (P < 0.001) was observed in lean women with PCOS, suggesting the depletion or downregulation of CYP8B1. Receiver operating characteristic curve analysis indicated that the combination of CDCA/CA and DHEAS could potentially be used as a characteristic factor for PCOS in lean women. It is possible that enzymatic modifications in the liver could play a role in regulating hyperandrogenism in this specific subgroup of lean women with PCOS.

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.

The expression of intestinal Cyp2c55 is regulated by the microbiota and inflammation.

Although the mutualistic relationship between the intestinal microbiota and the human host is crucial for maintaining health, the underlying mechanisms of this relationship remain unclear. In the present study, aiming to elucidate the regulatory mechanisms governing the Cyp2c55 expression, which is predominantly observed in colonic tissues, germ-free, antibiotic-administered and colitic mice, as well as mouse colonoids, were used as experimental models. RNA sequencing showed comparable decreases in the colonic Cyp2c55 expression in germ-free and antibiotic-administered mice, when compared with that in specific pathogen-free mice. Furthermore, administration of dextran sulfate sodium decreased the Cyp2c55 expression in colitic mice. For these mice, a Pearson correlation analysis also showed a positive correlation between the Cyp2c55 expression and unconjugated bile acids (BAs), including chenodeoxycholic, muricholic, deoxycholic, lithocholic, and ursodeoxycholic acids, as well as taurine (T)-conjugated secondary BAs, including deoxycholic acid. Moreover, bacterial genera, such as Muribaculaceae and unclassified Lachnospiraceae, also exhibited a positive correlation with these BAs. While administration of an agonist of the pregnane X receptor (PXR) increased the Cyp2c55 expression in mouse colonoids, inflammatory cytokines decreased it. In conclusion, Cyp2c55 was highly expressed in the colonic epithelial cells of mice in a microbiota-dependent manner. The underlying mechanism seemed to involve a BA-mediated PXR activation. In addition, the colonic expression of Cyp2c55 was regulated by the inflammatory response. Although the physiological function of Cyp2c55 remains largely unidentified, our findings suggested that Cyp2c55 may play a role in the mutualistic interaction between the intestinal microbiota and the intestinal homeostasis.

Silybin Meglumine Mitigates CCl4-Induced Liver Fibrosis and Bile Acid Metabolism Alterations.

Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl4-induced murine model. A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson's trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR. SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl4 via activating Farnesoid X receptor. These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism.

Biopharmaceutical modulatory effects of newly engineered bile acid-Tyloxapol nanogels for attenuation of cytotoxicity in auditory cells

This study presents novel thermoresponsive nanogels composed of chenodeoxycholic acid and Tyloxapol for potential inner ear drug delivery. The nanogels exhibit non-Newtonian, shear-thinning fluid behaviour and rapid gelation at body temperature. Biocompatibility studies were conducted on auditory and macrophage cell lines. Nanogels had a minimal impact on cellular viability, glycolysis, and mitochondrial respiration of auditory cells after 24 h of exposure. However, mitochondrial function analysis in macrophages revealed a significant decrease in oxidative phosphorylation and coupling efficiency after nanogel exposure, accompanied by increased proton leakage. Despite these metabolic disruptions, glycolysis remained unaffected. The Poloxamer matrix appears to be responsible for these effects, independent of the presence of bile acids or Tyloxapol. This study highlights the potential of bile acid-enriched nanogels in drug delivery, particularly their biocompatibility and injectability while acknowledging challenges related to mitochondrial dysfunction in immune cells. These findings suggest that thermoresponsive bile acid and Tyloxapol nanogels have the potential to be safe and effective drug delivery vehicles for inner ear applications.

