Changes In Bile Acid Composition Research Articles

Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism

BackgroundAPOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear. MethodsC57BL/6 WT and ApoH−/− mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed. ResultsApoH−/− mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH−/− mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH−/− mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism. ConclusionAPOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.

Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes. Male and female intestine-specific WASHC1-deficient mice (Washc1IKO) were challenged with either a standard chow diet or a high-cholesterol (1.25 %) diet (HCD). Washc1IKO mice fed a standard diet did not present any apparent phenotype, but when fed an HCD, their hepatic cholesterol levels were ~ 50 % lower compared to those observed in control mice. The intestinal cholesterol absorption was almost 2-fold decreased in Washc1IKO mice, which translated into increased fecal neutral sterol loss. The intestinal expression of cholesterogenic genes, such as Hmgcs1, Hmgcr, and Ldlr, was significantly higher in Washc1IKO mice than in control mice and correlated with increased whole-body de novo cholesterol synthesis, likely to compensate for impaired intestinal cholesterol absorption. Unexpectedly, the ratio of biliary 12α−/non-12α-hydroxylated bile acids (BAs) was decreased in Washc1IKO mice and reversing this reduced ratio by feeding the mice with the HCD supplemented with 0.5 % (w/w) sodium cholate normalized the improvement of hepatic cholesterol levels in Washc1IKO mice. Our data indicate that the intestinal WASH complex plays an important role in intestinal cholesterol absorption, likely by modulating biliary BA composition.

Barley consumption under a high-fat diet suppresses lipogenic genes through altered intestinal bile acid composition

We evaluated whether barley flour consumption in a high-fat environment affects lipid metabolism through signals mediated by bile acids. Four-week-old mice were fed a high-fat diet supplemented with cellulose (HC) or β-glucan-rich barley flour (HB) for 12 weeks. Bile acid composition in the intestinal tract and feces was measured by GC/MS. Gene expression levels involved in bile acid metabolism in the liver and intestinal tract were determined by RT-PCR. Similar parameters were measured in mice treated with antibiotics (antibiotics-cellulose [AC] and antibiotics-barley [AB]) to reduce the activity of intestinal bacteria. The Results showed that the HB group had lower liver blood cholesterol and triglyceride levels than the HC group. The HB group showed a significant decrease in primary bile acids in the gastrointestinal tract compared to the HC group. On the other hand, the concentration of secondary bile acids relatively increased in the cecum and feces. In the liver, Fxr activation suppressed gene expression levels in synthesizing bile acids and lipids. Furthermore, in the gastrointestinal tract, Tgr5 was activated by increased secondary bile acids. Correspondingly, AMP levels were increased in the HB group compared to the HC group, AMPK was phosphorylated in the liver, and gene expression involved in lipid synthesis was downregulated. A comparison of the AC and AB groups treated with antibiotics did not confirm these effects of barley intake. In summary, our results suggest that the prevention of lipid accumulation by barley consumption involves signaling through changes in bile acid composition in the intestinal tract.

Bsep/Abcb11 knockout ameliorates Schistosoma mansoni liver pathology by reducing parasite fecundity.

Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni-induced inflammation and fibrosis. Adult FVB/N wild type (WT) and Abcb11/Bsep-/- mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. Bsep-/- mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep-/- mice, inflammatory cells such as M2 macrophages and Mac-2/galectin-3+ cells were reduced in these animals. Accordingly, mRNA-expression levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased in Bsep-/- mice upon infection. Furthermore, infected Bsep-/- mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep-/- mice. The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni-induced hepatic inflammation and fibrosis.

Analysis of the Bile Acid Composition in a Fibroblast Growth Factor 19-Expressing Liver-Humanized Mouse Model and Its Use for CYP3A4-Mediated Drug-Drug Interaction Studies.

