Total Bile Acid Concentration Research Articles

Quantitative bile acid profiling in healthy adult dogs and pups from serum, plasma, urine, and feces using LC-MS/MS.

Synthesis and secretion of bile acids (BA) is a key physiological function of the liver. In pathological conditions like portosystemic shunt, hepatic insufficiency, hepatitis, or cirrhosis BA metabolism and secretion are disturbed. Quantification of total serum BA is an established diagnostic method to assess the general liver function and allows early detection of abnormalities, liver disease progression and guidance of treatment decisions. To date, data on comparative BA profiles in dogs are limited. However, BA profiles might be even better diagnostic parameters than total BA concentrations. On this background, the present study analyzed and compared individual BA profiles in serum, plasma, urine, and feces of 10 healthy pups and 40 adult healthy dogs using ultra-high performance liquid chromatography coupled to electrospray ionization mass spectrometry. Sample preparation was performed by solid-phase extraction for serum, plasma, and urine samples or by protein precipitation with methanol for the feces samples. For each dog, 22 different BA, including unconjugated BA and their glycine and taurine conjugates, were analyzed. In general, there was a great interindividual variation for the concentrations of single BA, mostly exemplified by the fact that cholic acid (CA) was by far the most prominent BA in blood and urine samples of some of the dogs (adults and pups), while in others, CA was under the detection limit. There were no significant age-related differences in the BA profiles, but pups showed generally lower absolute BA concentrations in serum, plasma, and urine. Taurine-conjugated BA were predominant in the serum and plasma of both pups (68%) and adults (74-75%), while unconjugated BA were predominant in the urine and feces of pups (64 and 95%, respectively) and adults (68 and 99%, respectively). The primary BA chenodeoxycholic acid and taurocholic acid and the secondary BA deoxycholic acid and lithocholic acid were the most robust analytes for potential diagnostic purpose. In conclusion, this study reports simultaneous BA profiling in dog serum, plasma, urine, and feces and provides valuable diagnostic data for subsequent clinical studies in dogs with different kinds of liver diseases.

Effects of replacing fishmeal with different proportions of mixed protein source in the diet of largemouth bass (Micropterus salmoides)

Fishmeal is an important protein source for largemouth bass (Micropterus salmoides). However, the production of fishmeal is decreasing each year and the price of fishmeal is rising. Therefore, it is necessary to find new high-quality and suitable protein sources. This study used a mixed animal protein source (chicken meal:blood meal:shrimp meal:brewer's yeast = 50:12.5:25:12.5) to replace fishmeal. Using a 48 % fishmeal group as the control, five diets with different fishmeal levels (FM48, FM44, FM40, FM36, FM32) were established to determine the effects on largemouth bass growth performance, liver health and intestinal health. There were no significant differences in the percentage weight gain, specific growth rate, feed conversion rate, and condition factor of largemouth bass, but the hepatosomatic and viscerosomatic indexes were significantly decreased when the dietary fishmeal level was reduced to 40 %. The content of taurine, glycine, and histidine was significantly reduced in the muscle of largemouth bass fed the FM32 diet compared with those fed the FM48 and FM44 diets. Mixed protein feed reduced the total bile acid content and increased the low-density lipoprotein cholesterol content in the plasma of largemouth bass. The replacement of fishmeal with the mixed protein source inhibited the expression of tnf-α and caspase 3 and enhanced the expression of apoa1 in the liver, as well as enhancing the protein expression of FXR and SREBP and inhibiting the protein expression of P-PPARA in the liver. The intestinal pparα expression was suppressed when dietary fishmeal was replaced. When dietary fishmeal decreased, the mucosal folds height and muscle layer thickness also decreased. In conclusion, partial replacement of fishmeal with the mixed protein source did not affect the growth performance, while lipid metabolism and intestinal health were negatively affected when dietary fishmeal levels were below 36 %.