An Efficient Chemoenzymatic Synthesis of Chenodeoxycholic Acid from its Allo‐Epimer through Stereoselective Hydrogenation of 3‐Oxo‐chol‐Δ1,4‐dien‐24‐oate Scaffold

An Efficient Chemoenzymatic Synthesis of Chenodeoxycholic Acid from its <i>Allo</i>‐Epimer through Stereoselective Hydrogenation of 3‐Oxo‐chol‐Δ^1,4‐dien‐24‐oate Scaffold

Metabolomic profiling reveals the step-wise alteration of bile acid metabolism in patients with diabetic kidney disease

BackgroundDiabetic kidney disease (DKD) is the major complication of diabetes concomitant with gut dysbiosis and glycometabolic disorder, which are strongly associated with bile acid (BA) metabolism. Yet studies investigating the BA metabolism involving in DKD pathogenesis are limited. This study aimed to explore the metabolomic profiling of BAs in DKD and analyze its association with DKD progression.MethodsAn ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to quantify BAs in the plasma, fecal and urine samples of patients with DKD or T2DM and healthy individuals (n = 30 for each group). The key BAs associated with DKD were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and receiver-operating characteristic (ROC) curve. Polynomial regression and Pearson’s correlation analyses were performed to assess the correlation between the key BAs and the clinical indicators reflecting DKD progression.ResultsMetabolomic profiling of 50 kinds of BAs presented the markedly step-wise alterations of BAs in plasma and feces as well as the little in urine of patients with DKD. Eight kinds of BAs in the plasma, eight kinds in the feces and three kinds in the urine were abnormally expressed, accompanying with the increased conjugated/unconjugated ratios of cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid and hyocholic acid in the plasma, and of cholic acid, chenodeoxycholic acid and lithocholic acid in the feces. Moreover, the increased plasma level of glycochenodeoxycholic acid, and the increased fecal levels of glycolithocholic acid, 7-ketodeoxycholic acid and chenodeoxycholic acid-3-β-D-glucuronide are strongly correlated with the clinical indicators reflecting DKD progression, including eGFR, 24 h urinary protein and 24 h urinary microalbumin.ConclusionsOur study for the first time disclosed the specific alterations of BA metabolism reflecting the step-wise progression of DKD, providing the basis for early identification and therapeutical strategies for DKD.

Cofactor-dependence alteration of 7β-hydroxysteroid dehydrogenase: Enhancing one-pot synthesis efficiency of chenodeoxycholic acid to ursodeoxycholic acid through cofactor self-recycling

NAD+-dependent 7α-hydroxysteroid dehydrogenase (7α-HSDH) and NADPH-dependent 7β-hydroxysteroid dehydrogenase (7β-HSDH) are involved in the biosynthesis of chenodeoxycholic acid (CDCA) to ursodeoxycholic acid (UDCA). To realize the one-pot synthesis of CDCA to UDCA through NAD+-NADH cycling, we aimed to improve the binding ability of Hyphomicrobium sp. 7β-HSDH to NADH. The 7β-HSDH structure was modeled and some potential residues to improve NADH affinity near conserved cofactor binding regions were screened, including Ala22, Gln23, Asn24, Asp44, Leu45, and Asn46. The dominant mutant A22T/Q23E/L45A/N46E significantly enhanced the binding affinity for NADH, resulting in a 44.9-fold increase in its kcat/Km value. It increased enzymatic activity by 65.2-fold and catalyzed the synthesis of UDCA at a yield of 77.6 % with 5 g/L 7K-LCA and 12.5 mM NADH. Molecular dynamics simulations indicated increased interactions of mutated 7β-HSDH and the ligand NADH by their spatially reduced binding distance and reaction energy. The modified cofactor-dependence of 7β-HSDH realized efficient one-pot synthesis of CDCA to UDCA through strengthening cofactor-recycling and reducing the use of cofactor, achieving 90.1 % UDCA yield and 54.1 g/L/d spatiotemporal yield when coupled with 7α-HSDH with only 0.5 mM NAD+ as coenzyme. This work also supplies a universal cofactor-dependence engineering technique for homologous HSDH enzymes.