Numerous biomedical applications have been described for liver-humanized mouse models, such as in drug metabolism or drug-drug interaction (DDI) studies. However, the strong enlargement of the bile acid (BA) pool due to lack of recognition of murine intestine-derived fibroblast growth factor-15 by human hepatocytes and a resulting upregulation in the rate-controlling enzyme for BA synthesis, cytochrome P450 (CYP) 7A1, may pose a challenge in interpreting the results obtained from such mice. To address this challenge, the human fibroblast growth factor-19 (FGF19) gene was inserted into the Fah-/- , Rag2-/- , Il2rg-/- NOD (FRGN) mouse model, allowing repopulation with human hepatocytes capable of responding to FGF19. While a decrease in CYP7A1 expression in human hepatocytes from humanized FRGN19 mice (huFRGN19) and a concomitant reduction in BA production was previously shown, a detailed analysis of the BA pool in these animals has not been elucidated. Furthermore, there are sparse data on the use of this model to assess potential clinical DDI. In the present work, the change in BA composition in huFRGN19 compared with huFRGN control animals was systematically evaluated, and the ability of the model to recapitulate a clinically described CYP3A4-mediated DDI was assessed. In addition to a massive reduction in the total amount of BA, FGF19 expression in huFRGN19 mice resulted in significant changes in the profile of various primary, secondary, and sulfated BAs in serum and feces. Moreover, as observed clinically, administration of the pregnane X receptor agonist rifampicin reduced the oral exposure of the CYP3A4 substrate triazolam. SIGNIFICANCE STATEMENT: Transgenic expression of FGF19 normalizes the unphysiologically high level of bile acids in a chimeric liver-humanized mouse model and leads to massive changes in bile acid composition. These adaptations could overcome one of the potential impediments in the use of these mouse models for drug-drug interaction studies.

Longitudinal Bile Acid Composition Changes Following Faecal Microbiota Transplantation for Clostridioides difficile Infection in Children With and Without Underlying Inflammatory Bowel Disease.

Faecal microbiota transplant [FMT] is effective in treating recurrent Clostridioides difficile infection [CDI] and restores gut microbiota composition. This is unlikely to account for its entire mechanism of efficacy, as studies have shown that factors such as bile acids influence the risk of infection by affecting Clostridioides difficile germination. We therefore aimed to investigate longitudinal changes in the gut bile acid composition after FMT performed for recurrent CDI, in children with and without inflammatory bowel disease [IBD]. Eight children received FMT; five had underlying IBD. Primary and secondary faecal bile acids were measured by liquid chromatography-mass spectrometry in recipients [pre-FMT and longitudinally post-FMT for up to 6 months] and donors. Pre-FMT, recipients had higher primary and lower secondary bile acid proportions compared with donors. Post-FMT, there was a gradual increase of secondary and decrease of primary bile acids. Whereas gut bacterial diversity had been shown to be restored in all children shortly after FMT, normalisation of bile acids to donor levels occurred only by 6 months. In children with IBD, although microbiota diversity returned to pre-FMT levels within 6 months, secondary bile acids remained at donor levels. The differences in bile acid profiles compared with gut bacterial diversity post-FMT suggests that interactions between the two may be more complex than previously appreciated and may contribute to FMT efficacy in different ways. This initial finding demonstrates the need to further investigate gut metabolites in larger cohorts, with longitudinal sampling to understand the mechanisms of FMT effectiveness.

