Altered Bile Acid Profiles Research Articles

Gut Microbiota Dysbiosis and Altered Bile Acid Catabolism Lead to Metabolic Disorder in Psoriasis Mice.

Patients with psoriasis tend to have significant comorbidities, such as hyperlipemia, diabetes mellitus, and obesity, which belong to metabolic disorders. The specific mechanism through which psoriasis increases the metabolic disorder risk is uncertain. In this study, we demonstrated that the dysbiotic gut microbiota of 6-month-old psoriasis-like model mice (K14-VEGF-A-transgenic) exacerbated psoriasis disease and induced metabolic disorder when transferred into 2-month-old mice. By 16S rRNA gene sequencing, we confirmed that the Parabacteroides distasonis decreased with age in K14-VEGF mice, and P. distasonis also decreased in the transferred mice. Metabolomic screening identified an altered bile acid profile, including a decrease in chenodeoxycholic acid (CDCA) in the feces of transferred mice. Additionally, CDCA supplements prevented metabolic disorders in K14-VEGF-A-transgenic mice. Consequently, we found that aberrant bile acid metabolism may contribute to metabolic disorder in K14-VEGF-A-transgenic mice, indicating the possibility to prevent and treat the metabolic disorder in psoriasis mice by targeting gut microbial metabolites.

Cinnamomum verum-derived bioactives-functionalized gold nanoparticles for prevention of obesity through gut microbiota reshaping.

Existing drugs have limited success in managing obesity in human due to their low efficacy and severe side-effects. Surface-modified gold nanoparticles have now received considerable attention of researchers for efficient biomedical applications owing to their superior uptake by cells, biocompatibility, hydrophilicity and non-immunogenicity. Here we prepared Cinnamomum verum derived bioactives-functionalized gold nanoparticles (Au@P-NPs) and assessed their impact on obesity and related immune-metabolic complications in high-fat diet (HFD)-induced obese mice using metabolic experiments along with 16S RNA gene-based gut microbial profiling and faecal microbiota transplantation (FMT). Au@P-NPs treatment prevented weight gain, decreased fat deposition, reduced metabolic inflammation and endotoxaemia in HFD-fed mice. Au@P-NPs-treated group exhibited better glucose tolerance and insulin sensitivity than HFD-fed control mice, and got completely protected against hepatic steatosis. These impacts were related to increased energy expenditure and enhanced Ucp1 expression in the brown adipose tissues of Au@P-NPs-administered animals, which strongly linked with the mRNA expression of the membrane bile acid receptor TGR5. Treatment of HFD-fed animals with Au@P-NPs altered plasma bile acid profile, and increased Akkermansia muciniphila and decreased Lactobacillus populations in the faeces. Au@P-NPs-treated animals revealed altered plasma bile acid profile, and increased Akkermansia muciniphila and decreased Lactobacillus populations in the faeces. FMT experiments showed lesser weight gain and greater energy expenditure in the mice fed with faecal suspension from Au@P-NPs-treated animals than that from HFD-fed mice. These results clearly establish that gold nanoparticles functionalized with bioactive compounds of C. verum have high potential to be an anti-obesity drug.

Role of the Gut Microbiota in Regulating Non-alcoholic Fatty Liver Disease in Children and Adolescents

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in children and adolescents. Although obesity is the leading cause of NAFLD, the etiologies of NAFLD are multifactorial (e.g., high-fat diet, a lack of exercise, gender, maternal obesity, the antibiotic use), and each of these factors leads to dysbiosis of the gut microbiota community. The gut microbiota is a key player in the development and regulation of the gut mucosal immune system as well as the regulation of both NAFLD and obesity. Dysbiosis of the gut microbiota promotes the development of NAFLD via alteration of gut-liver homeostasis, including disruption of the gut barrier, portal transport of bacterial endotoxin (lipopolysaccharide) to the liver, altered bile acid profiles, and decreased concentrations of short-chain fatty acids. In terms of prevention and treatment, conventional approaches (e.g., dietary and exercise interventions) against obesity and NAFLD have been confirmed to recover the dysbiosis and dysbiosis-mediated altered metabolism. In addition, increased understanding of the importance of gut microbiota-mediated homeostasis in the prevention of NAFLD suggests the potential effectiveness of gut microbiota-targeted preventive and therapeutic strategies (e.g., probiotics and fecal transplantation) against NAFLD in children and adolescents. This review comprehensively summarizes our current knowledge of the gut microbiota, focusing on its interaction with NAFLD and its potential therapeutic role in obese children and adolescents with this disorder.

