Explore the vast range of titles available.

Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases 1 – 3 . Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium . These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis. The microbiota of centenarians (aged 100 years and older) comprise gut microorganisms that are capable of generating unique secondary bile acids, including isoallolithocholic acid, a bile acid with potent antimicrobial effects against Gram-positive—but not Gram-negative—multidrug-resistant pathogens.

Bile acids have received increasing attention as a marker of the long-term prognosis and a potential therapeutic target in patients with biliary atresia, which is a progressive disease of the hepatobiliary system. A detailed analysis of serum and urinary bile acid compositions was conducted to assess the characteristics of bile acid profiles and the correlation between bile acid profiles and liver fibrosis markers in adult patients with biliary atresia who achieved bilirubin normalization. Serum total bile acids and glucuronide-conjugated (glyco- and tauro-) cholic acids (GCA and TCA) and chenodeoxycholic acids (GCDCA and TCDCA) were significantly higher in patients with biliary atresia than in healthy controls, whereas unconjugated CA and CDCA showed no significant difference. There were no significant differences in CA to CDCA ratios and glycine-to-taurine-conjugated ratios. Urinary glycocholic acid 3-sulfate (GCA-3S) was significantly higher in patients with biliary atresia. Serum GCDCA showed a strong positive correlation with Mac-2 binding protein glycosylation isomer (M2BPGi). These results demonstrate that bile acid congestion persists into adulthood in patients with biliary atresia, even after cholestasis has completely improved after Kasai portoenterostomy. These fundamental data on bile acid profiles also suggest the potential value of investigating bile acid profiles in patients with biliary atresia.

Few reports describe oxysterols in healthy children or in children with liver disease. We aimed to determine whether developmental changes in urinary and serum oxysterols occur during childhood, and to assess whether oxysterols might be biomarkers for pediatric liver disease. Healthy children enrolled as subjects (36 and 35 for urine and serum analysis, respectively) included neonates, infants, preschoolers, and school-age children, studied along with 14 healthy adults and 8 children with liver disease. We quantitated 7 oxysterols including 4β-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol using liquid chromatography/electrospray ionization-tandem mass spectrometry. Urinary total oxysterols were significantly greater in neonates than in infants ( P  <  0.05 ), preschoolers ( P  <  0.001 ), school-age children ( P  <  0.001 ), or adults ( P  <  0.001 ), declining with age. Serum total oxysterols in neonates were significantly lower than in infants ( P  <  0.05 ), preschoolers ( P  <  0.001 ), school-age children ( P  <  0.05 ), or adults ( P  <  0.01 ). Compared with healthy children, total oxysterols and 24(S)-hydroxycholesterol in liver disease were significantly increased in both urine ( P  <  0.001 and P  <  0.001 , respectively) and serum ( P  <  0.001 and P  <  0.05 , respectively). Oxysterols in liver disease, particularly 24(S)-hydroxycholesterol, were greater in urine than serum. Oxysterols change developmentally and might serve as a biomarker for pediatric liver disease. To our knowledge, this is the first such report.

BackgroundWe encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21 years between 1996 and 2017.AimWe aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency.MethodsDiagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography–mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems.ResultsMedians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted.ConclusionsWe concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.

An aqueous solution of a common food dye, Fast Green FCF (FG), mimics cholyl-lysyl-fluorescein to visualize embryonic bile flow via single peritoneal injection into intrauterine mouse embryos. Despite its efficacy in embryos, its suitability for adult mice and small to medium-sized mammals remained uncertain. In this study, we investigated FG cholangiography in adult mice, dogs, and goats. The results demonstrate that FG injection enables progressive cholangiography in these species, highlighting its versatility across different animal models without necessitating specialized equipment. To further evaluate diagnostic utility, FG cholangiography was performed in various mouse models of bile flow disorders. FG successfully visualized dilated lumina in the extrahepatic bile duct of BDL mice and revealed aberrant luminal structures in the gallbladder walls of Sox17 +/− or Shh-cre ; Sox17 flox/− mice. In Mab21l1 −/− mice with contracted gallbladders, FG influx was limited to the gallbladder neck. Moreover, stereomicroscopic video analysis of FG influx into the gallbladder post-fasting revealed differences in gallbladder wall state and its bile composition between Sox17 +/− and wild-type mice, suggesting the potential for detecting variations in gallbladder stored bile properties. These findings underscore the efficacy of FG in facilitating progressive cholangiography across mammalian species.

Diagnosis of biliary atresia (BA) can involve uncertainties. In the present prospective multicenter study, we considered whether urinary oxysterols represent a useful marker for diagnosis of BA in Japanese children. Subjects under 6 months old at 7 pediatric centers in Japan were prospectively enrolled, including patients with cholestasis and healthy controls (HC) without liver disease. Patients with cholestasis constituted 2 groups representing BA patients and others with cholestasis from other causes (non-BA). We quantitatively analyzed 7 oxysterols including 4β-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol by liquid chromatography/electrospray ionization-tandem mass spectrometry. Enrolled subjects included 14 with BA (median age 68 days; range 26–170) and 10 non-BA cholestatic controls (59; 14–162), as well as 10 HC (57; 25–120). Total urinary oxysterols were significantly greater in BA (median, 153.0 μmol/mol creatinine; range 24.1–486.7; P  < 0.001) and non-BA (36.2; 5.8–411.3; P  < 0.05) than in HC (2.7; 0.8–7.6). In patients with BA, urinary 27-hydroxycholesterol (3.61; 0.42–11.09; P  < 0.01) was significantly greater than in non-BA (0.71; 0–5.62). In receiver operating characteristic (ROC) curve analysis for distinguishing BA from non-BA, the area under the ROC curve for urinary 27-hydroxycholesterol was 0.83. In conclusion, this first report of urinary oxysterol analysis in patients with BA indicated that 27-hydroxycholesterol may be a useful marker for distinguishing BA from other causes of neonatal cholestasis.

