Serum Bile Acid Concentrations Research Articles

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Albireo Pharma, an Ipsen company.

Serum Bile Acids Concentrations and Liver Enzyme Activities after Low-Dose Trilostane in Dogs with Hyperadrenocorticism.

Hyperadrenocorticism (HAC) often leads to vacuolar hepatopathy. The impact of trilostane treatment on serum total bile acids (SBAs) concentrations in dogs with HAC remains unknown. This study investigated SBAs concentrations in healthy dogs and those with HAC following trilostane therapy. Ten healthy dogs and fifteen dogs with HAC were prospectively enrolled. A biochemistry profile and pre- and post-prandial SBAs concentrations were determined in each dog. Dogs with HAC were reassessed at 1 and 3 months after the initiation of trilostane treatment. Dogs with HAC had significantly higher serum ALT, ALP, and GGT activities, and cholesterol, triglyceride, and pre-prandial SBAs concentrations compared to healthy dogs. After 3 months of trilostane treatment, polyuria/polydipsia and polyphagia were completely resolved in 42.8% and 35.7%, respectively. Significant improvements in serum ALT and ALP activities and cholesterol concentrations were observed within 1-3 months of trilostane treatment. However, pre- and post-prandial SBAs concentrations did not significantly decrease. These findings suggest that treatment with low-dose trilostane for 3 months appears to reduce serum liver enzyme activities, but not SBAs concentrations. Further investigation is warranted to explore the effects of low-dose trilostane treatment on SBAs concentrations for a longer duration or after achieving appropriate post-ACTH cortisol levels.

Longitudinal characterization of the metabolome of dairy cows transitioning from one lactation to the next: Investigations in blood serum

The objective of this study was to characterize changes in the serum metabolome and various indicators of oxidative balance in dairy cows starting 2 wk before dry-off and continuing until wk 16 of lactation. Twelve Holstein dairy cows (body weight 745 ± 71 kg, body condition score 3.43 ± 0.66; mean ± SD) were housed in a tiestall barn from 10 wk before to 16 wk after parturition. Cows were dried off 6 wk before the expected calving date (mean dry period length = 42 d). From 8 wk before calving to 16 wk after calving, blood samples were taken weekly to study redox metabolism by determining antioxidant capacity, measured as the ferric-reducing ability of plasma, reactive oxidative metabolites, oxidative stress index, oxidative damage of lipids, measured as thiobarbituric acid reactive substances, and glutathione peroxidase activity. According to these results, dairy cows had the lowest serum antioxidant capacity and greater levels of oxidative stress during the dry-off period and the early postpartum period. For metabolomics, a subset of serum samples including wk -7 (before dry-off), -5 (after dry-off), -1, 1, 5, 10, and 15 relative to calving were used. A targeted metabolomics approach was performed using liquid chromatography and flow injection with electrospray ionization triple quadrupole mass spectrometry using the MxP Quant 500 kit (Biocrates Life Sciences AG). A total of 240 metabolites in serum were used in the final data analysis. Principal component analysis revealed a clear separation by days of sampling, indicating a remarkable shift in metabolic phenotype between the dry period and late and early lactation. Changes in many non-lipid metabolites associated with one-carbon metabolism, the tricarboxylic acid cycle, the urea cycle, and AA catabolism were observed in the study, with changes in AA serum concentrations likely related to factors such as energy and nitrogen balance, digestive efficiency, and changing diets. The study confirmed an extensive remodeling of the serum lipidome in peripartum dairy cows, highlighting the importance of changes in acylcarnitine (acylCN), phosphatidylcholines (PC), and triacylglycerols (TG), as they play a crucial role in lipid metabolism. Results showed that short-chain acylCN increased after dry-off and decreased thereafter, whereas lipid-derived acylCN increased around parturition, suggesting that more fatty acids could enter mitochondria. Phospholipids and sphingolipids in serum showed changes during lactation. In particular, concentrations of sphingomyelins, PC, and lysoPC decreased around calving but increased in mid- and late lactation. In contrast, concentrations of TG remained consistently low after parturition. The serum concentrations of bile acids fluctuated during the dry period and lactation, with glycocholic acid, cholic acid, glycodeoxycholic acid, and taurocholic acid showing the greatest concentrations. These changes are likely due to the interplay of diet, liver function, and the ability of the gut microbiota to convert primary to secondary bile acids. Overall, these descriptive results may aid in hypothesis generation and in the design and interpretation of future metabolite-based studies in dairy cows. Furthermore, they contribute to our understanding of the physiological ranges in serum metabolites relative to the lactation cycle of the dairy cow.

