RÉSUMÉ
BACKGROUND: Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. The regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA). RESULTS: Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by the human isolate Clostridium scindens is induced when CA is present, suggesting that CA-dependent transcriptional regulation is required for substantial 7-dehydroxylation of these primary BAs. This is supported by the finding that UDCA alone does not promote expression of bai genes. CDCA upregulates expression of the bai genes but the expression is greater when CA is present. In contrast, the murine isolate Extibacter muris exhibits a distinct response; CA did not induce significant 7-dehydroxylation of primary BAs, whereas BA 7-dehydroxylation was promoted upon addition of germ-free mouse cecal content in vitro. However, E. muris was found to 7-dehydroxylate in vivo. CONCLUSIONS: The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted bai operon gene expression and the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muris was promoted only after the addition of cecal content and the isolate did not alter bai gene expression in response to CA. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct bai gene expression across bacterial species.
Sujet(s)
Acides et sels biliaires , Acide cholique , Acide cholique/métabolisme , Animaux , Acides et sels biliaires/métabolisme , Souris , Humains , Clostridium/métabolisme , Clostridium/génétique , Régulation de l'expression des gènes bactériens , Hydroxylation , Opéron , Chénodiol/métabolisme , Acide ursodésoxycholique/métabolisme , Microbiome gastro-intestinalRÉSUMÉ
BACKGROUND: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. METHODS: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. RESULTS: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). CONCLUSIONS: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development.
Sujet(s)
Autophagie , Carcinome hépatocellulaire , Prolifération cellulaire , Acide cholique , Cytochrome P-450 CYP2E1 , Tumeurs du foie , Animaux , Carcinome hépatocellulaire/métabolisme , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/génétique , Carcinome hépatocellulaire/induit chimiquement , Tumeurs du foie/métabolisme , Tumeurs du foie/anatomopathologie , Tumeurs du foie/génétique , Tumeurs du foie/induit chimiquement , Humains , Cytochrome P-450 CYP2E1/métabolisme , Cytochrome P-450 CYP2E1/génétique , Mâle , Autophagie/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Rats , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris , Rat Sprague-Dawley , Transduction du signal , Protéomique/méthodes , Modèles animaux de maladie humaine , Souris nudeRÉSUMÉ
In this issue of Cell, Nie and co-authors report that the microbe-derived bile acid (BA) 3-succinylated cholic acid protects against the progression of metabolic dysfunction-associated liver disease. Intriguingly, its protective mechanism does not involve traditional BA signaling pathways but is instead linked to the proliferation of the commensal microbe Akkermansia muciniphila.
Sujet(s)
Akkermansia (genre) , Acides et sels biliaires , Périodiques comme sujet , Animaux , Humains , Souris , Akkermansia (genre)/métabolisme , Acides et sels biliaires/métabolisme , Acide cholique/métabolisme , Microbiome gastro-intestinal , Foie/métabolisme , Maladies du foie/métabolisme , Maladies du foie/microbiologie , Verrucomicrobia/métabolismeRÉSUMÉ
Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.
Sujet(s)
Marqueurs biologiques , Maladie veno-occlusive hépatique , Métabolomique , Alcaloïdes de type pyrrolizidine , Récepteurs cytoplasmiques et nucléaires , Alcaloïdes de type pyrrolizidine/toxicité , Animaux , Maladie veno-occlusive hépatique/induit chimiquement , Maladie veno-occlusive hépatique/métabolisme , Maladie veno-occlusive hépatique/traitement médicamenteux , Récepteurs cytoplasmiques et nucléaires/métabolisme , Récepteurs cytoplasmiques et nucléaires/agonistes , Mâle , Humains , Marqueurs biologiques/métabolisme , Souris , Foie/métabolisme , Foie/effets des médicaments et des substances chimiques , Acides et sels biliaires/métabolisme , Femelle , Adulte d'âge moyen , Souris de lignée C57BL , Acide cholique , AdulteRÉSUMÉ
BACKGROUND: The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC. METHODS: Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13). RESULTS: The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups. CONCLUSIONS: Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.