Background Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome. Results Germfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism ( Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta ; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity ( P =  0.30) and beta-diversity ( P  = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, ( P <  0.05), most notably deoxycholic acid (DCA) (P  < 0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na + /H + antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community. Conclusions This work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.

Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 [SLCO1B1]) and OATP1B3 (SLCO1B3) serve as transporters for hepatic uptake of important endogenous substances and several commonly prescribed drugs. Inactivation of both proteins together causes Rotor syndrome. How this OATP1B1/1B3 defect disturbs bile acid (BA) metabolism is largely unknown. In this study, we performed detailed BA analysis in 3 patients with genetically diagnosed Rotor syndrome. We found that BAs glucuronidated at the C‐3 position (BA‐3G) accounted for 50% or more of total BAs in these patients. In contrast but similarly to healthy controls, only trace amounts of BA‐3G were detected in patients with constitutional indocyanine green excretory defect (OATP1B3 deficiency) or sodium‐taurocholate cotransporting polypeptide (NTCP; gene, solute carrier family 10 member 1 [SLC10A1]) deficiency. Therefore, substantial amounts of BA‐3G are synthesized in hepatocytes. The cycling pathway of BA‐3G, consisting of excretion from upstream hepatocytes and uptake by downstream hepatocytes by OATP1B1/1B3 may exist to reduce the burden on upstream hepatocytes. Conclusion: Detailed BA analysis revealed glucuronidated bile acidemia in patients with Rotor syndrome. Further exploration of the physiologic role of glucuronidated BAs is necessary.

We investigated the age-dependent changes in urinary excretion of glucuronidated bile acids at the C-3 position. Bile acid 3-glucuronides accounted for 0.5% of urinary bile acids in neonates, and the proportion of bile acid 3-glucuronides plateaued at 1–3 years of age. The 3-glucuronides of secondary bile acids were first secreted at 3 months of age, the same time as the establishment of the gut bacterial flora in infants. A considerable portion of bile acid 3-glucuronides were present as non-amidated forms. Our results indicate dynamic hepatic enzyme activity in which the levels of uridine 5′-diphospho-glucuronosyltransferases (UGTs) differ by age group, with higher glucuronidation activity of UGTs towards nonamidated bile acids than amidated bile acids.

BACKGROUND:Hepatic encephalopathy(HE) can recur despite standard of care therapies. Our trial of capsular fecal microbiota transplant (FMT) demonstrated improvement in dysbiosis and cognition in pts randomized to FMT versus placebo. Despite compositional improvement, interaction of inflammation, bacterial translocation, microbial function (bile acid, BA) with cognition needs to be evaluation. Gut microbiota can transform BAs by deconjugating, converting primary to secondary BAs & tertiary(oxo, sulfated, urso and iso-BA) formation. Aim: Determine changes in fecal BA moieties as modulators of microbial function, inflammation and their linkage with cognition in FMT in cirrhosis and recurrent HE.METHODS:20 cirrhotics with recurrent HE on lactulose/rifaximin were randomized 1:1 into 15 FMT capsules once vs identical placebo. FMT was from a single donor enriched in Lachnospiraceae/Ruminococcaceae, which are associated with secondary BA generation. We collected stool/blood & analyzed cognition (EncephalApp; high = worse) at baseline and 30 days post-intervention (Figure 1a red arrows). Stool microbiota was analyzed using 16srRNA & BAs using LC/MS. Fecal BA moieties analyzed were (a) total (b) primary (c) secondary (d) deconjugated (e) tertiary BAs. Secondary/primary BA ratios were calculated. Serum was also analyzed for lipopolysaccharide-binding protein (LBP) & IL-6. Correlation networks between BAs, microbiota, LBP, IL-6 and cognition were created. Correlation network complexity was compared between post-FMT vs post-placebo states.RESULTS:All subjects completed the follow-up without any serious AEs related to FMT/placebo. EncephalApp total score (P < 0.05) improved in FMT pts only Microbiota: there was a significant engraftment of donor microbiota with higher Ruminoccaceae & Lachnospiraceae in stool/duodenum in FMT pts. Inflammation/translocation: A reduction in LBP & IL-6 was seen only in FMT pts (Figure 1b,d). BAs: There was a significant increase in secondary/primary BA ratio (Figure 1c) in FMT pts. Deconjugation and tertiary BAs remained similar between groups. Correlation network showed higher complexity after FMT compared to post-placebo (Figure 1e). Beneficial bacteria (Ruminococcaeae and Verrucomicrobiaceae) became significantly positively correlated with each other (blue lines) and negatively with inflammation (IL6 redlines) and associated with better EncephalApp score post-FMT (Figure 1f) compared to placebo at study end.CONCLUSIONS:Capsular FMT is safe and improves cognition in pts with cirrhosis and HE compared to placebo. These improvements are associated with beneficial changes in microbial composition and function and differential correlations with bacterial translocation and inflammation.