Could real-time sonoelastography-measured placental strain ratio (PSR) value be a soft marker for the diagnosis of intrahepatic cholestasis of pregnancy?: A case-control study and short reviews.

Diagnosis of intrahepatic cholestasis of pregnancy (ICP) is often decided upon with typical pruritus supported by elevated serum bile acid levels. However, there is confusion regarding the absolute reference range for serum bile acid . To confirm the utility of Placental Strain Ratio (PSR) measurement as a marker for the diagnosis of ICP and to reveal the extent to which it is correlated with serum bile acid concentration. A case-control study was conducted. The case group included 29 patients who were admitted to our hospital in the second or third trimester of pregnancy with typical itching and were clinically diagnosed with ICP with >10 mmol/L serum bile acid. The first 45 pregnant women were assigned to a control group. Real-time tissue elastography software was used for ultrasound assessment of all pregnant placentas. Software was used to estimate the SR values. Biochemical liver function parameters, hemograms, serum bile acid levels, and SR values were compared between these groups. PSR was found to predict the development of cholestasis with poor discrimination (area under the curve [AUC] = 0.524; 95% CI = 0.399-0.646). The optimal threshold value with the best sensitivity and specificity rates was calculated to be 0.46 PSR. ICP developed significantly more frequently in the low PSR group than in the high PSR group (60% vs 29.3%, P = .05, odds ratios [OR] = 0.276, 95% CI = 0.069-1.105). No correlation was found between the PSR and bile acid levels (rho = -0.029, P = .816). PSR values can support the diagnosis of ICP, predict serum bile acid levels, and can be used as soft markers.

A Low-Protein, High-Carbohydrate Diet Exerts a Neuroprotective Effect on Mice with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease by Regulating the Microbiota-Metabolite-Brain Axis and Fibroblast Growth Factor 21.

Parkinson's disease (PD) is closely linked to lifestyle factors, particularly dietary patterns, which have attracted interest as potential disease-modifying factors. Eating a low-protein, high-carbohydrate (LPHC) diet is a promising dietary intervention against brain aging; however, its protective effect on PD remains elusive. Here, we found that an LPHC diet ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced motor deficits, decreased dopaminergic neuronal death, and increased the levels of striatal dopamine, serotonin, and their metabolites in PD mice. Levels of fibroblast growth factor 21 (FGF-21), a member of the fibroblast growth factor family, were elevated in PD mice following LPHC treatment. Furthermore, the administration of FGF-21 exerted a protective effect on MPTP-induced PC12 cells, similar to the effect of an LPHC diet in MPTP-induced mice. Sequencing of the 16S rDNA from fecal microbiota revealed that an LPHC diet normalized the gut bacterial composition imbalance in PD mice, as evidenced by the increased abundance of the genera Bifidobacterium, Ileibacterium, Turicibacter, and Blautia and decreased abundance of Bilophila, Alistipes, and Bacteroides. PICRUSt-predicted fecal microbiome function revealed that an LPHC diet suppressed lipopolysaccharide biosynthesis and the citrate cycle (TCA cycle), biosynthesis of ubiquinone and other terpenoid-quinones, and oxidative phosphorylation pathways caused by MPTP, and enhanced the biosynthesis of amino acids, carbohydrate metabolism, and biosynthesis of other secondary metabolites. A nonmetabolomic analysis of the serum and feces showed that an LPHC diet significantly increased the levels of aromatic amino acids (AAAs), including tryptophan, tyrosine, and phenylalanine. In addition, an LPHC diet elevated the serum concentrations of bile acids (BAs), particularly tauroursodeoxycholic acid (TUDCA) and taurine. Collectively, our current findings point to the potential mechanism of administering an LPHC diet in attenuating movement impairments in MPTP-induced PD mice, with AAAs, microbial metabolites (TUDCA and taurine), and FGF-21 as key mediators along the gut-microbiota-brain axis.

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood. Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5. In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152µmol/L (C-statistics=0.68). Children with bile acid concentrations >152µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry. This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis

Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.

Congenital Portosystemic Shunts in Dogs and Cats: Classification, Pathophysiology, Clinical Presentation and Diagnosis.