Bile acid-receptor TGR5 deficiency worsens liver injury in alcohol-fed mice by inducing intestinal microbiota dysbiosis

Background & AimsBile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice.MethodsWe used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel.ResultsTGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated.ConclusionsA lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol.Lay summaryExcessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.

Berberine alters gut microbial function through modulation of bile acids

BackgroundBerberine (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.ResultsGermfree 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.ConclusionsThis 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.

Alteration of metabolic profile and potential biomarkers in the plasma of Alzheimer's disease

AbstractBackgroundThe expending of elderly population worldwide leads to a dramatical rising in the incidence of chronic diseases including Alzheimer’s Disease (AD) in the elderly. The inadequate understanding of the mechanisms underlying AD is deemed the greatest stumbling block against progress in definitive diagnosis and curative intervention of this disease. Efforts have been made towards the discovery of reliable AD biomarkers, but they are either invasive based on neuropathological markers in cerebrospinal fluid (CSF) or expensive using emission tomography scanning or magnetic resonance imaging techniques. With the emergence of high‐throughput technology that could detect and catalogue larger numbers of small metabolites, metabolomics offers hope for a better understanding of AD and subsequent identification of biomarkers.MethodHerein, using untargeted ultra‐performance liquid chromatography‐mass spectrometry we firstly measured concentrations of plasma metabolites in a cohort of AD subjects (n=44) and cognitively normal controls (Ctrl, n=94).ResultWe found remarkable reductions of polyunsaturated fatty acids (PUFAs), acyl‐carnitines, tryptophan degradation related metabolites and elevated levels of bile acids in AD compared to Ctrl. Followed by repeated validation in an independent cohort including AD (n=30), mild cognitive impairment (MCI, n=13), Ctrl (n=43) and non‐AD neurological disease controls (NDC, n=31), we further identified a metabolite panel consisting of five metabolites including cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid and tryptophan that can distinguish AD from both Ctrl and NDC with satisfactory sensitivity and specificity.ConclusionNotably, the concentrations of these metabolites are significantly correlated with disease severity. Our results also suggested the altered bile acid profiles in AD and MCI might provide clues for early risk of AD. Following further validation in larger cohorts, these findings are expected to provide new approaches for diagnosis of AD and offer novel insights into AD pathogenesis.

Self-reinoculation with fecal flora changes microbiota density and composition leading to an altered bile-acid profile in the mouse small intestine

BackgroundThe upper gastrointestinal tract plays a prominent role in human physiology as the primary site for enzymatic digestion and nutrient absorption, immune sampling, and drug uptake. Alterations to the small intestine microbiome have been implicated in various human diseases, such as non-alcoholic steatohepatitis and inflammatory bowel conditions. Yet, the physiological and functional roles of the small intestine microbiota in humans remain poorly characterized because of the complexities associated with its sampling. Rodent models are used extensively in microbiome research and enable the spatial, temporal, compositional, and functional interrogation of the gastrointestinal microbiota and its effects on the host physiology and disease phenotype. Classical, culture-based studies have documented that fecal microbial self-reinoculation (via coprophagy) affects the composition and abundance of microbes in the murine proximal gastrointestinal tract. This pervasive self-reinoculation behavior could be a particularly relevant study factor when investigating small intestine microbiota. Modern microbiome studies either do not take self-reinoculation into account, or assume that approaches such as single housing mice or housing on wire mesh floors eliminate it. These assumptions have not been rigorously tested with modern tools. Here, we used quantitative 16S rRNA gene amplicon sequencing, quantitative microbial functional gene content inference, and metabolomic analyses of bile acids to evaluate the effects of self-reinoculation on microbial loads, composition, and function in the murine upper gastrointestinal tract.ResultsIn coprophagic mice, continuous self-exposure to the fecal flora had substantial quantitative and qualitative effects on the upper gastrointestinal microbiome. These differences in microbial abundance and community composition were associated with an altered profile of the small intestine bile acid pool, and, importantly, could not be inferred from analyzing large intestine or stool samples. Overall, the patterns observed in the small intestine of non-coprophagic mice (reduced total microbial load, low abundance of anaerobic microbiota, and bile acids predominantly in the conjugated form) resemble those typically seen in the human small intestine.ConclusionsFuture studies need to take self-reinoculation into account when using mouse models to evaluate gastrointestinal microbial colonization and function in relation to xenobiotic transformation and pharmacokinetics or in the context of physiological states and diseases linked to small intestine microbiome and to small intestine dysbiosis.4XA-zWEeGyrQSh45UEwNDtVideo abstract.

