Total Bile Acid Concentration Research Articles

Intrahepatic cholestasis of pregnancy worsening perinatal depressive tendency: A follow-up study from the second trimester to the sixth week postpartum

The total bile acid (TBA) is usually used to diagnose intrahepatic cholestasis of pregnancy (ICP) as a common clinical index. Recently many research reports on the microbiota-gut-brain axis (MGB axis) suggest that bile acids have an influence on human mental illnesses such as anxiety and depression, linked closely to intestinal microbial population. However, there is still a lack of clinical data to support intrinsic relationships about human cases. In this study, we conducted a follow-up study of 25 ICP and 98 healthy pregnant women to investigate the influence of ICP disease on perinatal depression. To further explore the effect of TBA concentration, we reviewed data of another 41 ICP women then added their cross-sectional data. The results showed that ICP disease increased mental scale scores but a conventional efficient treatment by using ursodeoxycholic acid (UDCA) could not decrease scores, suggesting intrahepatic cholestasis might make some key bile acids not to be processed by gut microbiota. UDCA could not replace the function of gut microbiota for easing depression and the change of bile acid composition in intestines worsened perinatal depressive tendency through the MGB axis.

Bile acid metabolism disorder mediates hepatotoxicity of Nafion by-product 2 and perfluorooctane sulfonate in male PPARα-KO mice

Perfluorooctane sulfonate (PFOS) and Nafion by-product 2 (H-PFMO2OSA) induce hepatotoxicity in male mice via activation of the peroxisome proliferator-activated receptor α (PPARα) pathway; however, accumulating evidence suggests that PPARα-independent pathways also play a vital role in hepatotoxicity after exposure to per- and polyfluoroalkyl substances (PFASs). Thus, to assess the hepatotoxicity of PFOS and H-PFMO2OSA more comprehensively, adult male wild-type (WT) and PPARα knockout (PPARα-KO) mice were exposed to PFOS and H-PFMO2OSA (1 or 5 mg/kg/d) for 28 d via oral gavage. Results showed that although elevations in alanine transaminase (ALT) and aspartate aminotransferase (AST) were alleviated in PPARα-KO mice, liver injury, including liver enlargement and necrosis, was still observed after PFOS and H-PFMO2OSA exposure. Liver transcriptome analysis identified fewer differentially expressed genes (DEGs) in the PPARα-KO mice than in the WT mice, but more DEGs associated with the bile acid secretion pathway after PFOS and H-PFMO2OSA treatment. Total bile acid content in the liver was increased in the 1 and 5 mg/kg/d PFOS-exposed and 5 mg/kg/d H-PFMO2OSA-exposed PPARα-KO mice. Furthermore, in PPARα-KO mice, proteins showing changes in transcription and translation levels after PFOS and H-PFMO2OSA exposure were involved in the synthesis, transportation, reabsorption, and excretion of bile acids. Thus, exposure to PFOS and H-PFMO2OSA in male PPARα-KO mice may disturb bile acid metabolism, which is not under the control of PPARα.

White Wheat Flour Lowers Plasma Cholesterol and Increases Cecal Steroids Relative to Whole Wheat Flour, Wheat Bran and Wheat Pollard in Rats

Plasma cholesterol concentrations were significantly lower in rats fed a cholesterol-free diet containing white wheat flour than those fed the diet with whole wheat or wheat bran. Concentrations of total bile acids and neutral sterols in cecal digesta were significantly higher in rats fed wheat flour than in those fed whole wheat, wheat pollard or wheat bran. Digesta bile acids and neutral sterol pools correlated negatively with plasma cholesterol, indicating that excretion was regulating plasma concentration. Total cecal volatile fatty acid (VFA) concentrations were unaffected by diet but cecal propionate was higher and butyrate lower in rats fed wheat flour than in those fed whole wheat. Cecal digesta butyrate concentrations correlated negatively with the cholesterol metabolite, coprostanol, and with secondary bile acids. Cecal propionate correlated negatively with plasma cholesterol concentration, but butyrate correlated equally positively, suggesting these VFA were indicators rather than regulators of altered cecal steroid metabolism. Effects of white wheat flour on steroid metabolism and cecal VFA resemble those of oat bran and support the observation that wheat flour might be hypocholesterolemic in humans.