Invited Commentary for Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury

In this issue, Tecos et al [ 1 Tecos ME Steinberger AE Guo J Rubin DC Davidson NO Warner BW Disruption of enterohepatic circulation of bile acids ameliorates small bowel resection associated hepatic injury. J Pediatr Surg. 2023; (in press) Google Scholar ] expand on their previous demonstration that parenteral nutrition (PN)-independent hepatoxicity in a murine small bowel resection (SBR) model is region dependent and may be mitigated by tauroursodeoxycholic acid (TUDCA) supplementation. Interestingly, these results contradict a previous report from their own group as to the impact of proximal vs. distal resection, seemingly due to the presence or absence of the ileocecal valve (ICV) and adjacent bowel, which differed between the two studies [ 2 Barron LK Gayer GP Roberts A Golden JM Aladegbami BG Guo J Erwin CR Warner BW Liver steatosis induced by small bowel resection is prevented by oral vancomycin. Surgery. 2016; 160: 1485-1495 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar ]. Dr. Warner’s group was the first to report liver injury in a PN-independent murine SBR model [ 3 Chiang JYL Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 2017 Jun; 1: 3-9 Crossref PubMed Scopus (140) Google Scholar ]. In this latest study, they reveal that proximal SBR results in greater oxidative stress in the liver as evidenced by elevated mRNA transcripts for tumor necrosis factor-α, nicotininamide adenine dinucleotide phosphate oxidase, and glutathione synthetase with a greater compensatory antioxidant response consisting of elevated lipocalin 2. Furthermore, distal SBR demonstrated decreased hepatic bile acid content, smaller total bile acid pool size, and significant changes in bile acid composition, such as a decrease in the most insoluble, toxic, and hydrophobic bile acids, as well as an increase in de novo bile acid synthesis of physiologic, less toxic, hydrophilic bile acids. Equally compelling, the hepatotoxicity and injurious bile acid profile observed in proximal SBR was mitigated by exogenous TUDCA supplementation. In addition to these intriguing observations, the authors propose a mechanism for this difference. Distal SBR results in disruption of enterohepatic bile acid recycling, leading to amplified production of more physiologic, less toxic, and more hydrophilic bile acids, resulting in less oxidative stress to the liver and ultimately decreased liver injury. While TUDCA had similar hepatoprotective effects to distal SBR, they were not identical, and thus, the authors suggest it may differ in mechanism of action. Regardless, this study expands on the identification of therapeutic targets for intestinal failure-associated liver disease.

The Effects of Taurocholic Acid on Biliary Damage and Liver Fibrosis Are Mediated by Calcitonin-Gene-Related Peptide Signaling.

Background & aims: Cholangiocytes are the target cells of liver diseases that are characterized by biliary senescence (evidenced by enhanced levels of senescence-associated secretory phenotype, SASP, e.g., TGF-β1), and liver inflammation and fibrosis accompanied by altered bile acid (BA) homeostasis. Taurocholic acid (TC) stimulates biliary hyperplasia by activation of 3′,5′-cyclic cyclic adenosine monophosphate (cAMP) signaling, thereby preventing biliary damage (caused by cholinergic/adrenergic denervation) through enhanced liver angiogenesis. Also: (i) α-calcitonin gene-related peptide (α-CGRP, which activates the calcitonin receptor-like receptor, CRLR), stimulates biliary proliferation/senescence and liver fibrosis by enhanced biliary secretion of SASPs; and (ii) knock-out of α-CGRP reduces these phenotypes by decreased cAMP levels in cholestatic models. We aimed to demonstrate that TC effects on liver phenotypes are dependent on changes in the α-CGRP/CALCRL/cAMP/PKA/ERK1/2/TGF-β1/VEGF axis. Methods: Wild-type and α-CGRP−/− mice were fed with a control (BAC) or TC diet for 1 or 2 wk. We measured: (i) CGRP levels by both ELISA kits in serum and by qPCR in isolated cholangiocytes (CALCA gene for α-CGRP); (ii) CALCRL immunoreactivity by immunohistochemistry (IHC) in liver sections; (iii) liver histology, intrahepatic biliary mass, biliary senescence (by β-GAL staining and double immunofluorescence (IF) for p16/CK19), and liver fibrosis (by Red Sirius staining and double IF for collagen/CK19 in liver sections), as well as by qPCR for senescence markers in isolated cholangiocytes; and (iv) phosphorylation of PKA/ERK1/2, immunoreactivity of TGF-β1/TGF- βRI and angiogenic factors by IHC/immunofluorescence in liver sections and qPCR in isolated cholangiocytes. We measured changes in BA composition in total liver by liquid chromatography/mass spectrometry. Results: TC feeding increased CALCA expression, biliary damage, and liver inflammation and fibrosis, as well as phenotypes that were associated with enhanced immunoreactivity of the PKA/ERK1/2/TGF-β1/TGF-βRI/VEGF axis compared to BAC-fed mice and phenotypes that were reversed in α-CGRP−/− mice fed TC coupled with changes in hepatic BA composition. Conclusion: Modulation of the TC/ α-CGRP/CALCRL/PKA/ERK1/2/TGF-β1/VEGF axis may be important in the management of cholangiopathies characterized by BA accumulation.