EPA-enriched ethanolamine plasmalogen alleviates atherosclerosis via mediating bile acids metabolism

The possible underlying mechanism involved in the alleviation of dietary EPA-enriched ethanolamine plasmalogen (EPA-PlsEtn) on atherosclerosis. Administration with EPA-PlsEtn promoted excess cholesterol to synthesize bile acids via increasing CYP7A1 expression. Increased TMCAs might attribute to the suppression of FXR expression to further enhance the CYP7A1 transcription. • EPA-PlsEtn dramatically reduced atherosclerotic lesions and serum LDL-c levels. • EPA-PlsEtn increased excess cholesterol excrete into feces as bile acid. • EPA-PlsEtn altered bile acids profile and further suppressed FXR expression. The DHA/EPA enriched ethanolamine plasmalogens (EPA-PlsEtn) are widely present in seafood, and EPA-PlsEtn exhibits unique effects on improving cognitive functions. However, there were no reports on the alleviation of dietary EPA-PlsEtn on atherosclerosis. In the present study, supplementation with EPA-PlsEtn for 8 weeks dramatically reduced atherosclerotic lesions by 78% and serum LDL-c levels by 73.9% compared with model group. EPA-PlsEtn possessed lowest hepatic cholesterol levels associated with increased bile acids synthesis and excretion into feces. EPA-PlsEtn increased CYP7A1 expression through suppressing FXR activation. The increased proportion of bile acid TMCA, FXR antagonist, might contribute to the increased bile acid synthesis. In conclusion, different with EPA in form of EE or PC, EPA-PlsEtn efficiently alleviated atherosclerosis via lowering cholesterol levels by suppressing FXR expression. These findings provided new evidence and thought to explain the unique bioactivity of EPA-PlsEtn and new sight to re-understand the structure-activities relationship of DHA/EPA.

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer's Disease.

The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer’s disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.

Ratio of Conjugated Chenodeoxycholic to Muricholic Acids is Associated with Severity of Nonalcoholic Steatohepatitis.

Bile acids (BAs) are important molecules in the progression of nonalcoholic fatty liver disease. This study aimed to investigate BA profile alterations in Chinese nonalcoholic steatohepatitis (NASH) patients. BA profiles in serum and liver tissues were determined by ultraperformance liquid chromatography coupled to tandem mass spectrometry in patients from two different clinical centers. A total of 134 participants were enrolled in this study to serve as the training (n = 87) and validation (n = 47) cohorts. The ratio of circulating conjugated chenodeoxycholic acids to muricholic acids (P = 0.001) was elevated from healthy controls to non-NASH individuals to NASH individuals in a stepwise manner in the training cohort and was positively associated with the histological severity of NASH: steatosis (R2 = 0.12), lobular inflammation (R2 = 0.12), ballooning (R2 = 0.11), and fibrosis stage (R2 = 0.18). The ratio was elevated in the validation cohort of NASH patients (P < 0.001), and it was able to predict NASH (area under the receiver operating characteristic curve: 75%) and significant fibrosis (area under the receiver operating characteristic curve: 71%) in these two cohorts. Moreover, this elevated ratio and impaired farnesoid X receptor signaling were found in the NASH liver. Altered BA profile in NASH is closely associated with the severity of liver lesions, and it has the potential for predicting NASH development.

Targeted metabolomics study of serum bile acid profile in patients with end-stage renal disease undergoing hemodialysis.

BackgroundBile acids are important metabolites of intestinal microbiota, which have profound effects on host health. However, whether metabolism of bile acids is involved in the metabolic complications of end-stage renal disease (ESRD), and the effects of bile acids on the prognosis of ESRD remain obscure. Therefore, this study investigated the relationship between altered bile acid profile and the prognosis of ESRD patients.MethodsA targeted metabolomics approach based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the changes in serum bile acids between ESRD patients (n = 77) and healthy controls (n = 30). Univariate and multivariate statistical analyses were performed to screen the differential proportions of bile acids between the two groups.ResultsSix differentially expressed bile acids were identified as potential biomarkers for differentiating ESRD patients from healthy subjects. The decreased concentrations of chenodeoxycholic acid, deoxycholic acid and cholic acid were significantly associated with dyslipidemia in ESRD patients. Subgroup analyses revealed that the significantly increased concentrations of taurocholic acid, taurochenodeoxycholic acid, taurohyocholic acid and tauro α-muricholic acid were correlated to the poor prognosis of ESRD patients.ConclusionsThe serum bile acid profile of ESRD patients differed significantly from that of healthy controls. In addition, the altered serum bile acid profile might contribute to the poor prognosis and metabolic complications of ESRD patients.