Sujet(s)
Acides et sels biliaires , Angiocholite sclérosante , Cholestase , Angiocholite sclérosante/sang , Angiocholite sclérosante/microbiologie , Humains , Mâle , Acides et sels biliaires/sang , Acides et sels biliaires/analyse , Acides et sels biliaires/métabolisme , Femelle , Adulte d'âge moyen , Adulte , Cholestase/sang , Cholestase/microbiologie , Cholangiopancréatographie rétrograde endoscopique , Études cas-témoins , Sujet âgé , Conduits biliaires/microbiologie , Bile/métabolisme , Bile/microbiologie , Chénodiol/analyse , Acide cholique/analyse , Acide cholique/sangRÉSUMÉ
Alterations in gut microbiota composition are suggested to contribute to cardiometabolic diseases, in part by producing bioactive molecules. Some of the metabolites are produced by very low abundant bacterial taxa, which largely have been neglected due to limits of detection. However, the concentration of microbially produced metabolites from these taxa can still reach high levels and have substantial impact on host physiology. To explore this concept, we focused on the generation of secondary bile acids by 7α-dehydroxylating bacteria and demonstrated that addition of a very low abundant bacteria to a community can change the metabolic output dramatically. We show that Clostridium scindens converts cholic acid into the secondary bile acid deoxycholic acid (DCA) very efficiently even though the abundance of C. scindens is low, but still detectable by digital droplet PCR. We also show that colonization of germ-free female mice with a community containing C. scindens induces DCA production and affects host metabolism. Finally, we show that DCA correlates with impaired glucose metabolism and a worsened lipid profile in individuals with type 2 diabetes, which implies that this metabolic pathway may contribute to the development of cardiometabolic disease.
Sujet(s)
Acide désoxycholique , Diabète de type 2 , Microbiome gastro-intestinal , Glucose , Acide désoxycholique/métabolisme , Animaux , Microbiome gastro-intestinal/physiologie , Femelle , Glucose/métabolisme , Souris , Humains , Diabète de type 2/microbiologie , Diabète de type 2/métabolisme , Souris de lignée C57BL , Clostridium/métabolisme , Clostridium/génétique , Acide cholique/métabolisme , MâleRÉSUMÉ
BACKGROUND: All gastrointestinal pathogens, including Enterococcus faecalis and Enterococcus faecium, undergo adaptation processes during colonization and infection. In this study, we investigated by data-independent acquisition mass spectrometry (DIA-MS) two crucial adaptations of these two Enterococcus species at the proteome level. Firstly, we examined the adjustments to cope with bile acid concentrations at 0.05% that the pathogens encounter during a potential gallbladder infection. Therefore, we chose the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) as well as the secondary bile acid deoxycholic acid (DCA), as these are the most prominent bile acids. Secondly, we investigated the adaptations from an aerobic to a microaerophilic environment, as encountered after oral-fecal infection, in the absence and presence of deoxycholic acid (DCA). RESULTS: Our findings showed similarities, but also species-specific variations in the response to the different bile acids. Both Enterococcus species showed an IC50 in the range of 0.01- 0.023% for DCA and CDCA in growth experiments and both species were resistant towards 0.05% CA. DCA and CDCA had a strong effect on down-expression of proteins involved in translation, transcription and replication in E. faecalis (424 down-expressed proteins with DCA, 376 down-expressed proteins with CDCA) and in E. faecium (362 down-expressed proteins with DCA, 391 down-expressed proteins with CDCA). Proteins commonly significantly altered in their expression in all bile acid treated samples were identified for both species and represent a "general bile acid response". Among these, various subunits of a V-type ATPase, different ABC-transporters, multi-drug transporters and proteins related to cell wall biogenesis were up-expressed in both species and thus seem to play an essential role in bile acid resistance. Most of the differentially expressed proteins were also identified when E. faecalis was incubated with low levels of DCA at microaerophilic conditions instead of aerobic conditions, indicating that adaptations to bile acids and to a microaerophilic atmosphere can occur simultaneously. CONCLUSIONS: Overall, these findings provide a detailed insight into the proteomic stress response of two Enterococcus species and help to understand the resistance potential and the stress-coping mechanisms of these important gastrointestinal bacteria.
Sujet(s)
Acides et sels biliaires , Enterococcus faecium , Acides et sels biliaires/pharmacologie , Enterococcus faecalis/génétique , Enterococcus faecalis/métabolisme , Enterococcus faecium/génétique , Enterococcus faecium/métabolisme , Acide désoxycholique/pharmacologie , Protéomique , Acide cholique , Chénodiol/métabolisme , EnterococcusRÉSUMÉ
The aim of this study was to develop cholic-acid-stabilized itraconazole nanosuspensions (ITZ-Nanos) with the objective of enhancing drug dissolution and oral absorption. A laboratory-scale microprecipitation-high-pressure homogenization method was employed for the preparation of the ITZ-Nanos, while dynamic light scattering, transmission electron microscope analysis, X-ray diffraction, differential scanning calorimetry, and high-performance liquid chromatography analysis were utilized to evaluate their physicochemical properties. The absorption and bioavailability of the ITZ-Nanos were assessed using Caco-2 cells and rats, with Sporanox® pellets as a comparison. Prior to lyophilization, the particle size of the ITZ-Nanos measured approximately 225.7 nm. Both X-ray diffraction and differential scanning calorimetry confirmed that the ITZ remained crystalline within the nanocrystals. Compared to the pellets, the ITZ-Nanos exhibited significantly higher levels of supersaturation dissolution and demonstrated enhanced drug uptake by the Caco-2 cells. The AUC(0-t) value for the ITZ-Nanos in rats was 1.33-fold higher than that observed for the pellets. These findings suggest that cholic acid holds promise as a stabilizer for ITZ nanocrystals, as well as potentially other nanocrystals.