Triaging donor lungs based on a microaspiration signature that predicts adverse recipient outcome

Aspiration is a relative contraindication to accepting donor lungs for transplant and is currently assessed by visual inspection of the airways via bronchoscopy. However, this method is limited as it does not assess for microaspiration. Bile acids measured in large airway bronchial wash (LABW) samples have been shown to be a marker of aspiration in lung transplant recipients. Herein, we investigate the utility of measuring total bile acids (TBA) in donor LABW to predict performance of donor lungs and recipient outcomes. TBA was measured in 605 consecutive lung donors at the Toronto Lung Transplant Program. TBA levels were compared in donor lungs deemed unsuitable for transplant, requiring further assessment on ex vivo lung perfusion (EVLP), and those suitable for direct transplantation using Mann-Whitney-U tests. Relationships between LABW TBA concentrations and recipient outcomes were evaluated using multivariable Cox-PH models and log-rank analysis. Donor TBA was highest in lungs deemed unsuitable for transplant and correlated with clinical assessment of aspiration. LABW TBA concentration correlated with calcium, decreased pH, and increased pro-inflammatory mediators in EVLP perfusate. TBA cut-off of 1245 nM was able to differentiate donor lungs directly declined from those suitable for direct transplantation with a 91% specificity (AUROC: 73%). High donor TBA status was associated with the increased rate of primary graft dysfunction, longer time to extubation, and shorter time to chronic lung allograft dysfunction. In a large retrospective cohort, we observed that donor LABW TBA was associated with suitability of donor lungs for transplant, performance of the organ on EVLP, and adverse recipient outcomes.

High-grain diet feeding alters ileal microbiota and disrupts bile acid metabolism in lactating dairy cows.

Bile acids (BAs) play an important role in the regulation of lipid metabolic homeostasis, but little is known about their metabolism in dairy cows fed a high-grain (HG) diet. In the present study, we examined the bacterial community, BA profile, and the FXR/FGF19 signaling pathway in the ileum and liver to investigate the gut microbe-BA metabolism interactions response to HG diet and the changes in the subsequent enterohepatic circulation of dairy cows. The results showed that the ileal bacterial community was altered, with an increase of Paraclostridium, Anaerobutyricum, Shuttleworthia, and Stomatobaculum in the relative abundance in the HG group. Moreover, real-time polymerase chain reaction (PCR) showed that the abundance of total bacteria and bacterial bile-salt hydrolase (BSH) genes was increased in the ileal digesta in the HG group. Meanwhile, HG feeding also decreased the total BA content in the digesta of jejunum and ileum and in feces. HG feeding altered the BA profile in the ileal digesta by increasing unconjugated BAs and decreasing conjugated BAs. In addition, the intestinal FXR/FGF19 signaling pathway was activated. The expression of CYP7A1 (cholesterol 7α-hydroxylase) was depressed, which inhibited BAs synthesis in the liver of cows fed HG. Overall, HG feeding altered the ileal bacterial community and BA profile, and activated FXR/FGF19 signaling pathway, resulting in a decrease of BA level in the ileal digesta via the inhibition of hepatic BA synthesis. The findings provided novel insights into understanding the relationship between gut microbiota and the homeostasis of BAs in dairy cows fed a HG diet.

Effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal physiology

BackgroundKnowledge regarding the gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass is urgently needed to understand, prevent and treat the nutritional and pharmacological complications of bariatric surgery. AimTo investigate the effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility (e.g., transit and pressure), pH, and intestinal bile acid concentration. Material and methodsAn exploratory cross-sectional study was performed in six participants living with obesity, six participants who underwent sleeve gastrectomy, and six participants who underwent Roux-en-Y gastric bypass. During the first visit, a wireless motility capsule (SmartPill©) was ingested after an overnight fast to measure gastrointestinal transit, pH, and pressure. During the second visit, a gastric emptying scintigraphy test of a nutritional drink labeled with 99mTc-colloid by a dual-head SPECT gamma camera was performed to measure gastric emptying half-time (GET1/2). During the third visit, two customized multiple lumen aspiration catheters were positioned to collect fasting and postprandial intestinal fluids to measure bile acid concentration. ResultsImmediate pouch emptying (P = 0.0007) and a trend for faster GET1/2 (P = 0.09) were observed in both bariatric groups. There was a tendency for a shorter orocecal transit in participants with sleeve gastrectomy and Roux-en-Y gastric bypass (P = 0.08). The orocecal segment was characterized by a higher 25th percentile pH (P = 0.004) and a trend for a higher median pH in both bariatric groups (P = 0.07). Fasting total bile acid concentration was 7.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) and 3.5-fold higher in the jejunum after sleeve gastrectomy (P = 0.009) compared to obesity. Postprandial bile acid concentration was 3-fold higher in the jejunum after sleeve gastrectomy (P = 0.0004) and 6.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) compared to obesity. ConclusionThe anatomical alterations of sleeve gastrectomy and Roux-en-Y gastric bypass have an important impact on gastrointestinal physiology. This data confirms changes in transit and pH and provides the first evidence for altered intraluminal bile acid concentration.