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). MethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. ResultsIn AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. DiscussionWe report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers

IntroductionBile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. MethodSerum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). ResultsOf 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 (“A”) and three with CSF p-tau181 (“T”) (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (“N”), respectively (corrected P < .05). DiscussionThis is the first study to show serum-based BA metabolites are associated with “A/T/N” AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

Sa1770 - The Relationship Between Cholecystectomy and the Development of Clostridium Difficile Infection: Are Altered Bile Acid Profiles Protective?

Sa1770 - The Relationship Between Cholecystectomy and the Development of Clostridium Difficile Infection: Are Altered Bile Acid Profiles Protective?

Abstract B72: Characteristic features of serum bile acids profile in patients with non-alcoholic steatohepatitis with hepatocellular carcinoma

Abstract Background: It has been reported that modulation of gut microbiota can be a possible cause of non-alcoholic steatohepatitis (NASH). Furthermore, recent report revealed that increase of secondary bile acids (BA) triggers senescence-associated secretory phenotype, and associate with hepatocarcinogenesis in a rodent model. As formation of various secondary BAs and deconjugation of BAs are regulated by specific intestinal bacterial taxa, it is possible that serum BA profile, reflecting re-absorbed BAs from intestine, can be a functional marker of individual intestinal microbiota. Materials and Methods: Sera obtained from healthy volunteer (CTL) (n=40), biopsy-proven NASH with hepatocellular carcinoma (NASH-HCC) (n=11) and without HCC (NASH w/o HCC) (n=28), were subjected to analysis of serum BA composition by using LC-MS/MS. Results: (1) Increase in total serum BA concentration: Serum total BA concentration in NASH (7.67 ± 5.5 µM) was significantly higher regardless of the presence of HCC compared to CTL (4.13 ± 0.42 µM, P&amp;lt; 0.001). No significant difference was seen between NASH w/o HCC and NASH-HCC. Serum 7alpha-hydroxy-4-cholestene-3-one (C4), a biomarker of BA synthesis, was not significantly different between CTL and NASH, suggesting enhanced BA synthesis is not a direct cause of the increased serum BA concentration. (2) Decrease in unconjugated BAs: The proportion of unconjugated BA in total BA was significantly lower in NASH (44.5 ± 21 %) compared to CTL (60.5 ± 20.5 %)(P&amp;lt;0.01). No difference was seen between NASH-HCC and w/o HCC . (3) Decrease in secondary BAs: Serum concentrations of various secondary BAs were not different between CTL and NASH. However, the ratio of secondary BAs to total BA was significantly lower in NASH (24.5 ± 2 %) compared to CTL (37.8 ± 2 %, P&amp;lt; 0.01). Free cholic acid (FCA) and free chenodeoxycholic acid (FCDCA), unconjugated primary BAs, were significantly higher in NASH-HCC (FCA 1.18 ± 1.6 μM, FCDCA 2.10 ± 2.5 µM) compared to NASH w/o HCC (FCA 0.27 ± 0.2 µM, FCDCA 0.83 ± 0.8 µM, P&amp;lt;0.05, respectively). Conclusions: It is speculated that the presence of these specific serum BA pattern in NASH and NASH-HCC supports possible alteration of intestinal microbiota in these diseases as previously reported. However, increase of secondary BA reported in animal model study was not observed, suggesting inter-species difference of BA metabolism. Since only modest change between NASH and NASH -HCC was observed, altered BA profile may not be a screening marker for high-risk group of HCC development among NASH patients. Citation Format: Tadashi Ikegami, Akira Honda, Teruo Miyazaki, Shoichiro Yara, Yasushi Matsuzaki. Characteristic features of serum bile acids profile in patients with non-alcoholic steatohepatitis with hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B72.