Quantification of Bile Acids in Cerebrospinal Fluid: Results of an Observational Trial.

(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood-brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [-0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood-brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood-brain barrier.

Elobixibat improves rectal sensation in patients with chronic constipation aged ≥60 years: a randomised placebo-controlled study

ObjectiveHigh rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the...

Percutaneous transvenous coil embolization (PTCE) for treatment of single extrahepatic portosystemic shunt in dogs

BackgroundThere is limited information regarding percutaneous transvenous coil embolization (PTCE) for single extrahepatic portosystemic shunt (PSS). This study aimed to describe the procedure and outcome of PTCE in dogs with a single extrahepatic PSS. Forty-two privately owned dogs were included in this study. All dogs were diagnosed with extrahepatic PSS by computed tomography (CT). Preoperative CT images were used to evaluate the diameter of the PSS for coil placement. A multipurpose balloon catheter was percutaneously inserted into the PSS via the jugular vein, and transvenous retrograde portography (TRP) and measurement of blood pressure in the PSS (pPSS) were performed during balloon inflation; one or more embolization coils were implanted via the catheter.ResultsIn most cases, preoperative median fasting and postprandial serum total bile acid (TBA) concentrations were high (fasting, 86.5 μmol/L [ 3.7–250.0 μmol/L]; postprandial, 165.5 μmol/L [ 1.5–565.0 μmol/L]). CT revealed that 30 dogs had left gastrophrenic shunt; eight had left gastroazygos shunt; and one each had left gastrocaval, splenocaval, splenophrenic, and left colocaval shunt. TRP revealed that intrahepatic portal vascularity was clearly detectable in all dogs. The median values of pPSS before and during the balloon occlusion were 4.8 mmHg [2.0–13.0 mmHg] and 8.6 mmHg [5.0–18.0 mmHg], respectively. The median number and diameter of coils used were 2 coils [1 – 5 coils] and 8.0 mm [4.0 – 12.0 mm], respectively. The median times of irradiation and PTCE were 9 min [4–26 min] and 40 min [23–75 min], respectively. The median fasting and postprandial TBAs significantly decreased to 8.2 μmol/L [0.3–45.1 μmol/L, n = 38, p = 0.0028] and 19.8 μmol/L [0.3–106.7 μmol/L, n = 38, p = 0.0018], respectively, approximately 1 month after PTCE. The clinical success rate of PTCE without requirement for a second surgery was 95.2% (40/42 dogs). During revision surgery, one dog underwent surgical ligation and, in another dog, an ameroid constrictor was placed.ConclusionsPTCE was clinically effective in treating single extrahepatic PSS in dogs. Preoperative CT and TRP prior to PTCE might be clinically valuable for choosing the size of embolization coils, deciding the appropriate location of coil implantation, and estimating the number of coils to be implanted. PTCE is a promising alternative to conventional surgical procedures for single extrahepatic PSS in dogs.

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.

Taurine-conjugated bile acids are the predominant form in hens and have potential impact on lipid metabolism in the liver

In mammals, bile acids composition varies with species, age, physiological conditions. However, the role of bile acids in the laying cycle of hens and their impact on lipid metabolism in chicken liver is not well understood. This study aimed to elucidate the role of bile acids in hen laying cycles, investigating their distribution across ages and assessing the impact of taurine-conjugated lithocholic acid (TLCA) on oleic acid-induced fatty liver cells in chickens. Results revealed an age-related increase in total bile acid concentration in hens blood, with taurine-conjugated bile acids prevailing. Among specific bile acids analysed, taurodeoxycholic acid (TDCA) decreased with age, while taurochenodeoxycholic acid (TCDCA) increased (n = 8). TLCA concentration also decreased gradually, while lycocholic acid (GCA) was elevated in 16-week-old hens (n = 8). Primary bile acids, cholic acid (CA), and chenodeoxycholic acid (CDCA) were higher at 16 weeks compared to egg production commencement (22 weeks) and 34 weeks (n = 8). Moreover, 5ß-Cholenic acid-7a-ol-3-one concentration was elevated in 74-week-old hens post-laying (n = 8). Investigating TLCA's impact on chicken liver lipid metabolism, TLCA significantly reduced lipid droplet accumulation, especially at 20 μM, while upregulating TLCA concentrations correlated with decreased SREBP1 protein expression responsible for triglyceride synthesis. In conclusion, taurine-conjugated bile acids potentially regulate lipid metabolism in hens, offering avenues for enhancing hens health and production through further mechanistic exploration and their potential integration into hens feed.