Extraesophageal reflux and reflux aspiration in dogs with respiratory diseases and in healthy dogs.

Salivary bile acids are used to diagnose extraesophageal reflux (EER) and to evaluate the risk of reflux aspiration that is associated with respiratory diseases in dogs. To study total bile acid (TBA) concentrations in saliva and in bronchoalveolar lavage fluid (BALF) to investigate EER and reflux aspiration in dogs with respiratory diseases and in healthy dogs. Thirty-one West Highland White Terriers (WHWTs) with idiopathic pulmonary fibrosis (IPF), 12 dogs with inflammatory airway disease (IAD), 6 dogs with recurrent pneumonia (RP), 26 brachycephalic dogs (BD), 27 healthy WHWTs (HW), 52 healthy dogs (HD). All privately-owned dogs. Saliva and BALF were collected from dogs in each group. Salivary TBA concentrations were higher in IPF (median 0.1692 μM, interquartile range [IQR] 0.1115-0.2925 μM, Cohen's d 3.4, 95% confidence interval [CI] 2.2-4.0, P < .001) and BD (0.0256 μM, IQR 0.0086-0.0417 μM, d 0.5, CI -0.1 to 1.1, P=.003) compared to HD (0μM, IQR not quantifiable [n.q.]-0.0131 μM). Bronchoalveolar lavage fluid TBA concentrations were higher in IPF (0.0117 μM, IQR 0.0048-0.0361 μM, d 0.5, CI 0-1.1, P < .001) compared to HD (0μM, IQR n.q.-0.0074 μM). Extraesophageal reflux and reflux aspiration occur in healthy dogs and those with respiratory diseases.

Apple juice relieves loperamide-induced constipation in rats by downregulating the intestinal apical sodium-dependent bile acid transporter ASBT.

Apples are known to exhibit various beneficial effects on human health. In the present study, we investigated the effect of continuous intake of apple juice (AJ) on constipation status. A single dose of loperamide in rats as the constipation model markedly decreased the weight and number of fecal pellets compared to saline-administered rats as a control. After the administration of AJ twice a day for seven days, recovery of defecation close to that of the control was observed in loperamide-treated rats. In addition, the total bile acid content in the feces increased from day 4 after the administration of AJ. Among hepatic and intestinal transporters and enzymes that regulate bile acids, the mRNA expression of the apical sodium-dependent bile acid transporter (Asbt, slc10a2) was decreased by AJ in rats. Furthermore, the Asbt-mediated bile acid transport activity in the rat ileum decreased after AJ administration. Moreover, in human colonic cancer-derived Caco-2 cells, AJ exposure for 24 and 48 h decreased the expressions of ASBT mRNA and protein, and the uptake activity of taurocholic acid in both 7- and 21-d cultures. Several components of AJ, such as procyanidins, decreased the expression of ASBT in Caco-2 cells. In conclusion, ASBT downregulation is a possible mechanism responsible for the constipation-relieving effect of apples, and procyanidins may play a role in downregulating ASBT, which leads to the beneficial effects of apples against constipation. Although it is generally agreed that the common dietary compositions play a role in constipation relief, the novel specific mechanism of apples found in this study would facilitate understanding food functions.

Lead and copper influenced bile acid metabolism by changing intestinal microbiota and activating farnesoid X receptor in Bufo gargarizans