Abstract 401: Altered Bile Acid Profiles With Colesevelam Treatment Are Associated With Improved Glycemic Control in Type 2 Diabetes

Bile acid sequestrants (BAS) such as colesevelam are effective therapies for lowering LDL-cholesterol and improving glycemic control in individuals with type 2 diabetes. It is however not clear if changes in glucose metabolism with BAS treatment are regulated via changes in whole body BA metabolism. We performed a post-hoc analysis of circulating bile acid levels to investigate whether changes in glucose and lipid parameters are associated with alterations in plasma bile acids (BA) concentrations with colesevelam treatment. Subjects with type 2 diabetes (n=49) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were treated with 3.75 g/day colesevelam for 12 weeks. Fasting bile acid concentrations were measured by LC/MS and glucose and lipid kinetics were measured using stable isotope techniques at baseline and post-treatment. Colesevelam treatment reduced fasting LDL-cholesterol and increased HDL-cholesterol and triglyceride concentrations. No changes were seen in fasting total cholesterol concentrations and de novo lipogenesis (DNL). Beta-cell function (HOMA-B), glycolytic disposal of oral glucose and fasting plasma glucose clearance improved significantly. Colesevelam treatment resulted in a smaller (-40% from baseline) and more hydrophilic fasting plasma BA pool. All BA’s measured except for cholic acid, glycocholic acid and taurocholic acid decreased with treatment. Changes in total BA concentrations were inversely correlated with changes in A1C and a positive correlation was seen with fasting insulin concentrations. Changes in BA concentrations did not correlated with changes in lipid parameters. These data suggest that altered bile acids levels may contribute to improved glycemic control with colesevelam treatment in subjects with type 2 diabetes.

Influence of ethinyloestradiol propanolsulphonate on serum bile acids in healthy volunteers

The present work was done to clarify the relevance of altered serum bile acid (BA) profile in healthy women after the administration of the depot oestrogen ethinyloestradiol propanolsulphonate (EES). In the serum of 20 healthy women before and two times after oral EES application, 11 free and 14 taurine- and glycine-conjugated BA were analysed by HPLC with postcolumn derivatisation and fluorescence detection. EES significantly enhanced the total serum BA concentration and that of taurine-conjugated BAs, more pronounced the secondary BAs taurodeoxycholic, tauroursodeoxycholic and taurolithocholic acid. These secondary BAs are produced in the intestine by bacteria due to 7alpha-dehydroxylation of the primary BAs cholic and chenodeoxycholic acid. Because of unchanged free BAs, also produced by intestinal bacteria due to deconjugation, the results were interpreted as a sign of disturbed transport of BAs into the liver. Inhibition of the liver Na(+)-bile salt co-transporter (Ntcp) in the sinusoidal membrane by ethinyloestradiol, formed from the prodrug EES, may be responsible for the altered BA profile in serum.

Altered bile acid profile in diet-induced pigment stones: [formula omitted], K. Fox-Talbot, P.A. Lipsett, K.D. Lillemoe, H.A. Pitt. The Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Altered bile acid profile in diet-induced pigment stones: [formula omitted], K. Fox-Talbot, P.A. Lipsett, K.D. Lillemoe, H.A. Pitt. The Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Altered bile acid profiles in duodenal bile and urine in diabetic subjects.

The bile acid composition in duodenal bile was analysed in 22 diet-treated and 11 insulin-treated middle-aged patients with diabetes mellitus and in 20 normoglycaemic controls. In 10 subjects with diabetes mellitus the bile acid profile in urine was also investigated. In the non-insulin-dependent diabetic patients the percentage of cholic acid was reduced and that of deoxycholic acid increased. As a highly significant finding there was a three-fold increase of the percentage of 12-ketolithocholic acid in duodenal bile in non-insulin-dependent diabetics, whereas the bile acid composition in insulin-dependent diabetics was similar to that in a control group. The percentage of 12-ketolithocholic acid in duodenal bile was positively correlated to the percentage in urine. In nine of the subjects studied, 12-ketolithocholic acid was the major individual bile acid in urine. It constituted 36.3 +/- 4.4% of the bile acids analysed and the excretion was 6.1 +/- 2.3 mumol 24 h-1. Together with 3 alpha, 12 beta-dihydroxy-5 beta-cholanoic acid it was predominantly present in the glycine conjugate fraction, whereas in bile its conjugation was similar to that of the other bile acids. The results may reflect an increased formation of secondary bile acids from cholic acid combined with a metabolic disturbance in non-insulin-dependent diabetics affecting the oxidoreduction of bile acids at C-12.