Using targeted LC‐MS/MS‐based metabolomics to measure a broad constellation of bile acids/salts in disorders of human health

BackgroundBile is an important liver secretion which aids the digestion of fats in the intestine. Bile acids are the major organic solute component of bile and are synthesized from cholesterol in the liver and stored in the gallbladder. After secretion in the intestine, bile acids are re‐absorbed in the distal small intestine (ileum). Imbalances in the reabsorption of bile acids can lead to bile acid diarrhea when bile acid malabsorption occurs. Conversely, when there is an increase in bile acid absorption hepatic disorders such as nonalcoholic fatty liver disease can arise. A wide array of distinct bile acid structures have been identified in vertebrates. Developing and refining experimental tools to identify the role of bile acids in health and disease will enhance our ability to treat complex disorders impacting multiple organ systems.Methods &amp; ResultsWe have expanded our existing reverse‐phase liquid chromatography‐tandem mass spectrometry (LC‐MS/MS)‐based targeted metabolomics method to accommodate a simple‐to‐use standards kit that includes reference standards for 16 bile acids/salts and their corresponding deuterated isotopologs as internal standards. LC‐MS/MS method enhancements include scheduled Selected‐Reaction Monitoring (sSRM) to reduce instrument duty cycle, and carefully tailored chromatographic conditions to resolve the following groups of structurally similar or isobaric bile acids/salts: i) Glycocholic Acid (GCA) and Taurocholic Acid (TCA); ii) Lithocholic Acid (LCA), Glycolithocholic Acid (GLCA), and Taurolithocholic Acid (TLCA); iii) isobaric Cholic Acid (CA) and beta‐Muricholic Acid (b‐MCA); iv) isobaric Ursodeoxycholic Acid (UDCA), Chenodeoxycholic Acid (CDCA), and Deoxycholic Acid (DCA); v) isobaric Glycoursodeoxycholic Acid (GUDCA), Glycochenodeoxycholic Acid (GCDCA), and Glycodeoxycholic Acid (GDCA); and vi) isobaric Tauroursodeoxycholic Acid (TUDCA), Taurochenodeoxycholic Acid (TCDCA), and Taurodeoxycholic Acid (TDCA). Our tissue processing and metabolite extraction procedures have been optimized for hepatic and fecal tissues. Individuals with inactivating mutations in the molecular motor, Myosin Vb, have severe diarrhea and often present with liver cholestasis. We used an animal model of loss of Myosin Vb to determine alterations in bile acid composition in the distal small intestine and liver. Whole segments of the ileum and liver were processed in methanol and analyzed by LC‐MS/MS.ConclusionWe have developed a targeted metabolomics method to accurately identify and quantify bile acids by LC‐MS/MS and this technique can be used to investigate changes in bile acid composition in gastrointestinal disorders.

Abstract 123: Intestinal Deletion Of 3-hydroxy-3-methylglutaryl-coenzyme A Reductase Promotes Expansion Of The Resident Stem Cell Compartment

While the intestine is the critical interface between cholesterol absorption and excretion, surprisingly little is known about the role of de novo cholesterol synthesis in this organ and how it affects whole body cholesterol homeostasis. The mevalonate pathway is most well-known for the production of cholesterol, but it is also required for the production of essential non-sterol isoprenoids. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, is regulated by a three-protein complex made up of INSIG, SCAP, and SREBP2. Intestine specific knockouts of Scap and Srebp2 both result in severe enteropathy and reduced mouse survival. Here, we assessed the hypothesis that Hmgcr is required for enterocyte viability. Mice harboring floxed alleles for Hmgcr were bred with the Villin-Cre transgene to specifically knock out this enzyme in the villus and crypt epithelial cells of the small intestine (i-KO). The i-KO mice are viable through adulthood and fertile. Hmgcr is efficiently deleted based on analysis via drop digital PCR and qPCR. RNA sequencing shows reduction in all SREBP2 target genes throughout the mevalonate pathway in intestinal epithelial cells. Lipidomics confirms substantial reductions in abundance of all sterol and non-sterol isoprenoids, except 7-dehydrocholesterol and cholesterol. Cholesterol is likely maintained through reabsorption of biliary cholesterol or increased uptake from the circulation. Circulating cholesterol levels and cholesterol absorption are not altered in i-KO mice, but triglyceride absorption is increased through compensatory changes in bile acid composition and intestinal growth. At the cellular level, the intestine rapidly compensates for loss of Hmgcr via dramatic expansion of the stem cell compartment within the crypts. In conclusion, the mechanisms by which the intestine compensates for genetic loss of Hmgcr include altered triglyceride absorption, bile acid composition, increased absorptive surface area, and expansion of the resident stem cell compartment. Together these studies provide insight into the effects of HMGCR knockout in intestinal development and lipid metabolism.