Lead (Pb) and copper (Cu) are ubiquitous metal contaminants and can pose a threat to ecosystem and human health. Bile acids have recently received considerable attention for their role in the maintenance of health. However, there were few studies on whether Pb and Cu affect bile acid metabolism in amphibians. In this study, a combination approach of histological analysis, targeted metabolomics, 16S rDNA sequencing and qPCR was used to explore the impacts of Pb, Cu and their mixture (Mix) on bile acid in Bufo gargarizans tadpoles. The results showed that Pb, Cu, and Mix resulted in intestinal damage and altered the bile acid profiles. Specifically, Pb and Mix exposure decreased total bile acid concentrations while increased toxic bile acid levels; in contrast, Cu exposure increased total bile acid levels. And hydrophilic bile acids were reduced in all treated tadpoles. Moreover, Pb and/or Cu changed the composition of intestinal microbiota, especially Clostridia, Bacteroides and Eubacterium involved in bile acid biotransformation. qPCR revealed that the decreased total bile acid concentrations in Pb- and Mix-treated tadpoles were most likely attributed to the activation of intestinal farnesoid X receptor (Fxr), which suppressed bile acid synthesis and reabsorption. While activated fxr in the Cu treatment group may be a regulatory mechanism in response to increased bile excretion, which is a detoxification route of tadpoles under Cu stress. Collectively, Pb, Cu and Mix changed bile acid profiles by affecting intestinal microbial composition and activating Fxr signaling. This study provided insight into the impacts of Pb and Cu on bile acid metabolism and contributed to the assessment of the potential ecotoxicity of heavy metals on amphibians.

Profiling of bile acids and activated receptor S1PR2 in gingival tissues of periodontitis patients.

Bile acids, as a group of cholesterol metabolites, play important roles in inflammation and bone metabolism. However, the possible link between bile acids and periodontitis is still unclear. This study aimed to clarify the alterations of the bile acid profile and corresponding receptor expression levels in periodontitis patients, and evaluate their association with periodontitis severity. The concentrations of 15 bile acids in gingival tissues from 16 periodontitis patients and 16 healthy individuals were tested by metabolomics. Sphingosine-1-phosphate receptor 2 (S1PR2) expression was determined by real-time PCR and immunohistochemistry, which was also validated in two datasets, GSE16134 and GSE10334. The correlation between bile acids, S1PR2, and clinical parameters was analyzed by Spearman's correlation analysis, and receiver-operator characteristic (ROC) curves were examined to access the ability of bile acids and S1PR2 for defining local periodontitis status. In the periodontitis group, concentrations of total bile acids were elevated by increases of all bile acid forms, and five conjugated bile acids were significantly increased. Meanwhile, the expression of their receptor, S1PR2, was also upregulated in the periodontitis group. Positive correlations were further observed between glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), S1PR2, and periodontal clinical parameters. ROC analysis also showed combinations of two bile acids (GCA and TCDCA) with S1PR2 as novel signatures for indicating local periodontitis status. Our findings demonstrated the alterations of the bile acid profile and receptor S1PR2 expression in periodontitis patients, and provided evidence of association between bile acids and periodontitis status.

Superoxide Dismutase 2 Val16Ala Polymorphism is Associated with Amiodarone-Associated Liver Injury

Abstract Association of SOD2 V16A single-nucleotide polymorphism (rs4880) with drug hepatotoxicity were reported but relationships with amiodarone prescriptions remained unexplored. Research was an exploratory, controlled prospective clinical trial. Patients hospitalized and treated in Clinical Center in Kragujevac, Serbia (in year 2017) were divided into experimental (using amiodarone, having liver injury, n=29, 19 males, the mean age 66.8±10.4 years), control A (neither amiodarone use nor hepatotoxicity, n=29, 19, 66.1±10.3) and control B group (using amiodarone, not having hepatotoxicity, n=29, 19, 66.8±9.8). From blood samples, among other routine biochemistry, genotyping for SOD2 polymorphism Val16Ala was conducted using real-time PCR method with TaqMan® Genotyping Master Mix and TaqMan® DME Genotyping Assay for rs4880. Patients taking amiodarone and having liver injury were mostly carriers of Val/Val (TT) genotype (13 of 24 patients, 54.2%) while Val/Ala (TC) and Ala/Ala (CC) genotypes prevailed in control group A (19 of 40, 47.5%) and control group B (9 of 23, 39.1%), respectively (2=10.409, p=0.034). Frequency of Val (T) and Ala (C) alleles were 0.51 and 0.49, respectively in the whole study sample (Hardy Weinberg equilibrium, 2=0.56, p=0.454). Carriers of TT genotype had significantly higher ALT (437.0±1158.0 vs 81.9131.5 U/L), total bilirubin (28.320.5 vs 15.313.0 mol/L) and total bile acid concentrations (10.910.2 vs 6.45.3 mol/L) compared to carriers of TC genotype (U=2.331, p=0.020, U=3.204, p=0.001 and U=2.172, p=0.030, respectively). Higher incidence of 47T allele of SOD2 was inpatients with amiodarone-associated liver injury as compared to patients on amiodarone not experiencing hepatotoxic effects.