Congenital portosystemic shunts (CPSS) are abnormal vascular communications between the portal and the systemic circulation, bypassing the hepatic parenchyma and resulting in liver hypoplasia and hepatic insufficiency. Such connections develop in utero and persist postnatally. CPSS are among the two most common congenital vascular anomalies of the liver in small animals, along with primary hypoplasia of the portal vein without portal hypertension (PHPV without PH). CPSS can be extrahepatic (ECPSS), most commonly diagnosed in small and toy breed dogs and cats, or intrahepatic (ICPSS), most commonly seen in large breed dogs. Single ECPSS is the most common type encountered in both dogs and cats. Clinical signs of CPSS are non-specific and may wax and wane, while laboratory findings can raise clinical suspicion for CPSS, but they are also not specific. Definitive diagnosis will be established by evaluation of liver function tests, such as determination of fasting plasma ammonia (FA) levels, and pre- and postprandial serum bile acids concentrations, and diagnostic imaging. The purpose of this article is to review the definition, classification, pathogenesis, clinical presentation, and diagnosis of CPSS in dogs and cats, highlighted by the authors' clinical experience.

Comparison of Serum Bile Acid Concentrations Between Maltese and Other Breeds of Dogs With Portosystemic Shunt.

Congenital portosystemic shunt (PSS) is a vascular anomaly forming a direct communication between portal and central venous systems, thus bypassing the liver. This condition is related to various clinical symptoms including those manifesting in the central nervous system, gastrointestinal tract, and urinary tract. Treatment of PSS includes medical management and surgery. When evaluating prognosis of dogs with PSS, serum biochemistry profiles including serum bile acid (SBA) and ammonia concentrations are routinely used as screening tests. However, the use of SBA concentration in Maltese is controversial because it can be measured above the reference range even in normal dogs of this breed. In addition, utilizing SBA levels to assess surgical prognosis of PSS is not widely understood in this breed. Thus, the present study evaluated whether SBA could be used as a screening test for PSS in Maltese dogs. Medical records of dogs in the Veterinary Teaching Hospital from 2018 to 2020 were retrospectively reviewed. A total of 23 dogs with PSS and 30 Maltese dogs without PSS were analyzed. Although preoperative SBA levels were significantly higher in Maltese dogs (192 μmol/l) than in other dog breeds (137 μmol/l) with portocaval shunt, its concentrations were significantly decreased after surgery in both Maltese and other breeds of dogs. No significant difference was observed in postoperative SBA levels between Maltese and other dog breeds. The mean SBA levels for Maltese dogs without PSS (8 μmol/l) were within the reference interval (0-25 IU/l). Measuring pre- and post-operative SBA levels to evaluate prognosis of PSS might also be available for Maltese.

Gastrodia elata Blume extract improves high-fat diet-induced type 2 diabetes by regulating gut microbiota and bile acid profile.

In this study, we aimed to characterize the anti-type 2 diabetes (T2D) effects of Gastrodia elata Blume extract (GEBE) and determine whether these are mediated through modification of the gut microbiota and bile acids. Mice were fed a high-fat diet (HFD), with or without GEBE, and we found that GEBE significantly ameliorated the HFD-induced hyperglycemia, insulin resistance, and inflammation by upregulating glucose transporter 4 (GLUT4) and inhibiting the toll-like receptor 4-nuclear factor kappa-B signaling pathway in white adipose tissue (WAT). In addition, we found that GEBE increased the abundance of Faecalibaculum and Lactobacillus, and altered the serum bile acid concentrations, with a significant increase in deoxycholic acid. The administration of combined antibiotics to mice to eliminate their intestinal microbiota caused a loss of the protective effects of GEBE. Taken together, these findings suggest that GEBE ameliorates T2D by increasing GLUT4 expression in WAT, remodeling the gut microbiota, and modifying serum bile acid concentrations.

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.

Evaluation of Resting Serum Bile Acid Concentrations in Dogs with Sepsis.

Recent studies in the human literature suggest that serum bile acid concentrations could be an early predictor of short-term survival in critically ill patients. However, there is no available information in the veterinary literature regarding serum bile acid concentrations in dogs with sepsis. We aimed to evaluate if resting serum bile acid concentrations differ between septic and non-septic dogs. This was a retrospective observational study, of medical records at a single referral center over a twelve-year period. Twenty-six client-owned dogs diagnosed with sepsis were identified. Twenty-one dogs presenting with a non-hepatobiliary systemic disease and twenty-nine dogs admitted for an elective orthopedic procedure, considered otherwise healthy, were selected as control groups. Resting serum bile acid concentrations were significantly higher in the septic compared to the non-septic groups (ill control and orthopedic control groups). However, when assessing bile acid concentrations between groups individually, no difference was identified between the septic and the orthopedic control group. These results should be interpreted cautiously.

Multi-Omics Reveals Mechanisms of Partial Modulation of COVID-19 Dysregulation by Glucocorticoid Treatment.

Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK’s National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both ‘omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of ‘omics dysregulation caused by COVID-19 infections.

Increased concentrations of conjugated bile acids are associated with osteoporosis in PSC patients

Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Rats with high aerobic capacity display enhanced transcriptional adaptability and upregulation of bile acid metabolism in response to an acute high-fat diet.

Rats selectively bred for the high intrinsic aerobic capacity runner (HCR) or low aerobic capacity runner (LCR) show pronounced differences in susceptibility for high‐fat/high sucrose (HFHS) diet‐induced hepatic steatosis and insulin resistance, replicating the protective effect of high aerobic capacity in humans. We have previously shown multiple systemic differences in energy and substrate metabolism that impacts steatosis between HCR and LCR rats. This study aimed to investigate hepatic‐specific mechanisms of action via changes in gene transcription. Livers of HCR rats had a greater number of genes that significantly changed in response to 3‐day HFHS compared with LCR rats (171 vs. 75 genes: >1.5‐fold, p < 0.05). HCR and LCR rats displayed numerous baseline differences in gene expression while on a low‐fat control diet (CON). A 3‐day HFHS diet resulted in greater expression of genes involved in the conversion of excess acetyl‐CoA to cholesterol and bile acid (BA) synthesis compared with the CON diet in HCR, but not LCR rats. These results were associated with higher fecal BA loss and lower serum BA concentrations in HCR rats. Exercise studies in rats and mice also revealed higher hepatic expression of cholesterol and BA synthesis genes. Overall, these results suggest that high aerobic capacity and exercise are associated with upregulated BA synthesis paired with greater fecal excretion of cholesterol and BA, an effect that may play a role in protection against hepatic steatosis in rodents.

Resting and postpradial serum cholecystokinin concentrations and evaluation of the effect of seeing and/or smelling food on serum cholecystokinin and bile acid concentrations in healthy dogs

Serum bile acids concentrations rise postprandially. However, some dogs show paradoxical serum bile acids results with higher pre-prandial than post-prandial concentrations. The aim of this study was to evaluate serum cholecystokinin (CCK) concentrations and determine whether they correspond to paradoxical serum bile acids concentrations. In addition, seeing and smelling food was investigated as a possible cause for paradoxical serum bile acids results. Eight healthy dogs owned by volunteers enrolled in this experimental study. Food was withheld from the dogs for 12 h with great care not to expose them to any sight or smell of food. Blood samples were collected at 0, 30, 60, 120, 180, 240, 480 and 720 min after feeding. Food was then withheld again for 24 h, and blood samples were collected at 0, 30, 60, 120, 180, 240, 480 and 720 min after seeing and smelling food. After feeding, serum CCK concentrations increased, but paradoxical serum CCK concentrations were observed in some of dogs, but only one of those had also paradoxical serum bile acids concentrations. After seeing and smelling food, serum CCK and serum bile acids concentrations did not significantly increase. In conclusion, paradoxical serum CCK concentrations can occur in some healthy dogs after feeding. However, no correlation with paradoxical serum bile acids concentrations was found. Seeing or smelling food are unlikely causes for paradoxical serum bile acids concentrations. Additional studies are warranted to further evaluate the relationship of serum CCK and bile acids concentrations in healthy dogs and dogs with gastrointestinal disease.

Anamnestic and biochemical predictors of obstetric and perinatal complications in intrahepatic cholestasis of pregnancy

Objective. To determine the anamnestic and biochemical predictors of obstetric and perinatal complications in women with intrahepatic cholestasis of pregnancy (ICP).Materials and methods. 59 women with ICP and 30 pregnant women included into the comparison group were examined. The characteristics of the reproductive history, anamnesis of the disease, complaints, biochemical parameters of liver function (syndromes of cholestasis and hepatocyte cytolysis, function of protein synthesis), features of the course and treatment of ICP were studied.Results. The main predictors of preterm birth in the women with ICP were: age (P(U)=0.027), multiple pregnancy (OR=17.5, p=0.033); alkaline phosphatase (ALP) blood level &gt; 499 U/l (AUC=0.801; p=0.008); De Ritis Ratio value ≤ 0.49 (AUC=0.757; p=0.005). The main prognostic markers for meconium staining of amniotic fluid (MSAF) in the patients with ICP were: ICP in previous pregnancies (OR=7.1; p=0.029); serum bile acid concentration &gt; 14 μmol/l (AUC=0.718; p=0.043); total bilirubin blood level &gt; 13 μmol/l (AUC=0.773; p=0.007); ALP activity &gt; 484 U/l (AUC=0.728; p=0.033); blood creatinine concentration ≤ 60 μmol/l (AUC=0.930; p=0.0001) in asymptomatic course. The development of respiratory disorders in children born to women with asymptomatic ICP was associated with a total protein concentration in the blood of 78 g/l or less (AUC=0.852; p=0.0001).Conclusion. The anamnesis of the disease and the determination of the levels of the biochemical parameters of liver function allows predicting obstetric and perinatal complications in ICP.