Per- and Poly-fluoroalkyl Substances and Bile Acid Profiles in Pregnant Women.

Alterations in bile acid (BA) profiles are closely associated with adverse outcomes in pregnant women and their offspring and may be one potential pathway underlying the related metabolic effects of per- and poly-fluoroalkyl substances (PFAS) exposure. However, evidence of associations between PFAS exposure and BA profiles in pregnant women is scarce. This study examined the associations of individual PFAS and PFAS mixture with BA profiles of pregnant women. We obtained quantitative data on the plasma concentrations of 13 PFAS and 15 BAs in 645 pregnant women from the Jiashan birth cohort. In Bayesian kernel machine regression models, the PFAS mixture was associated with increased plasma CA, TCA, TCDCA, and GLCA levels but with decreased GCA and LCA concentrations. Furthermore, the PFAS mixture was associated with increased concentrations of total BAs and the secondary/primary BA ratio but with decreased conjugated/unconjugated and glycine/taurine-conjugated BA ratios. PFHxS, PFUdA, PFOS, PFNA, and PFDA were the dominant contributors. The results of the linear regression analysis of individual PFAS were generally similar. Our findings provide the first epidemiological evidence for the associations of a PFAS mixture with BA profiles in pregnant women and may provide explanatory insights into the biological pathways underlying the related metabolic effects of PFAS exposure.

OR22-01 Sex Differences In Enterohepatic Circulation Mediated By Hepatic FXR And SHP Depletions In Mice

Abstract Disclosure: F. Reichardt: None. C. Galuke: None. S. Anakk: None. Bile acids are transported via the portal vein to the liver after their absorption through the distal intestine mucosa. In hepatocytes, they activate the nuclear receptors, Farnesoid-X-receptor (FXR) and Small Heterodimer Partner (SHP), which exert negative feedback on bile acids synthesis. The aim of this project is to decipher how hepatic FXR/SHP deletion impact BA composition, enterohepatic circulation, and its cross talk with the gut microbiota. Enterohepatic circulation was investigated by measuring total bile acids in intestinal, hepatic tissues and fecal tissues and in portal and systemic blood, using 3-5 months-old fed female and male wildtype (WT) and LDKO (liver specific FXR/SHP depletions) mice. We also examined if intestinal dysmotility mediated the alteration in bile acids absorption by following methylene blue dye progression in overnight fasted WT and LDKO mice. Portal and systemic total bile acids concentrations were higher in LDKO mice compared to WT, despite of no significant change in hepatic and intestinal levels. Sex differences were seen only in LDKO mice with higher systemic and portal concentrations in females compared to males. Intestinal transit time and fecal total bile acids were equivalent between all mice. Intriguingly, we observed that portal bile acids levels correlated to the liver weight to body weight ratio and to cecum weight to body weight ratio, suggesting that bile acids alterations within the enterohepatic loop could be associated to cecal dysbiosis. These preliminary findings highlight altered BA recirculation in LDKO mice compared to WT, but also between females and males LDKO. We hypothesize that these sex-specific modifications are associated with intestinal dysbiosis impacting bile acid compositions, and to test this we will be analyzing the influence of sex, and BA composition on the microbiome. Further investigations using fasted or HFD-fed LDKO and WT mice will help us to better understand the role of hepatic FXR and SHP in bile acids circulation between intestine and liver. Acknowledgement: University of Illinois Urbana-Champaign, American Cancer Society and Cancer Center at Illinois Seed grant Presentation: Saturday, June 17, 2023