Glycocholic acid supplementation improved growth performance and alleviated tissue damage in the liver and intestine in Pelteobagrus fulvidraco fed a high-pectin diet.

In a study on the anti-nutritional effect of dietary fiber, it was noticed that a high-pectin diet (PEC diet) caused growth retardation, hepatic cholestasis, steatosis, fibrosis, and enteritis accompanied by decreased glycocholic acid (GCA) in Pelteobagrus fulvidraco. This study was conducted to investigate the potential alleviating effects of supplementation with GCA. A PEC diet and a diet supplemented with 0.6gkg-1 GCA based on the PEC diet (named the GCA diet) were formulated and randomly fed to juvenile Pelteobagrus fulvidraco. Compared to fish that were fed the PEC diet for 7days, the GCA content in liver increased significantly in fish fed the GCA diet, the incidence of abnormal liver color, gallbladder somatic index (GBSI), total bile acid concentration in serum and liver, and the expression of arnesoid X receptor gene (fxr) upregulated and genes involved in bile acid (BA) synthesis and uptake in liver decreased significantly. After 56days, the SGR, the expression of fxr and genes involved in BA synthesis and transportation in the liver, the serum content of total bilirubin, total protein, and globulin were significantly higher, while the hepatosomatic index, GBSI, liver lipid and collagen content, and the incidence of distal intestine tissue damage were lower in fish fed the GCA diet than in those fed the PEC diet. These results suggested that GCA improved growth performance and alleviated hepatic cholestasis and tissue damage to the liver and intestine induced by a high-pectin diet, which might occur through activating FXR.

Ursodeoxycholic acid use in lactating female patients is associated with clinically negligible concentrations of this bile acid in breast milk

In the literature on the safety of ursodeoxycholic acid (UDCA) during breastfeeding, insufficient data has been reported to date. Thus, the aim of our study was to analyze bile acid (BA) concentrations in breast milk in a cohort of patients, treated with UDCA, and with various cholestatic liver diseases. The study was carried out on a cohort of 20 patients with various cholestatic diseases. All the patients were treated with UDCA (500–1500 mg daily). Concentrations of BA, sampled on day 3 after delivery were analyzed using the GS-MS technique, and then compared to untreated women. Total BA concentrations in the breast milk of the UDCA-treated patients were equal to those of the untreated women controls (3.2 ± 1 vs. 3.2 ± 0.2 µmol/L, respectively). The UDCA concentrations in breast milk remained negligible in UDCA-treated patients (0.69 µmol/L), and in any event did not contribute to the newborn BA pool. No apparent side-effects of the maternal UDCA treatment were observed in any newborn infant, and no deterioration in postnatal development was observed during the routine 1-year follow-ups. Therapeutic administration of UDCA during lactation is safe for breastfed babies since UDCA only gets into breast milk in negligible amounts. UDCA treatment should be allowed and included into the guidelines for the therapy of cholestatic diseases in breastfeeding mothers.

Microbial Bile Acid Metabolism Shapes Effector T Cell Responses during Inflammation in Mouse and Human