Sujet(s)
Itraconazole , Nanoparticules , Solubilité , Tensioactifs , Itraconazole/composition chimique , Itraconazole/pharmacocinétique , Itraconazole/administration et posologie , Nanoparticules/composition chimique , Humains , Cellules Caco-2 , Animaux , Rats , Administration par voie orale , Tensioactifs/composition chimique , Mâle , Biodisponibilité , Taille de particule , Diffraction des rayons X , Calorimétrie différentielle à balayage , Acide cholique/composition chimiqueRÉSUMÉ
Human cytochrome P450 3A4 (CYP3A4) is a drug-metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human-like regulation of the coding genes. A normal diet (ND, CE-2), CE-2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE-2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo.
Sujet(s)
Cholestérol , Acide cholique , Cytochrome P-450 CYP3A , Foie , Microsomes du foie , Triazolam , Acide cholique/métabolisme , Animaux , Cytochrome P-450 CYP3A/métabolisme , Cytochrome P-450 CYP3A/génétique , Microsomes du foie/métabolisme , Cholestérol/métabolisme , Cholestérol/sang , Souris , Foie/métabolisme , Foie/effets des médicaments et des substances chimiques , Mâle , Triazolam/pharmacocinétique , Triazolam/métabolisme , Humains , Souris transgéniques , HydroxylationRÉSUMÉ
Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.
Sujet(s)
Acides et sels biliaires , Acide cholique , Facteurs de croissance fibroblastique , Foie , Souris knockout , Récepteurs cytoplasmiques et nucléaires , Animaux , Récepteurs cytoplasmiques et nucléaires/métabolisme , Récepteurs cytoplasmiques et nucléaires/génétique , Acides et sels biliaires/métabolisme , Foie/métabolisme , Foie/effets des médicaments et des substances chimiques , Facteurs de croissance fibroblastique/métabolisme , Facteurs de croissance fibroblastique/génétique , Acide cholique/métabolisme , Mâle , Souris de lignée C57BL , Acide désoxycholique/toxicité , Cholestanetriol 26-monooxygenase/génétique , Cholestanetriol 26-monooxygenase/métabolisme , Souris , Acide ursodésoxycholique/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Cholesterol 7-alpha-hydroxylaseRÉSUMÉ
The major characteristic of type 2 diabetes is insulin resistance, which is associated with plasma level of 12-hydroxylated bile acids (BAs) in humans. In this study, we investigated whether the rise of enterohepatic 12-hydroxylated BAs associates with glucose tolerance and/or insulin secretion using rats fed a diet supplemented with cholic acid (CA) at a level of 0.5 g/kg diet. Almost no increase was observed in plasma insulin in response to the intraperitoneal glucose administration in the CA-fed rats despite the significant increase of plasma insulin in control with the same treatment. In contrast, the changes in insulin secretion were observed in both groups and no difference was detected between the groups in the oral glucose tolerance test. Increases were observed in pancreatic expressions of Ins1 and Ins2 although the insulin protein content decreased in the pancreas without any sign in ectopic fat accumulation and histological damage in the CA-fed rats. Our results suggest that enterohepatic 12-hydroxylated BAs modulate insulin secretion in response to intraperitoneal glucose administration. The decrease in insulin store might be responsible for the reduction in the insulin secretion in the CA-fed rats.
Sujet(s)
Diabète de type 2 , Glucose , Humains , Rats , Animaux , Glucose/métabolisme , Acide cholique , Sécrétion d'insuline , Glycémie/métabolisme , Diabète de type 2/métabolisme , Acides et sels biliaires , Insuline , Compléments alimentairesRÉSUMÉ
BACKGROUND AND OBJECTIVE: Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico. METHODS: After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (Papp) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin. RESULTS: Both CA and DCA at the highest studied concentration of 100 µM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids. CONCLUSIONS: The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.
