BACKGROUND: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. METHODS: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. RESULTS: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. CONCLUSIONS: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.

• MeSH
• játra metabolismus   MeSH
• lidé MeSH
• receptory cytoplazmatické a nukleární * metabolismus   MeSH
• receptory spřažené s G-proteiny * metabolismus   MeSH
• transkripční faktory MeSH
• žluč chemie   MeSH
• žlučové kyseliny a soli * farmakologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• hepatobiliární exkrece MeSH
• klinické lékařství MeSH
• nemoci jater MeSH
• nemoci žlučového ústrojí MeSH
• žlučové kyseliny a soli biosyntéza   fyziologie   metabolismus   terapeutické užití   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hepatologie

BACKGROUND AND AIMS: Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt-FGF19 axis. APPROACH AND RESULTS: Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7-α-hydroxy-4-cholesten-3-one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up-regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. CONCLUSIONS: CR in patients with IF-TDE restored bile salt-FGF19 signaling and improved gut-liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.

• MeSH
• anastomóza chirurgická škodlivé účinky   MeSH
• enterální výživa metody   MeSH
• enterostomie škodlivé účinky   MeSH
• fibroblastové růstové faktory krev   metabolismus   MeSH
• gastrointestinální obsah * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nutriční stav MeSH
• prospektivní studie MeSH
• selhání střeva krev   etiologie   metabolismus   terapie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• žlučové kyseliny a soli krev   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH

Bile acid malabsorption (BAM) is a common but an underestimated and often neglected sign of inflammatory bowel diseases (IBDs), especially those affecting the distal ileum. Clinically relevant BAM is most often present in patients with Crohn's ileitis and particularly in ileal-resected Crohn's disease patients. However, deterioration of bile acid (BA) metabolism occurs also in patients with IBD without ileal disease or in those in clinical remission, and the role of BAM in these patients is not well appreciated by clinicians. In a majority of cases, BAM in IBD is caused by impaired conjugated BA reabsorption, mediated by apical sodium/BA cotransporting polypeptide, localized at the luminal surface of the ileal enterocytes. As a consequence, numerous pathological sequelae may occur, including the malfunction of lipid digestion with clinical steatorrhea, impaired intestinal motility, and/or significant changes in the intestinal microflora environment. In this review, a detailed description of the pathophysiological mechanisms of BAM-related diarrhea is presented. Although BAM is present in a significant number of patients with Crohn's disease, its laboratory assessment is not routinely included in diagnostic workups, partially because of costs, logistical reasons, or the unavailability of the more sophisticated laboratory equipment needed. Simultaneously, novel findings related to the effects of the BA signaling pathways on immune functions (mediated through TGR5, cell membrane G protein-coupled BA receptor 1, nuclear farnesoid X receptor, nuclear pregnane X receptor, or nuclear vitamin D receptor) are discussed along with intestinal metabolism in its relationship to the pathogenesis of IBD.

• MeSH
• idiopatické střevní záněty etiologie   patologie   MeSH
• lidé MeSH
• prognóza MeSH
• průjem komplikace   patologie   MeSH
• steatorea komplikace   patologie   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Enzymatic assays based on bacterial 3α-hydroxysteroid dehydrogenase are the method of choice for quantification of total bile acids (BAs) in serum. Although non-specific, it is generally considered precise and robust. The aim of this study was to investigate how changes in the BA spectrum might affect the reliability of the method. We measured standard solutions of twenty-three human and murine BAs using a commercial enzymatic assay and compared the measured vs. expected concentrations. Additionally, total BA concentrations in rat and human cholestatic samples with an abnormal BA spectrum were measured using an enzymatic assay, and a more specific LC-MS/MS method. We observed a great variability in the response of individual BAs in the enzymatic assay. Relative signal intensities ranged from 100% in glycocholic acid (reference) to only 20% in α-muricholic acid. The enzymatic assay markedly underestimated the BA concentrations in both human and rat cholestatic sera when compared to the LC-MS/MS assay. Our study indicated that the performance of an enzymatic assay largely depends on the BA spectrum, and the total concentration of BAs can be markedly underestimated. Samples with an atypical BA spectrum (viz. in rodents) should preferably be measured by other methods.

• MeSH
• 3-alfa-hydroxysteroiddehydrogenasa (B-specifická) chemie   MeSH
• cholestáza metabolismus   MeSH
• enzymatické testy metody   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• reprodukovatelnost výsledků MeSH
• žlučové kyseliny a soli krev   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A fast, non-invasive, high-performance liquid chromatographic screening method with electrospray ionization mass spectrometric detection was developed for the analysis of three major glycine-conjugated bile acids in human saliva. Using a mobile phase composed of 80% methanol and 0.1% formic acid, glycocholic, glycodeoxycholic, and glycochenodeoxycholic acids were separated in less than 4 minutes with sensitivity in the low nM range. Bile acids are thought to contribute to the pathology of various complications in gastroesophageal reflux disease, for instance, Barrett's esophagus, which may eventually lead to esophageal carcinoma. In this pilot study, samples of saliva obtained from 15 patients with Barrett's esophagus of various severities were compared to saliva samples from 10 healthy volunteers. Glycochenodeoxycholic acid was significantly elevated in the patients and principal component analysis of all bile acids could distinguish the most severe Barrett's esophagus patients. We also reported on the detection of glycochenodeoxycholic acid in exhaled breath condensate for the first time. The promising results of this pilot study warrant future investigation, aiming at non-invasive diagnostics of Barrett's esophagus susceptibility in patients with gastroesophageal reflux disease.