Microbial transformation of bile acids (BAs) regulates intestinal immune homeostasis but their effect on T cell-driven pathologies is unknown. We previously reported that gut dysbiosis in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) is associated with increased graft-versus-host disease (GVHD), in which graft-derived T cells recognize the host as foreign. We hypothesized that the dramatic changes in intestinal microbiome composition during GVHD would lead to changes in the BA pool, which would alter immunoregulatory mechanisms governing T cell responses. Using a preclinical MHC-disparate GVHD model (B6 into BALB/c) and quantifying BAs with liquid chromatography-mass spectrometry, we found that GVHD was associated with a significant decrease in total BA concentration with a preferential loss of microbiota-dependent unconjugated primary BA (PBAs) and secondary BA (SBAs) (p=0.0002 and p<0.001, n=10/group). Metagenomic sequencing revealed changes in microbiota composition, including reduced abundance of Lactobacillus johnsonii and expansion of Enterococcus faecalis in GVHD mice (FDR=0.03, n=5/group) as previously reported. These changes were accompanied by a reduction in the abundance of bile salt hydrolase (BSH) genes (p=0.008) encoded by the gut microbiome (mainly Lactobacillus johnsonii). BSH catalyzes the deconjugation of PBAs, which is the gateway reaction leading to SBAs formation, suggesting that GVHD affects the BA pool by compromising early steps in microbial BA metabolism. To investigate the effects of GVHD on host metabolism, we profiled the liver transcriptome by bulk RNA-sequencing analysis. Pathways involved in BA metabolism were reduced in the livers of GVHD mice, which was associated with reduced levels of transcripts for genes involved in BA synthesis (Abcd3, Hsd17b11, Cyp7b1, Hsd17b6) and secretion (Abcg8, Slc22a18). As BAs regulate their synthesis via farnesoid X receptor (FXR) in a negative feedback loop, these results suggested that FXR activation may be increased because of loss of SBAs. Indeed, SBAs counteracted the activation of FXR by the natural agonist chenodeoxycholic acid, in FXR reporter assay and FXR TR-FRET coactivator assay, suggesting that bacterial transformation of BAs generally decreases FXR activity in vivo. Pharmacological activation of FXR (B6 into BALB/c, treatment with selective FXR agonist GW4064 day -1 to day 7, p<0.0001, n=20/group) showed increased mortality, whereas genetic ablation of FXR in donor T cells decreased GVHD and improved OS in two preclinical models (B6 into BALB/c, p<0.0001, n=30/group, Fig. 1a and B6 into 129, p<0.0001, n=20/group). Mice transplanted with TΔFXRcells had reduced GVHD-related pathology compared to recipients of TWT on day 28 post allo-HCT (p=0.006, n=10/group). Furthermore, we found reduced IFNγ production by CD4+ and CD8+ TΔFXR cells in the lamina propria of the large intestine on day 14 post-transplant (p=0.01 and p=0.02, n=10/group). Finally, we set out to corroborate our preclinical findings in allo-HCT patients. We compared 63 fecal samples from allo-HCT patients with lower gastrointestinal GVHD obtained at peri-GVHD onset (+/- 10 days) with 61 samples from control allo-HCT patients without GVHD, who were matched for age, graft type and HLA compatibility. Samples from controls were selected +/-10 days from pseudo-GVHD day that was assigned based on their paired GVHD patient. Most of the samples were exposed to the SBA ursodeoxycholic acid (UDCA, 93%). Similar to our findings in mice, we found that SBAs (non-UDCA, Fig. 1b) and unconjugated PBAs, as well as BSH abundances were decreased in GVHD patients compared to controls (p=0.007, p=0.008, and p=0.02 respectively). Notably, we found that important immunomodulatory SBAs were reduced in GVHD patients compared to controls, including 3-oxolithocholic acid, isolithocholic acid and ω-muricholic acid (p=0.01, p=0.004, and p<0.001). Lastly, in 747 allo-HCT recipients, we found that UDCA exposure was associated with a lower incidence of Enterococcus sp. domination (p=0.001), lower aGVHD cumulative incidence (p=0.005) and improved OS (p=0.017) as previously reported. Our results in mice and humans suggest that loss of SBA and increased FXR activation may amplify T-cell driven disease such as GVHD and provide a rationale to target the host-microbiota BA network to improve clinical outcomes in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Altered Serum Bile Acid Profile Associated with Chronic Allograft Dysfunction in Kidney Transplant Recipients.

BACKGROUND Chronic allograft dysfunction (CAD) is the leading cause of graft loss among kidney transplant recipients (KTRs). Bile acids (BAs) play an important role in regulating inflammatory process, which is the major contributor to the development of CAD. The aim of this study was to evaluate the association between BAs metabolic dysregulation and CAD in KTRs. MATERIAL AND METHODS Fifteen serum BA species were determined in 43 healthy controls (HCs) and 131 KTRs by UPLC-MS/MS. KTRs were grouped into stable renal function (STA) and CAD1 and CAD2 groups based on eGFR levels. Circulating CYP7A1, CYP7B1, CYP27A1, and SLCO2B1 mRNA levels were determined by RT-PCR. RESULTS Total BA concentrations were comparable among the 4 groups. However, KTRs showed significantly different BAs profiling compared to HCs. KTRs with severe CAD (CAD2) had significantly lower unconjugated BAs and secondary BAs (SBAs) compared to the other 3 groups. KTRs had significantly lower SBAs/primary BAs (PBAs) ratios than HCs, which were comparable among the 3 KTR groups. Conjugated/unconjugated BAs ratios increased significantly with the deterioration of allograft function, which was further confirmed by correlation analysis. Differential correlation network analysis revealed that perturbations in intraclass and interclass BA coregulation existed during CAD progression. Moreover, relative gene expressions of CYP7B1 and CYP27A1 were positively correlated with eGFR. CONCLUSIONS BA species profiling, but not total BA concentrations, was significantly altered in KTRs with CAD. The shifts from unconjugated BAs toward conjugated BAs, SBAs toward PBAs, and distinct pairwise BAs coregulation patterns were the main characteristics of KTRs with CAD.