High-concentrate diet decreases lamb fatty acid contents by regulating bile acid composition

Feeding sheep with high-concentrate diet (HCD) to shorten production cycle is a well-developed feeding strategy to increase lamb production. Here, metabolomics were performed to explore the mechanism that HCD changes lamb nutrition composition. Differential metabolites were enriched in primary bile acid biosynthesis. Significantly higher content of bile acids including taurodeoxycholic acid sodium salt (TDCA), taurochenodeoxycholic acid sodium salt (TCDCA) and taurocholic acid (TCA) was observed in lamb of HCD, while the content of lithocholic acid (LCA), cholic acid (CA), chenodeoxycholic acid (CDCA) and Chenodeoxycholic acid-3-beta-D-glucuronide (CDCA-3Gln) were higher in the controls. Furthermore, a significantly decreased content of fatty acids was observed in lamb of HCD group. Finally, primary skeletal cells treated with CA or TCA showed a significant decrease in contents of fatty acids, while TCA showed a stronger effect in decreasing fatty acid contents. Collectively, we suggest that HCD decreases lamb fatty acid contents by regulating bile acid composition.

Taurine/chenodeoxycholic acid ratio as a potential serum biomarker for low vitamin B12 levels in humans.

Deficiency of vitamin B12 (B12 or cobalamin), an essential water-soluble vitamin, leads to neurological damage, which can be irreversible and anaemia, and is sometimes associated with chronic disorders such as osteoporosis and cardiovascular diseases. Clinical tests to detect B12 deficiency lack specificity and sensitivity. Delays in detecting B12 deficiency pose a major threat because the progressive decline in organ functions may go unnoticed until the damage is advanced or irreversible. Here, using targeted unbiased metabolomic profiling in the sera of subjects with low B12 levels v control individuals, we set out to identify biomarker(s) of B12 insufficiency. Metabolomic profiling identified seventy-seven metabolites, and partial least squares discriminant analysis and hierarchical clustering analysis showed a differential abundance of taurine, xanthine, hypoxanthine, chenodeoxycholic acid, neopterin and glycocholic acid in subjects with low B12 levels. Random forest multivariate analysis identified a taurine/chenodeoxycholic acid ratio, with an AUC score of 1, to be the best biomarker to predict low B12 levels. Mechanistic studies using a mouse model of B12 deficiency showed that B12 deficiency reshaped the transcriptomic and metabolomic landscape of the cell, identifying a downregulation of methionine, taurine, urea cycle and nucleotide metabolism and an upregulation of Krebs cycle. Thus, we propose taurine/chenodeoxycholic acid ratio in serum as a potential biomarker of low B12 levels in humans and elucidate using a mouse model of cellular metabolic pathways regulated by B12 deficiency.

Safflower dietary fiber alleviates functional constipation in rats via regulating gut microbiota and metabolism

A functional constipation rat model was established by loperamide hydrochloride (LOP), and then safflower dietary fiber (SDF) was supplemented to constipated rats. The results revealed that SDF increased the serum levels of excitatory gastrointestinal active peptides such as motilin (MTL), gastrin (GAS), and substance P (SP), while concurrently decreasing the levels of inhibitory peptides like somatostatin (SS) and vasoactive intestinal peptide (VIP). SDF restored the ratio of Firmicutes/Bacteriodetes (F/B), upregulated the relative abundance of Lactobacillus and Clostridium, and downregulated the relative abundance of Oscillopira, Ruminococcus, Coprococcus, and Akkermansia; analysis of metabolites revealed that the levels of bile acid, deoxycholic acid, chenodeoxycholic acid, and taurocholic acid were notably elevated after SDF treatment, while the levels of indole-3-lactic acid, putrescine, and L-arginine were significantly decreased. Pathway enrichment analysis found that SDF regulates Taurine and hypotaurine metabolism, Primary bile acid biosynthesis, and Bile secretion. Correlation analysis between gut microbiota and metabolites revealed that Fusibacter and Actinomyces may contribute to alleviating constipation by regulating the level of bile acid in the intestine. SDF intervention increased the mRNA expressions of FABP1 and SLC1A5 in constipated rats. Furthermore, SDF exhibited notable abilities in retaining water and undergoing swelling. The above results showed that SDF helped the intestine lock water and promoted intestinal peristalsis by increasing friction. On the other hand, SDF supplementation increased the relative abundance of Lactobacillus and Clostridium, decreased the relative abundance of Oscillopira, increased the levels of various bile acids such as deoxycholic acid and chenodeoxycholic acid, further regulated intestinal lipid metabolism, up-regulated FABP1 mRNA expression, promoted intestinal cell proliferation, restored intestinal homeostasis, and thus alleviated constipation.