Cyp2c-deficiency depletes muricholic acids and protects against high-fat diet-induced obesity in male mice but promotes liver damage

ObjectiveMurine-specific muricholic acids (MCAs) are reported to protect against obesity and associated metabolic disorders. However, the response of mice with genetic depletion of MCA to an obesogenic diet has not been evaluated. We used Cyp2c-deficient (Cyp2c−/−) mice, which lack MCAs and thus have a human-like bile acid (BA) profile, to directly investigate the potential role of MCAs in diet-induced obesity. MethodsMale and female Cyp2c−/− mice and wild-type (WT) littermate controls were fed a standard chow diet or a high-fat diet (HFD) for 18 weeks. We measured BA composition from a pool of liver, gallbladder, and intestine, as well as weekly body weight, food intake, lean and fat mass, systemic glucose homeostasis, energy expenditure, intestinal lipid absorption, fecal lipid, and energy content. ResultsCyp2c-deficiency depleted MCAs and caused other changes in BA composition, namely a decrease in the ratio of 12α-hydroxylated (12α-OH) BAs to non-12α-OH BAs, without altering the total BA levels. While WT male mice became obese after HFD feeding, Cyp2c−/− male mice were protected from obesity and associated metabolic dysfunctions. Cyp2c−/− male mice also showed reduced intestinal lipid absorption and increased lipid excretion, which was reversed by oral gavage with the 12α-OH BA and taurocholic acid (TCA). Cyp2c−/− mice also showed increased liver damage, which appeared stronger in females. ConclusionsMCA does not protect against diet-induced obesity but may protect against liver injury. Reduced lipid absorption in Cyp2c-deficient male mice is potentially due to a reduced ratio of 12α-OH/non-12α-OH BAs.

Characteristics of bile acid composition in high fat diet-induced nonalcoholic fatty liver disease in obese diabetic rats.

Bile acid has attracted attention as a signal transmission molecule in energy metabolism. Although a high-fat diet (HFD) or obesity is known to increase hepatic fat content and alter bile acid composition, the changes in bile acid composition due to HFD or obesity remain to be elucidated. We sought to examine the bile acid composition in high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in obese diabetic rats. Eight-week-old male spontaneously diabetic Torii fatty (SDTF) rats or control rats were fed an HFD. Twelve weeks post the commencement of HFD, serum and hepatic bile acid compositions and serum GLP-1 levels, which is stimulated by the secondary bile acid deoxycholic acid (DCA), were measured. The correlation between the bile acid composition and serum GLP-1 levels was also examined. While serum and hepatic levels of cholic acid (CA), a primary bile acid, tended to decrease in HFD-fed control rats, they were significantly decreased in HFD-fed SDTF rats. Hepatic CYP8B1, which plays a role in CA synthesis, the mRNA levels were significantly decreased in HFD-fed control and SDTF rats. In contrast, while serum and hepatic DCA levels were not changed in HFD-fed control rats, they were decreased in HFD-fed SDTF rats. Hepatic DCA/CA did not change in HFD-fed SDTF rats, but significantly increased in HFD-fed control rats. While serum GLP-1 levels were not changed in SDTF rats, they were significantly increased in HFD-fed control rats. Hepatic DCA/CA tended to correlate with serum GLP-1 levels, which tended to negatively correlate with the hepatic triglyceride content in SDTF rats. These results indicate that relatively increased DCA might contribute to an increase in serum GLP-1 levels, which inhibits hepatic steatosis in NAFLD.