• MeSH
• analýza hlavních komponent MeSH
• Barrettův syndrom metabolismus   patologie   MeSH
• dospělí MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pilotní projekty MeSH
• počítačové zpracování signálu MeSH
• referenční standardy MeSH
• reprodukovatelnost výsledků MeSH
• sliny chemie   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• žlučové kyseliny a soli analýza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of β-muricholic acid and tauro-β-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.

• MeSH
• antiastmatika terapeutické užití   MeSH
• antigeny roztočů domácího prachu toxicita   MeSH
• bronchiální astma farmakoterapie   etiologie   metabolismus   patofyziologie   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• dospělí MeSH
• dusíkaté sloučeniny terapeutické užití   MeSH
• hubenost MeSH
• játra účinky léků   metabolismus   MeSH
• kyselina glykocholová krev   MeSH
• kyselina ursodeoxycholová analogy a deriváty   krev   MeSH
• kyseliny olejové terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastné kyseliny chemie   fyziologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita komplikace   metabolismus   patofyziologie   MeSH
• plíce patofyziologie   MeSH
• preklinické hodnocení léčiv MeSH
• respirační alergie chemicky indukované   farmakoterapie   metabolismus   MeSH
• usilovný výdechový objem MeSH
• vitální kapacita MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Bile acids (BA), for decades considered only to have fat-emulsifying functions in the gut lumen, have recently emerged as novel cardio-metabolic modulators. They have real endocrine effects, acting via multiple intracellular receptors in various organs and tissues. BA affect energy homeostasis through the modulation of glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), as well as the cytoplasmic membrane G protein-coupled BA receptor TGR5 in a variety of tissues; although numerous other intracellular targets of BA are also in play.The roles of BA in the pathogenesis of diabetes, obesity, metabolic syndrome, and cardiovascular diseases are seriously being considered, and BA and their derivatives seem to represent novel potential therapeutics to treat these diseases of civilization.

• MeSH
• hypoglykemika terapeutické užití   MeSH
• hypolipidemika terapeutické užití   MeSH
• kardiovaskulární látky terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   metabolismus   MeSH
• látky proti obezitě terapeutické užití   MeSH
• lidé MeSH
• metabolické nemoci farmakoterapie   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• objevování léků MeSH
• probiotika terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• střeva účinky léků   metabolismus   mikrobiologie   MeSH
• střevní mikroflóra MeSH
• žlučové kyseliny a soli metabolismus   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high-saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl-coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet-fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

• MeSH
• atorvastatin farmakologie   MeSH
• biologické markery MeSH
• biologické modely MeSH
• dieta s vysokým obsahem tuků MeSH
• homeostáza * MeSH
• játra metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nealkoholová steatóza jater farmakoterapie   etiologie   metabolismus   patologie   MeSH
• statiny farmakologie   MeSH
• triglyceridy biosyntéza   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Complexation of bilirubin (BR) and biliverdin (BV) with biogenic and toxic metals (Mn, Cu, Cd, Co, Fe, Ni, Zn, and Ag) has been studied by means of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD). Poly-L-lysine and beta-cyclodextrin in water were chosen as matrices capable of recognizing the single stereoconformer of the pigments with defined M-helicity. Such systems allow structural changes caused by complexation of pigments with metals in aqueous solution at pH 10-11 to be followed using chiroptical methods, which are intrinsically sensitive to spatial structure. These and other spectroscopic techniques have revealed that BV and BR form monomeric complexes with Cd, Cu, and Zn and dimeric complexes with Mn. The stabilities of the complexes with Fe, Ni, Co, and Ag are remarkably lower. The sign of the ECD and VCD patterns of the complexed BV does not change for the chelates of any of the studied metals other than Zn, this exception being interpreted in terms of manifestation of the opposite helicity of BV in its chelate with Zn. In the case of BR, the observed inversion of ECD signal after complexation, together with the analysis of VCD spectra, reveals that a flattening of the molecule takes place, i.e., an increase in the angle between the pyrrinone chromophores without an inversion of helicity. This chiral stereoselectivity, which is very specific in the case of the Zn chelates, is discussed in connection with the specific inhibition of Zn-required enzymes by bile pigments.

• MeSH
• bilirubin analýza   chemie   MeSH
• biliverdin analýza   chemie   MeSH
• cirkulární dichroismus metody   MeSH
• elektrony MeSH
• molekulární struktura MeSH
• polylysin MeSH
• spektrofotometrie infračervená MeSH
• těžké kovy analýza   chemie   MeSH
• vibrace MeSH
• Publikační typ
• práce podpořená grantem MeSH