Enhanced performance of dye-sensitized solar cells via anthocyanin, chlorophyll, benzothiadiazole and diphenylacridine co-sensitizers and amine-based co-adsorbents

Anthocyanin (ANT) and chlorophyll (CHL) natural dyes extracted from blue butterfly pea flowers and spinach leaves and two synthetic metal-free dyes (BIM33 and C1) were evaluated as sensitizers/co-sensitizers in dye-sensitized solar cells (DSSCs). To suppress the possible dye aggregation, triethylamine (TEA) and diethylenetriamine (DETA) were utilized as alternative co-adsorbents to the commonly used chenodeoxycholic acid (CDCA). Furthermore, CHL, BIM33, and C1 were co-sensitized with ANT to achieve panchromatic light absorption and, hence, enhance the photovoltaic performance. Therefore, the power conversion efficiencies (PCEs) of DSSCs based on the dyes were significantly improved from 1.19–5.01 % to 2.39–6.31 % by the co-sensitization and utilization of co-adsorbents. Meanwhile, the efficiencies of DSSCs based on TEA or DETA were superior to those based on CDCA under the same conditions. This study provides effective strategies for improving the performance of DSSCs based on environment-friendly dyes.

Integration of UPLC-MS/MS-based metabolomics and desorption electrospray ionization-mass spectrometry imaging reveals that Shouhui Tongbian Capsule alleviates slow transit constipation by regulating bile acid metabolism

Slow transit constipation (STC) is a common intestinal disorder. Some studies reported that Shouhui Tongbian Capsule (SHTB) can effectively mitigate STC symptoms. A detailed understanding of the changes in the endogenous metabolite profile of rats is crucial for a more accurate comprehension of the molecular pathological characteristics of SHTB in treating STC. In the present study, a method integrating metabolomics based on Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Desorption electrospray ionization (DESI)-mass spectrometry imaging (MSI) was proposed to investigate serum, feces and colon tissue metabolic alterations of STC rats induced by diphenoxylate and the effect of SHTB treatment on metabolism. Then, Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis for verifying the potential mechanism of SHTB in treating STC. As a result, we first indicated that SHTB significantly improved intestinal peristalsis and low fecal water content in STC rats. Furthermore, after treatment with SHTB, the thickness of muscle layers was increased, demonstrated SHTB’s effectiveness in reducing intestinal injury in STC rats. Besides, bile acid (BA) metabolomics based on UPLC-MS/MS revealed significant increase in serum levels of Cholic acid (CA), Deoxycholic acid (DCA), Chenodeoxycholic acid (CDCA), Ursodeoxycholic acid (UDCA), and Glycolithocholic acid (GLCA), whereas the contents of CA and DCA in feces were significantly decreased in STC rats. Nonetheless, they returned to the control levels after the SHTB administration. ELISA results showed that SHTB significantly hindered the excessive reabsorption of BAs by inhibiting apical sodium-dependent bile acid transporter (ASBT), organic solute transporter alpha (OSTα) and organic solute transporter beta (OSTβ) in the ileum tissue of STC rats. Furthermore, the DESI-MSI analysis revealed that SHTB remarkably enhanced DCA in the colon tissue of STC rats. The WB results indicated that SHTB reinstated Takeda G-protein–coupled receptor 5 (TGR5) expression, a receptor for BAs and a key regulator of colonic motility. Consequently, DCA exerted its effects on TGR5, leading to the promotion of colonic motility. This study provided more comprehensive and detailed information about the BA metabolomics in the serum, feces and colon of STC rats. These findings highlighted the promising potential of metabolomics based on UPLC-MS/MS and DESI-MSI method for application in the study of STC diseases.