Sujet(s)
Acides et sels biliaires , Clindamycine , Humains , Clindamycine/pharmacologie , Clindamycine/métabolisme , Acides et sels biliaires/métabolisme , Peau/métabolisme , Absorption cutanée , Acide cholique , PerméabilitéRÉSUMÉ
In this study, we aimed to explore the protective effects of Bifidobacterium in colitis mice and the potential mechanisms. Results showed that Bifidobacterium breve (B. breve) effectively colonized the intestinal tract and alleviated colitis symptoms by reducing the disease activity index. Moreover, B. breve mitigated intestinal epithelial cell damage, inhibited the pro-inflammatory factors, and upregulated tight junction (TJ)-proteins. Gut microbiota and metabolome analysis found that B. breve boosted bile acid-regulating genera (such as Bifidobacterium and Clostridium sensu stricto 1), which promoted bile acid deconjugation in the intestine. Notably, cholic acid (CA) was closely associated with the expression levels of inflammatory factors and TJ-proteins (p < 0.05). Our in vitro cell experiments further confirmed that CA (20.24 ± 4.53 pg/mL) contributed to the inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression (49.32 ± 5.27 pg/mL) and enhanced the expression of TJ-proteins (Occludin and Claudin-1) and MUC2. This study suggested that B. breve could be a probiotic candidate for use in infant foods.
Sujet(s)
Bifidobacterium breve , Colite , Microbiome gastro-intestinal , Humains , Nourrisson , Animaux , Souris , Bifidobacterium breve/génétique , Acide cholique/effets indésirables , Colite/induit chimiquement , Colite/génétique , Colite/microbiologie , Muqueuse intestinale , Bifidobacterium , Inflammation , Souris de lignée C57BL , Modèles animaux de maladie humaine , Sulfate dextran/effets indésirablesRÉSUMÉ
BACKGROUND: Peritoneal dialysis (PD) helps prevent lethal complications of end-stage renal disease (ESRD). However, the clinical outcomes are affected by PD-related complications. We investigated metabolic biomarkers to estimate the clinical outcomes of PD and identify patients at high risk of downstream complications and recurrent/relapsing infections. METHODS: Metabolites of normal control and ESRD patient were compared via an untargeted metabolomic analysis. Potential metabolic biomarkers were selected and quantified using a multiple reaction monitoring-based target metabolite detection method. A nomogram was built to predict the clinical outcomes of PD patients using clinical features and potential metabolic biomarkers with the least absolute shrinkage and selection operator Cox regression model. RESULTS: Twenty-five endogenous metabolites were identified and analyzed. ESRD-poor clinical outcome-related metabolic modules were constructed. Adenine, isoleucine, tyramine, xanthosine, phenylacetyl-L-glutamine, and cholic acid were investigated using the weighted gene correlation network analysis blue module. Potential metabolic biomarkers were differentially expressed between the NC and ESRD groups and the poor and good clinical outcomes of PD groups. A 3-metabolite fingerprint classifier of isoleucine, cholic acid, and adenine was included in a nomogram predicting the clinical outcomes of PD. CONCLUSION: Metabolic variations can predict the clinical outcomes of PD in ESRD patients.
Sujet(s)
Défaillance rénale chronique , Dialyse péritonéale , Humains , Isoleucine , Études rétrospectives , Défaillance rénale chronique/diagnostic , Dialyse péritonéale/effets indésirables , Dialyse péritonéale/méthodes , Adénine , Acide cholique , Marqueurs biologiques , Dialyse rénale/effets indésirablesRÉSUMÉ
INTRODUCTION: When the kidneys or liver fail, toxic metabolites accumulate in the patient's blood, causing cardiovascular and neurotoxic complications and increased mortality. Conventional membrane-based extracorporeal blood purification procedures cannot remove these toxins efficiently. The aim of this in vitro study was to determine whether commercial hemoperfusion adsorbers are suitable for removing protein-bound retention solutes from human plasma and whole blood as well as to compare the removal to conventional hemodialysis. METHODS: For in vitro testing of the removal of protein-bound substances, whole blood and plasma were spiked with uremic retention solutes (homocysteine, hippuric acid, indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid) and the toxins of liver failure (bilirubin, cholic acid, tryptophan, phenol). Subsequently, the protein binding of each retention solute was determined. The adsorption characteristics of the hemoperfusion adsorbers, Jafron HA and Biosky MG, both approved for the adsorption of protein-bound uremic retention solutes and Cytosorb, an adsorber recommended for adsorption of cytokines, were tested by incubating them in spiked whole blood or plasma for 1 h. Subsequently, the adsorption characteristics of the adsorbers were tested in a dynamic system. For this purpose, a 6-h in vitro hemoperfusion treatment was compared with an equally long in vitro hemodialysis treatment. RESULTS: Hippuric acid, homocysteine, indoxyl sulfate, and tryptophan were most effectively removed by hemodialysis. Bilirubin and cholic acid were removed best by hemoperfusion with Cytosorb. A treatment with Jafron HA and Biosky MG showed similar results for the adsorption of the tested retention solutes and were best for removing phenol. 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid could not be removed with any treatment method. DISCUSSION/CONCLUSION: A combination of hemodialysis with hemoperfusion seems promising to improve the removal of some toxic metabolites in extracorporeal therapies. However, some very strongly protein-bound metabolites cannot be removed adequately with the adsorbers tested.