Review article: Elobixibat: a novel treatment for chronic constipation.

A subset of patients with chronic constipation has associated slow colonic transit and reduced faecal bile acid excretion. In addition to traditional approaches to treat chronic constipation, a novel therapeutic option is to increase the colonic concentration of intraluminal bile acids. This can be achieved through inhibition of the ileal bile acid transporter. To evaluate the evidence for efficacy and safety of an ileal bile acid transport inhibitor in the treatment of chronic constipation METHODS: We reviewed published literature on elobixibat, based on a PubMed search. Elobixibat is a novel ileal bile acid transport inhibitor that has demonstrated efficacy in proof of concept studies in experimental animals as well as phase 1, 2 and 3 trials in humans. Phase 4 studies have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content. The studies documented efficacy in patients with severe constipation, which is often associated with slow colonic transit. These changes in bile acid composition were associated with minor differences in the faecal microbiota in patients treated with elobixibat compared to placebo. Elobixibat appears to be safe. The only adverse effects of note are associated with its pharmacological actions in patients with chronic constipation,namely the induction of diarrhoea and abdominal pain. This new class of compound appears to be safe and efficacious in the treatment of chronic constipation.

Induction of blood-circulating bile acids supports recovery from myelosuppressive chemotherapy

AbstractChemotherapeutic agents can reduce bone marrow (BM) activity, causing myelosuppression, a common life-threatening complication of cancer treatment. It is challenging to predict the patients in whom prolonged myelosuppression will occur, resulting in a delay or discontinuation of the treatment protocol. An early indicator of recovery from myelosuppression would thus be highly beneficial in clinical settings. In this study, bile acids (BAs) were highly increased in the systemic circulation as a natural response during recovery from myelosuppression, supporting regeneration of BM cells. BA levels in the blood of pediatric cancer patients and mice treated with chemotherapeutic agents were increased, in synchrony with early proliferation of BM cells and recovery from myelosuppression. In a mouse model of altered BA composition, Cyp8b1 knockout mice, a subset of mice recovered poorly after chemotherapy. The poor recovery correlated with low levels and changes in composition of BAs in the liver and systemic circulation. Conversely, BA supplementation in chemotherapy-treated wild-type mice resulted in significantly improved recovery. The results suggest that part of the mechanism by which BAs support recovery is the suppression of endoplasmic reticulum stress pathways in expanding and recovering hematopoietic cells. The findings propose a novel role of BAs as early markers of recovery and active components of the recovery process after chemotherapy.

Decrease in major secondary bile acid, hyodeoxycholic acid, was the main alteration in hepatic bile acid compositions in a hypertensive nonalcoholic fatty liver disease model.

Previous findings on hepatic bile acid compositions in nonalcoholic fatty liver disease (NAFLD) have been inconsistent and complicated. The aim of this study was to investigate the effects of steatosis on hepatic bile acid composition in a hypertensive NAFLD model without obesity and diabetes mellitus and compare hepatic bile acid composition between hypertensive rats with and without steatosis. Two groups of hypertensive rats were studied: spontaneously hypertensive rats (SHR) fed with a normal diet (SHR-N) or a choline-deficient diet (SHR-CD). Two groups of normotensive rats were studied: Wistar Kyoto rats (WKY) fed a normal diet (WKY-N) or a choline-deficient diet (WKY-CD). Hepatic bile acid analysis was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry. Regarding bile acid composition, the hyodeoxycholic acid (HDCA) species in the SHR-CD group showed the largest change in bile acid composition, significantly decreasing to 21.9% of that found in the SHR-N group. In the WKY-CD group, no reduction of HDCA species was observed. We demonstrated that the decrease in HDCA species was the main alteration in a hypertensive NAFLD model. It was suggested that the decrease in HDCA species in the SHR-CD group was caused by dysbiosis.