Dietary deoxycholic acid decreases fat accumulation by activating liver farnesoid X receptor in grass crap (Ctenopharyngodon idella)

The mechanism underlying the efficacy of different bile acids (BAs) as feed additives to prevent or treat fatty liver disease in cultured fish remains poorly understood. This study compared the effect of different types of BAs on farnesoid X receptor (FXR) activity and lipid accumulation in grass carp. A survey revealed that grass carp (608.24 ± 17.511 g) with severe fatty liver had impaired FXR activity and increased liver total bile acids (TBA) content. In an in vitro study, four typical BAs, chenodeoxycholic acid (CDCA), cholic acid (CA), lithocholic acid (LCA), and deoxycholic acid (DCA), were found to significantly upregulate the expression of FXR and small heterodimer partner (SHP) and decreased lipid droplet accumulation in the hepatocytes of grass carp. Among these, DCA and CDCA exerted the most significant effects. In an in vivo study, grass carp (6.29 ± 0.05 g) were fed 100 mg/kg CDCA, CA, LCA, and DCA for 8 weeks; DCA alone significantly reduced lipid content in the liver and total cholesterol (T-CHO), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDLC) content in the serum. In addition, DCA improved the lipid catabolic activity, inhibited the lipid anabolic activity, and alleviated inflammation in the liver. In contrast, LCA, CDCA, and CA had the opposite effect on these indices. Mechanistically, DCA had a dominant impact on activating FXR in the liver, whereas the other BAs either inhibited gut FXR activity or had the risk in damaging liver cells. In conclusion, our results suggest that different BAs have varying effects on regulating fat accumulation, and DCA appears to be a particularly effective BA in suppressing fat accumulation via FXR pathway activation in the liver of grass crap.

Prophylactic feeding of neomycin to Holstein calves alters gut microbiota, bile acid metabolism, and expression of genes involved in immunometabolic regulation.

The objective of this study was to evaluate the effects of prophylactic neomycin administration on Holstein bull calves' intestinal microbiota, bile acid (BA) metabolism, and transcript abundance of genes related to BA metabolism. A total of 36 calves were blocked by body weight and assigned to either non-medicated milk replacer (CTL), or neomycin for 14 days (ST) or 28 days (LT) in their milk replacer. At the end of the study, calves were euthanized to collect tissue and digesta samples from the gastrointestinal tract, liver, and adipose tissue for analysis of intestinal microbial diversity, bile acid concentration and profile in various body tissues, and gene expression related to bile acid, lipid, carbohydrate metabolism, and inflammation. Calves that received prophylactic administration of neomycin for 28 d (LT) had reduced species richness (chao1 index), and tended to have reduced phylogenetic diversity in the ileum tissue. The relative abundance of Lactobacillus, and Bifidobacterium in ileum and colon digesta were decreased in LT compared with CTL. Concentrations of primary, secondary, and total BA were increased by ST in ileal tissue. In plasma, ST and LT treatments had lower concentrations of secondary BA. Gene expression of the BA receptor FXR was increased in ileum and liver by LT compared to CTL. The expression of FXR and TGR5 in the liver was increased in the ST group compared with CTL, and in adipose tissue, 5 genes related to triglyceride, gluconeogenesis, and immune activation were differentially expressed between CTL and ST. In conclusion, we provide evidence that prophylactic administration of neomycin leads to aberrant changes in BA concentration and profile in different compartments of the enterohepatic system through a process that possibly entails antimicrobial disruption of key bacterial groups, which persists even after cessation of neomycin administration. Additionally, we uncovered an apparent link between dysregulated BA metabolism and changes in lipid metabolism and immune activation in adipose tissue and liver.