Chenodeoxycholic acid fortified diet drives ovarian steroidogenesis to improve embryo implantation through enhancing uterine receptivity via progesterone receptor signaling pathway in rats

Infertility is a worldwide reproductive health problem influenced by the embryo implantation efficiency. We previously revealed that dietary chenodeoxycholic acid (CDCA) positively influence the early embryo implantation. But how CDCA regulate embryo implantation is largely unexplored. Herein, we investigated the mechanism behind CDCA's regulation on embryo implantation in rats. Results showed that CDCA promoted uterine receptivity, leading to increased number of implantation sites. Mechanistically, CDCA reshaped maternal amino acid metabolism and enhanced serum progesterone levels. CDCA enhanced ovarian progesterone synthesis by improving steroidogenesis-related protein (StAR and CYP11A1) expression via Takeda G-protein-coupled receptor 5. Elevated progesterone exaggerated uterine progesterone but weakened the estradiol signaling in the CDCA group, contributing to better uterine receptive for embryo implantation. Additionally, elevated transcription repressor Stat5b induced the down-regulation of progesterone-metabolizing enzyme 20-hydroxysteroid dehydrogenase 20α-HSD, complementally explained uterine progesterone signaling enhancement. Overall, our data revealed that CDCA drove ovarian steroidogenesis to improve embryo implantation through enhancing uterine receptivity via progesterone receptor pathway in rats. Therefore, CDCA diet may be a potential favorable nutritional strategy for infertility and pregnancy management.

Combined effects of polyvinyl chloride or polypropylene microplastics with cadmium on the intestine of zebrafish at environmentally relevant concentrations

Cadmium (Cd) is a common additive in polyvinyl chloride (PVC) and polypropylene (PP) plastics. Aquatic organisms were inevitably co-exposed to PVC/PP microplastics (MPs) and Cd, but their combined toxicity is still unknown. In this study, adult zebrafish were exposed to 200 μg/L MPs (PVC or PP) and 10 μg/L Cd alone or in combination for 28 days to investigate their toxicity and mechanisms. Results showed that combined exposure with PVC/PP enhanced the Cd accumulation in the zebrafish intestine. Subsequently, toxicology analyses showed that both PVC and PP possessed synergistic toxicity with Cd, manifested by the exfoliation and necrosis of intestinal epithelial cells, and increased levels of interleukin-1β (IL-1β), superoxide dismutase (SOD) and malondialdehyde (MDA). PP exhibited a stronger synergistic effect than PVC. Integration of non-targeted metabolomics and 16S rRNA gene sequencing revealed that combined exposure to PVC and Cd induced intestine toxicity mainly through bile acid (BA) biosynthesis, fructose (Fru) and mannose (Man) metabolism, and pentose phosphate pathway (PPP). The combined exposure of PP and Cd induced toxicity through the arginine (Arg) and glutathione (GSH) metabolisms. Meanwhile, combined exposure of PVC/PP and Cd increased the abundance of intestinal Proteobacteria and pathogen Vibrio, and decreased the abundance of Gemmobacter. These changes indrectly promoted the synergistic toxicity of PVC/PP and Cd through metabolites, such as indole-3-pyruvate (IPyA), chenodeoxycholic acid (CDCA), and cholic acid (CA). These findings highlighted that more attention should be paid to the toxicity of chemicals at environmentally relevant concentrations, particularly those co-existing with MPs.

Selective Agonism of Liver and Gut FXR Prevents Cholestasis and Intestinal Atrophy in Parenterally Fed Neonatal Pigs.

We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days. Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

Pangenome analysis of Clostridium scindens : a collection of diverse bile acid and steroid metabolizing commensal gut bacterial strains.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids deoxycholic acid and lithocholic acid from the primary bile acids cholic acid and chenodeoxycholic acid, respectively, as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized in vitro and in vivo to any significant extent. The formation of secondary bile acids is important in maintaining normal gastrointestinal function, in regulating the structure of the gut microbiome, in the etiology of such diseases such as cancers of the GI tract, and in the prevention of Clostridium difficile infection. We therefore wanted to determine the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the 34 strains of C. scindens have an open pangenome with 12,720 orthologous gene groups, and a core genome with 1,630 gene families, in addition to 7,051 and 4,039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The core genome contains 39% of the proteins with predicted metabolic function, and, in the unique genome, the function of storage and processing of information prevails, with 34% of the proteins being in that category. The pangenome profile including the MAGs also proved to be open. The presence of bile acid inducible ( bai ) and steroid-17,20-desmolase ( des ) genes was identified among groups of strains. The analysis reveals that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, confirmed by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

Congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variation in 2 cases and literature review

Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.