Characteristics of bile acids metabolism profile in the second and third trimesters of normal pregnancy

PurposeBile acids are a group of cholesterol metabolites functioning as key regulators of glucose, lipid, and energy metabolism. Their homeostatic control is essential to the physiology of the normal pregnancy. Abnormalities of bile acids regulation in pregnancy lead to intrahepatic cholestasis of pregnancy, a serious condition associated with a number of fetal and maternal morbidities. Dysregulation of glucose and lipids is also tied to perturbations in bile acid concentrations. Changes in bile acid metabolic profiles in the second and third trimesters of pregnancy have been incompletely explored. We seek to establish pregnancy-specific normative ranges for a number of bile acids in women in the second and third trimesters and explore changes in their concentrations in the period from 12 to 40 weeks gestation. ProcedureIn this cross-sectional study, a total of 782 normal pregnant women were enrolled including n = 290 in the second trimester (12–28 weeks) and n = 492 in the third trimester (29–40 weeks). The concentrations of 14 bile acids were measured by liquid chromatography and mass spectrometry (LC-MS) and compared at various time points. Reference intervals of these bile acids were calculated using standard statistical techniques. ResultsA reference interval profile of 14 bile acids from a cohort of 782 normal pregnant women was developed. Significant differences in concentration were found between the second trimester and the third trimester. Unconjugated bile acids dominate the bile acid profile in the second trimester, while conjugated bile acids, especially (taurine-conjugated) dominate in the third trimester. 28–31 weeks gestation was the notable change period of bile acid metabolism. ConclusionThis study establishes pregnancy-specific reference intervals for bile acids in the second and third trimesters. As bile acid composition changes with gestational age, this study establishes a foundation for trimester-specific clinical interpretation of bile acid metabolic profiles in pregnant women.

Клинические рекомендации Российской гастроэнтерологической ассоциации по диагностике и лечению дискинезии желчевыводящих путей

Aim of publication. To present the guidelines on diagnostics and treatment of biliary dyskinesia to practical doctors. Summary. The gallbladder dyskinesia and sphincter of Oddi dyskinesia are defined as the diseases of functional origin caused by motility and visceral sensitivity disorders. The pathogenesis of these disorders is not completely understood. Development of sphincter of Oddi dysfunction is related to previous cholecystectomy. Contractility disorders along with increased lithogenicity followed by cyclooxygenase-2 overactivation in biliary tract tissue play significant pathogenic role; putative change in bile acid composition may be involved as well. Diagnosis of biliary dyskinesia requires first the careful analysis of pattern of pain and compliance of symptoms to biliary pain criteria; second, instrumental tests that exclude organic origin of biliary disease. Estimation of the type of biliary dysfunction is established on compliance of the detected symptoms to proposed criteria. Conclusion. Biliary dyskinesia pathogenesis is not studied well. Development of attacks of biliary pain (according to established criteria) and lack of organic disorders evidence, may help to suspect the presence of biliary dyskinesia. To exclude organic biliary diseases with confidence, informative modern diagnostic tests of biliary tract visualization should be applied. Therapeutic approach should include correction of diet and lifestyle modification, administration of antispasmodic medications and agents modulating the state of nervous system, in selected cases the option of papillosphincterotomy should be considered.

Mice lacking ARV1 have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

Metabolic syndrome (MetS) is a term used to characterize individuals having at least three of the following diseases: obesity, dyslipidemia, hyperglycemia, insulin resistance, hypertension, and nonalcoholic fatty liver disease (NAFLD). It is widespread, and the number of individuals with MetS is increasing. However, the events leading to the manifestation of MetS are not well-understood. Here, we show that loss of murine ARV1 (mARV1) results in resistance to acquiring diseases associated with MetS. Arv1-/- animals fed a high-fat diet were resistant to diet-induced obesity, had lower blood cholesterol and triglyceride levels, and retained glucose tolerance and insulin sensitivity. Livers showed no gross morphological changes, contained lower levels of cholesterol, triglycerides, and fatty acids, and showed fewer signs of NAFLD. Knockout animals had elevated levels of liver farnesol X receptor (FXR) protein and its target, small heterodimer protein (SHP). They also had decreased levels of CYP7α1, CYP8β1, and mature SREBP1 protein, evidence suggesting that liver FXR signaling was activated. Strengthening this hypothesis was the fact that peroxisome proliferator-activating receptor α (PPARα) protein was elevated, along with its target, fibroblast growth factor 21 (FGF21). Arv1-/- animals excreted more fecal cholesterol, free fatty acids, and bile acids. Their small intestines had 1) changes in bile acid composition, 2) an increase in the level of the intestinal FXR antagonist, tauromuricholic acid, and 3) showed signs of attenuated FXR signaling. Overall, we believe that ARV1 function is deleterious when consuming a high-fat diet. We further hypothesize that ARV1 is critical for initiating events required for the progression of diseases associated with MetS and NAFLD.