Plasma Bile Acid Profiling and Modulation of Secreted Mucin 5AC in Cholangiocarcinoma.

Studies investigating the potential role of circulating bile acids (BAs) as diagnostic biomarkers for cholangiocarcinoma (CCA) are sparse and existing data do not adjust for confounding variables. Furthermore, the mechanism by which BAs affect the expression of the oncogenic mucin 5AC (MUC5AC) has never been investigated. We performed a case-control study to characterise the profile of circulating BAs in patients with CCA (n = 68) and benign biliary disease (BBD, n = 48) with a validated liquid chromatography-tandem mass spectrometry technique. Odd ratios (OR) for CCA associations were calculated with multivariable logistic regression models based on a directed acyclic graph structure learning algorithm. The most promising BAs were then tested in an in vitro study to investigate their interplay in modulating MUC5AC expression. The total concentration of BAs was markedly higher in patients with CCA compared with BBD controls and accompanied by a shift in BAs profile toward a higher proportion of primary conjugated BAs (OR = 1.50, CI: 1.14 to 1.96, p = 0.003), especially taurochenodeoxycholic acid (TCDCA, OR = 42.29, CI: 3.54 to 504.63, p = 0.003) after multiple adjustments. Western blot analysis of secreted MUC5AC in human primary cholangiocytes treated with primary conjugated BAs or with TCDCA alone allowed us to identify a novel 230 kDa isoform, possibly representing a post-translationally modified MUC5AC specie.

Effects of glyphosate exposure on gut–liver axis: Metabolomic and mechanistic analysis in grass carp (Ctenopharyngodon idellus)

Glyphosate, one of the most widely used herbicide worldwide, is potentially harmful to non-target aquatic organisms. However, the environmental health risks regarding impacts on metabolism homeostasis and underlying mechanisms remain unclear. Here we investigated bioaccumulation, metabolism disorders and mechanisms in grass carp after exposure to glyphosate. Higher accumulation of glyphosate and its major metabolite, aminomethylphosphonic acid, in the gut was detected. Intestinal inflammation, barrier damage and hepatic steatosis were caused by glyphosate exposure. Lipid metabolism disorder was confirmed by the decreased triglyceride, increased total cholesterol and lipoproteins in serum and decreased visceral fat. Metabolomics analysis found that glyphosate exposure significantly inhibited bile acids biosynthesis in liver with decreased total bile acids content, which was further supported by significant downregulations of cyp27a1, cyp8b1 and fxr. Moreover, the dysbiosis of gut microbiota contributed to the inflammation in liver and gut by increasing lipopolysaccharide, as well as to the declined bile acids circulation by reducing secondary bile acids. These results indicated that exposure to environmental levels of glyphosate generated higher bioaccumulation in gut, where evoked enterohepatic injury, intestinal microbiota dysbiosis and disturbed homeostasis of bile acids metabolism; then the functional dysregulation of the gut-liver axis possibly resulted in ultimate lipid metabolism disorder. These findings highlight the metabolism health risks of glyphosate exposure to fish in aquatic environment.

Risk-stratified management strategies for intrahepatic cholestasis of pregnancy: A tertiary center population review over nearly 5 years.

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes, resulting in a higher risk of perinatal morbidity and mortality. The authors conducted a retrospective study of 2385 singletons with ICP who underwent risk-stratified management strategies. To explore the risks of perinatal outcomes of ICP, subgroup analyses were performed using different total bile acid (TBA) levels. In this study, there was only one stillbirth and one neonatal death. Among the study cohort, 2299 patients had ICP with a TBA level ≥10 μmol/L and 86 had ICP with a TBA level <10 μmol/L. The 2299 patients with ICP (TBA level ≥ 10 μmol/L) were divided into three groups: mild ICP (n = 1803), severe ICP (n = 400), and extremely severe ICP (n = 96). Increased TBA concentration was associated with an increased incidence of preterm birth, newborn asphyxia, neonatal intensive care unit hospitalization, meconium-stained amniotic fluid, and low birth weight in the three groups (P < 0.05). Furthermore, severe and extremely severe ICP with hypotonic absonant uterine contraction had a significant effect on neonatal asphyxia (odds ratio, 5.06 [95% confidence interval, 1.09-23.37]; P < 0.05) and meconium-stained amniotic fluid (odds ratio, 2.37 [95% confidence interval, 1.43-3.93]; P < 0.05). Hypotonic absonant uterine contractions could be high-risk stressors for severe and extremely severe ICP; hence, proper prenatal care is recommended. Risk-stratified management strategies for ICP are critical to obtaining better maternal-fetal outcomes.