Deep Learning Algorithm-Based Magnetic Resonance Imaging Feature-Guided Serum Bile Acid Profile and Perinatal Outcomes in Intrahepatic Cholestasis of Pregnancy.

This study was aimed to explore magnetic resonance imaging (MRI) based on deep learning belief network model in evaluating serum bile acid profile and adverse perinatal outcomes of intrahepatic cholestasis of pregnancy (ICP) patients. Fifty ICP pregnant women diagnosed in hospital were selected as the experimental group, 50 healthy pregnant women as the blank group, and 50 patients with cholelithiasis as the gallstone group. Deep learning belief network (DLBN) was built by stacking multiple restricted Boltzmann machines, which was compared with the recognition rate of convolutional neural network (CNN) and support vector machine (SVM), to determine the error rate of different recognition methods on the test set. It was found that the error rate of deep learning belief network (7.68%) was substantially lower than that of CNN (21.34%) and SVM (22.41%) (P < 0.05). The levels of glycoursodeoxycholic acid (GUDCA), glycochenodeoxycholic acid (GCDCA), and glycocholic acid (GCA) in the experimental group were dramatically superior to those in the blank group (P < 0.05). Both the experimental group and the blank group had notable clustering of serum bile acid profile, and the experimental group and the gallstone group could be better distinguished. In addition, the incidence of amniotic fluid contamination, asphyxia, and premature perinatal infants in the experimental group was dramatically superior to that in the blank group (P < 0.05). The deep learning confidence model had a low error rate, which can effectively extract the features of liver MRI images. In summary, the serum characteristic bile acid profiles of ICP were glycoursodeoxycholic acid, glycochenodeoxycholic acid, and glycocholic acid, which had a positive effect on clinical diagnosis. The toxic effects of high concentrations of serum bile acids were the main cause of adverse perinatal outcomes and sudden death.

Circulating Bile Acids and Adenoma Recurrence in the Context of Strict Adherence to a High-Fiber, High-Fruit and -Vegetable, and Low-Fat Dietary Intervention

ObjectivesDiet may affect BA metabolism and signaling, and, in turn, chronically higher bile acid (BA) concentrations may be associated with colorectal cancer risk. Further evidence regarding these interrelationships among human populations is needed. Therefore, we investigated 1) the effect of strict adherence to a high-fiber, high-fruit and -vegetable, low-fat dietary intervention on serum BA concentrations; and 2) associations of BA concentrations with adenoma recurrence. MethodsThe Polyp Prevention Trial is a 4-year randomized dietary intervention that investigated the effect of a high-fiber, high-fruit and vegetable, and low-fat diet on colorectal adenoma recurrence. We used targeted, quantitative liquid chromatography–tandem mass spectrometry panels to measure 13 BAs in serially collected serum at baseline, year-2, and year-3 of the trial among 170 intervention participants who strictly adhered to the intervention and 198 comparable control arm participants. We estimated the effect of the dietary intervention on mean year-2 and year-3 BA concentrations using repeated-measures linear mixed-effects models. We estimated associations of BA concentrations with adenoma recurrence 3–4 years after baseline using multivariable logistic regression. We estimated temporal variability of BA concentrations over 3 years using intraclass correlation coefficients (ICCs). ResultsWe found no effects of the high-fiber, high-fruit and -vegetable, low-fat diet intervention on serum BA concentrations; however, pre-trial dietary fiber intake was inversely associated with total BAs (Spearman = –0.15; PFDR = 0.03). Baseline total BA concentrations were positively associated with adenoma recurrence (ORQ3 vs. Q1 = 2.17; 95% CI = 1.19–4.04; P-trendFDR = 0.05). These findings were inconsistent when considering BA concentrations at year-2 and year-3, potentially reflecting our findings of moderate temporal stability of BAs over 3 years (ICC for total BAs = 0.53; 95% CI = 0.46–0.59) and underlying changes in adenoma status across the follow-up period. ConclusionsA high-fiber, high-fruit and -vegetable, low-fat diet may not modify serum BA concentrations; however, BAs concentrations may be positively associated with risk of adenoma recurrence. Funding SourcesIntramural Research Program, National Cancer Institute, NIH.