Sujet(s)
Hippurates , Toxines biologiques , Urémie , Humains , Toxines urémiques , Indican , Tryptophane/métabolisme , Dialyse rénale/effets indésirables , Liaison aux protéines , Phénols , Bilirubine , Acide cholique , Homocystéine/métabolismeRÉSUMÉ
Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/- ) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4 ) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.
Sujet(s)
Cellules étoilées du foie , Cirrhose du foie , Animaux , Humains , Souris , Acides et sels biliaires , Acide cholique/effets indésirables , Acide cholique/métabolisme , Modèles animaux de maladie humaine , Protéines de transport d'acides gras/métabolisme , Cellules étoilées du foie/métabolisme , Cirrhose du foie/anatomopathologieRÉSUMÉ
Biofilm infections are mainly caused by Gram-positive bacteria (GPB) like Staphylococcus aureus, Gram-negative bacteria (GNB) like Pseudomonas aeruginosa, and fungi like Candida albicans. These infections are responsible for antimicrobial tolerance, and commensal interactions of these microbes pose a severe threat to chronic infections. Treatment therapies against biofilm infections are limited to eradicating only 20-30% of infections. Here, we present the synthesis of a series of bile acid-derived molecules using lithocholic acid, deoxycholic acid, and cholic acid where two bile acid molecules are tethered through 3'-hydroxyl or 24'-carboxyl terminals with varying spacer length (trimethylene, pentamethylene, octamethylene, and dodecamethylene). Our structure-activity relationship investigations revealed that G21, a cholic acid-derived gemini amphiphile having trimethylene spacer tethered through the C24 position, is a broad-spectrum antimicrobial agent. Biochemical studies witnessed that G21 interacts with negatively charged lipoteichoic acid, lipopolysaccharide, and phosphatidylcholine moieties of GPB, GNB, and fungi and disrupts the microbial cell membranes. We further demonstrated that G21 can eradicate polymicrobial biofilms and wound infections and prevent bacteria and fungi from developing drug resistance. Therefore, our findings revealed the potential of G21 as a versatile antimicrobial agent capable of effectively targeting polymicrobial biofilms and wound infections, suggesting that it is a promising antimicrobial agent for future applications.
Sujet(s)
Anti-infectieux , Cyclopropanes , Infection de plaie , Humains , Acide cholique/pharmacologie , Anti-infectieux/pharmacologie , Acides et sels biliaires/pharmacologie , Biofilms , Infection de plaie/traitement médicamenteux , Bactéries à Gram positifRÉSUMÉ
BACKGROUND: Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3ß-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ4-3-oxosteroid 5ß-reductase (Δ4-3-oxo-R) deficiency. METHODS: Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed. RESULTS: First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆4 derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity. CONCLUSIONS: Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency.
Sujet(s)
Acides et sels biliaires , Maladies métaboliques , Enfant , Humains , Acide cholique/usage thérapeutique , Études rétrospectives , Qualité de vie , Maladies métaboliques/traitement médicamenteux , Oxidoreductases/génétiqueRÉSUMÉ
The activation of TGR5 bestows on bile acids the ability to modulate nongenomic signaling pathways, which are responsible of physiological actions including immunosuppressive and anti-inflammatory properties as well as the regulation of glucose metabolism and energy homeostasis. TGR5 agonists have therefore emerged in drug discovery and preclinical appraisals as promising compounds for the treatment of liver diseases and metabolic syndrome. In this study, we have been devising site-selected chemical modifications of the bile acid scaffold to provide novel chemical tools able to modulate the functions of TGR5 in different tissues. Biological results of the tested collection of semisynthetic cholic acid derivatives were used to extend the structure-activity relationships of TGR5 agonists and to clarify the molecular basis and functional role of TGR5 hot-spots in the receptor activation and selectivity. Some unexpected properties deriving from the molecular structure of bile acids have been unveiled as relevant to the receptor activation and may hence be used to design novel, selective and potent TGR5 agonists.