Associations between Ileal Juice Bile Acids and Colorectal Advanced Adenoma.

There is an urgent need to identify biomarkers for advanced adenoma, an important precursor of colorectal cancer (CRC). We aimed to determine alterations in ileal juice bile acids associated with colorectal advanced adenoma. We quantified a comprehensive panel of primary and secondary bile acids and their conjugates using an ultraperformance liquid chromatography triple-quadrupole mass spectrometric assay in ileal juice collected at colonoscopy from 46 study subjects (i.e., 14 biopsy-confirmed advanced adenomas and 32 controls free of adenoma or cancer). Using analysis of covariance (ANCOVA), we examined the differences in bile acid concentrations by disease status, adjusting for age, sex, body mass index, smoking status and type 2 diabetes. The concentrations of hyodeoxycholic acid (HCA) species in ileal juice of the advanced adenoma patients (geometric mean = 4501.9 nM) were significantly higher than those of controls (geometric mean = 1292.3 nM, p = 0.001). The relative abundance of ursodeoxycholic acid (UDCA) in total bile acids was significantly reduced in cases than controls (0.73% in cases vs. 1.33% in controls; p = 0.046). No significant difference between cases and controls was observed for concentrations of total or specific primary bile acids (i.e., cholic acid (CA), chenodeoxycholic acid (CDCA) and their glycine- and taurine-conjugates) and total and specific major secondary bile acids (i.e., deoxycholic acid and lithocholic acid). Colorectal advanced adenoma was associated with altered bile acids in ileal juice. The HCA species may promote the development of colorectal advanced adenoma, whereas gut microbiota responsible for the conversion of CDCA to UDCA may protect against it. Our findings have important implications for the use of bile acids as biomarkers in early detection of colorectal cancer.

The regulatory role of bile acid microbiota in the progression of liver cirrhosis.

Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.

Stigmasterol Protects Against Steatohepatitis Induced by High-Fat and High-Cholesterol Diet in Mice by Enhancing the Alternative Bile Acid Synthesis Pathway

BackgroundHepatic cholesterol accumulation is a significant risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis. However, the precise mechanism by which stigmasterol (STG) mitigates this process remains unclear. ObjectivesThis study aimed to investigate the potential mechanism underlying the protective effect of STG in mice with NAFLD progressing to steatohepatitis while being fed a high-fat and high-cholesterol (HFHC) diet. MethodsMale C57BL/6 mice were fed an HFHC diet for 16 wk to establish the NAFLD model. Subsequently, the mice received STG or a vehicle via oral gavage while continuing the HFHC diet for an additional 10 wk. The study evaluated hepatic lipid deposition and inflammation as well as the expression of key rate-limiting enzymes involved in the bile acid (BA) synthesis pathways. BAs in the colonic contents were quantified using ultra-performance liquid chromatography-tandem mass spectrometry. ResultsCompared with the vehicle control group, STG significantly reduced hepatic cholesterol accumulation (P < 0.01) and suppressed the gene expression of NLRP3 inflammasome and interleukin-18 (P < 0.05) in the livers of HFHC diet-fed mice. The total fecal BA content in the STG group was nearly double that of the vehicle control group. Additionally, the administration of STG increased the concentrations of representative hydrophilic BAs in the colonic contents (P < 0.05) along with the upregulation of gene and protein expression of CYP7B1 (P < 0.01). Furthermore, STG enhanced the α-diversity of the gut microbiota and partially reversed the alterations in the relative abundance of the gut microbiota induced by the HFHC diet. ConclusionsSTG mitigates steatohepatitis by enhancing the alternative pathway for BA synthesis.