Quantitative profiling of 19 bile acids in rat plasma, liver, bile and different intestinal section contents to investigate bile acid homeostasis and the application of temporal variation of endogenous bile acids

Bile acid homeostasis is maintained by liver synthesis, bile duct secretion, microbial metabolism and intestinal reabsorption into the blood. When drug insults result in liver damage, the variances of bile acids (BAs) are related to the physiological status of the liver. Here, we established a method to simultaneously quantify 19 BAs in rat plasma, liver, bile and different intestinal section contents (duodenum, jejunum, ileum, cecum and colon) using high-performance liquid chromatography-tandem mass spectrometry (LC–MS/MS) to reveal the pattern of bile acid homeostasis in the enterohepatic circulation of bile acids in physiological situations. Dynamic changes in bile acid composition appeared throughout the enterohepatic circulation of the BAs; taurine- and glycine-conjugated BAs and free BAs had different dynamic homeostasis levels in the circulatory system. cholic acid (CA), beta-muricholic acid (beta-MCA), lithocholic acid (LCA), glycocholic acid (GCA) and taurocholic acid (TCA) greatly fluctuated in the bile acid pool under physiological conditions. Taurine- and glycine-conjugated bile acids constituted more than 90% in the bile and liver, whereas GCA and TCA accounted for more than half of the total bile acids and the secretion of bile mainly via conjugating with taurine. While over 80% of BAs in plasma were unconjugated bile acids, CA and HDCA were the most abundant elements. Unconjugated bile acids constituted more than 90% in the intestine, and CA, beta-MCA and HDCA were the top three bile acids in the duodenum, jejunum and ileum content, but LCA and HDCA were highest in the cecum and colon content. As the main secondary bile acid converted by microflora in the intestine, LCA was enriched in the cecum and DCA mostly in the colon. As endogenous substances, the concentrations of plasma BAs were closely related to time rhythm and diet. In conclusion, analyzing detailed BA profiles in the enterohepatic circulation of bile acids in a single run is possible using LC–MS/MS. Based on the physiological characteristics of the metabolic profiling of 19 BAs in the total bile acid pool and the time rhythm variation of the endogenous bile acids, this study provided a new valuable method and theoretical basis for the clinical research of bile acid homeostasis.

Bile acid composition of gallbladder contents in dogs with gallbladder mucocele and biliary sludge.

OBJECTIVE To examine bile acid composition of gallbladder contents in dogs with gallbladder mucocele and biliary sludge. ANIMALS 18 dogs with gallbladder mucocele (GBM group), 8 dogs with immobile biliary sludge (i-BS group), 17 dogs with mobile biliary sludge (m-BS group), and 14 healthy dogs (control group). PROCEDURES Samples of gallbladder contents were obtained by use of percutaneous ultrasound-guided cholecystocentesis or during cholecystectomy or necropsy. Concentrations of 15 bile acids were determined by use of highperformance liquid chromatography, and a bile acid compositional ratio was calculated for each group. RESULTS Concentrations of most bile acids in the GBM group were significantly lower than those in the control and m-BS groups. Compositional ratio of taurodeoxycholic acid, which is 1 of 3 major bile acids in dogs, was significantly lower in the GBM and i-BS groups, compared with ratios for the control and m-BS groups. The compositional ratio of taurocholic acid was significantly higher and that of taurochenodeoxycholic acid significantly lower in the i-BS group than in the control group. CONCLUSIONS AND CLINICAL RELEVANCE In this study, concentrations and fractions of bile acids in gallbladder contents were significantly different in dogs with gallbladder mucocele or immobile biliary sludge, compared with results for healthy control dogs. Studies are needed to determine whether changes in bile acid composition are primary or secondary events of gallbladder abnormalities.