Intrauterine growth retardation affects liver bile acid metabolism in growing pigs: effects associated with the changes of colonic bile acid derivatives

BackgroundIntrauterine growth retardation (IUGR) is associated with severely impaired nutrient metabolism and intestinal development of pigs. Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon. However, the consequences of IUGR on bile acid metabolism in pigs remained unclear. The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of growing pigs with IUGR using bile acid targeted metabolomics. Furthermore, we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight (NBW) pigs at different growth stages that were 7, 21, and 28-day-old, and the average body weight (BW) of 25, 50, and 100 kg of the NBW pigs.ResultsThe results showed that the plasma total bile acid concentration was higher (P < 0.05) at the 25 kg BW stage and tended to increase (P = 0.08) at 28-day-old in IUGR pigs. The hepatic gene expressions related to bile acid synthesis (CYP7A1, CYP27A1, and NTCP) were up-regulated (P < 0.05), and the genes related to glucose and lipid metabolism (ATGL, HSL, and PC) were down-regulated (P < 0.05) at the 25 kg BW stage in IUGR pigs when compared with the NBW group. Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs. The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased (P < 0.05), while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased (P < 0.05) in IUGR pigs, when compared with the NBW pigs at the 25 kg BW stage. Moreover, Spearman’s correlation analysis revealed that colonic Unclassified_[Mogibacteriaceae], Lachnospira, and Slackia abundances were negatively correlated (P < 0.05) with dehydrolithocholic acid, as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.ConclusionsThese findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs, especially at the 25 kg BW stage, these effects being paralleled by a modification of bile acid derivatives concentrations in the colonic content. The plausible links between these modified parameters are discussed.

Effects of palm olein and palm stearin on cecal and fecal microbiota of C57BL/6J mice under low and high fat intakes

This work aimed to study the effects of dietary lipid composition and content on cecal and fecal microbiota of mice fed the following diets for 8 weeks: palm olein (PO)-based low-fat diet, PO-based high-fat diet, palm stearin (PS)-based low-fat diet, and PS-based high-fat diet. Increasing the dietary PS level favored the growth of Firmicutes over Bacteroidetes in the cecum and feces. In addition, it significantly elevated the total lipid (p < 0.01) and bile acid content (p < 0.01) in feces, resulting in the enrichment of fat-degrading and bile-acid tolerant genera within the families Ruminococcaceae and Lachnospiraceae. Although increasing the PO intake also caused obesity in mice, it did not affect the microbial structure. When fat intake is constant, only at a high-fat level can PS (vs PO) induce the above-mentioned microbial shifts. These results highlighted the combined roles of lipid quality and quantity on the gut microbiota.

Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency.

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

Duodenal-jejunal bypass reduces serum ceramides via inhibiting intestinal bile acid-farnesoid X receptor pathway.

BACKGROUNDBile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass (DJB). Serum bile acids are elevated postoperatively. However, the clinical relevance is not known. Bile acids in the peripheral circulation reflect the amount of bile acids in the gut. Therefore, a further investigation of luminal bile acids following DJB is of great significance.AIMTo investigate changes of luminal bile acids following DJB.METHODSSalicylhydroxamic acid (SHAM), DJB, and DJB with oral chenodeoxycholic acid (CDCA) supplementation were performed in a high-fat-diet/streptozotocin-induced diabetic rat model. Body weight, energy intake, oral glucose tolerance test, luminal bile acids, serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTSCompared to SHAM, DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor (FXR) - inhibitory bile acids within the common limb. Intestinal ceramide synthesis was repressed with decreased serum ceramides, and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSIONDJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels. There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats.

BACKGROUNDThe mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.AIMTo investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.METHODSTwenty diabetic rats were randomly allocated to the sham (n = 10) and DJB (n = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.RESULTSThe DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.CONCLUSIONDJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.