Chronic corticosterone exposure disrupts hepatic and intestinal bile acid metabolism in chicken.

Chronic stress leads to a high circulating level of glucocorticoids, which disrupts lipid metabolism and causes non-alcoholic fatty liver disease in mice and humans. Meanwhile, bile acid (BA), a class of metabolites initially synthesized in the liver and further metabolized by gut microbiota, plays a vital role in lipid metabolism. This study aimed to investigate the effects of glucocorticoids on BA metabolism and gut microbiota in chickens. In this study, 35-day-old chickens were injected with 4 mg/kg/day corticosterone (Cort) for 14 days to simulate chronic stress. Cort treatment significantly increased the triglyceride contents in the plasma and the liver. HE and oil-red staining showed that Cort treatment induced fatty liver in chickens. Meanwhile, Cort exposure downregulated total bile acid (TBA) content in the liver while increasing the TBA in feces. UPLC-HRMS results showed that Cort exposure significantly decreased the hepatic levels of CDCA, T-alpha-MCA, and T-beta-MCA. Moreover, Cort exposure significantly reduced the expression of genes related to BA synthesis (CYP8B1 and CYP27A1), conjugation (BACS), and regulation (KLβ and FGFR4). 16s sequencing results showed that Cort treatment significantly decreased the amount of Lachnospiraceae, Eisenbergiella, Blautia, and Eubacterium and increased the abundance of Barnesiella, Lactobacillus, and Helicobacter. Spearman correlation analysis showed a significant positive correlation between fecal TBA and the abundance of Lactobacillales, Lactobacillus, and Barnesiella. In comparison, TBA in the liver was positively correlated with Eubacterium, and negatively correlated with Helicobacter. In summary, chronic Cort exposure disrupts hepatic and intestinal bile acid metabolism inducing gut microbiome dysbiosis, which might associate with the development of fatty liver in chickens.

Interactive effects of gestational diabetes mellitus and maximum level of total bile acid in maternal serum on adverse pregnancy outcomes in women with intrahepatic cholestasis of pregnancy

ObjectiveTo study the combined effect of gestational diabetes mellitus (GDM) and maximum level of maternal serum total bile acid (TBA) on the incidence of adverse pregnancy outcomes in women with intrahepatic cholestasis of pregnancy (ICP).MethodsThis was an observational study with 724 women with ICP. Perinatal outcomes were compared by the presence of GDM. Logistic regression was used to assess the independent and multiplicative interactions of GDM and maximum maternal serum TBA on adverse pregnancy outcomes. Additive interactions were calculated using an Excel sheet developed by Andersson to calculate relative excess risks.ResultsThe incidence of GDM in patients with ICP was 21.55%. Maternal age, pre-pregnancy weight, parity, and gravidity were positively correlated with GDM. Hypertensive disorders of pregnancy (HDP) and fetal distress rates were higher in the GDM vs. non-GDM group. There were no significant differences in biochemical outcomes (i.e., Triglyceride (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bile acid (TBA)) between the two groups. In terms of adverse pregnancy outcomes, GDM was only associated with maximum TBA concentration for cesarean section. No additive or pairwise interactions were detected between GDM and maximum TBA concentration and HDP, PPH, preterm delivery, LGA, SGA, and cesarean section.ConclusionGDM independently contributes to adverse pregnancy outcomes among women with ICP. However, the combined effects of GDM and maximum TBA concentration on adverse pregnancy outcomes do not appear to be multiplicative or additive.

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.