Changes In Serum Bile Acids Research Articles

THU142 One-year Change In Bile Acids And Its Association With Changes In Metabolic Profile After Sleeve Gastrectomy In Youth

Abstract Disclosure: S. Tuli: None. S. Kaur: None. M. Bredella: None. M. Misra: None. V. Singhal: None. Introduction: Bile acids (BAs) are hydroxylated steroid acids. Primary (10) BAs (cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized by the liver. Secondary (20) BAs (deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) are formed from 10 BAs by the action of intestinal flora. Preclinical studies indicate a role of BAs in weight loss and metabolic improvements after metabolic and bariatric surgery (MBS). Data are inconsistent regarding changes in BAs after sleeve gastrectomy (SG), the most common MBS. Further, how BA changes contribute to metabolic improvements after SG is unclear. Objective: Evaluate changes in serum BAs 1 year after SG in youth with obesity and associations with changes in metabolic parameters. Methods: 16 adolescents (75% females) 13-22 years old with severe obesity were followed for one-year post-SG with assessments at baseline and during a mixed meal tolerance test (MMTT). We measured fasting BAs, glucose, insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lipids. Blood was drawn at 15, 30, 60, 90, and 120 minutes for glucose and insulin and at 0, 15, 60, and 120 minutes for BAs. Data are reported as changes over 15 minutes [t15–t0 of MMTT (Δ15)], area under the curve (AUC), and % change. Results: BMI decreased by 25.7% (p<0.0001). For 10 BAs: fasting CA levels decreased (33.3%, p=0.005), while Δ15 CA, CDCA and, total 10 BAs (113.3%, 188.9%, 152.9%, p<0.005), and AUC for CDCA and total 10 BAs (34.2%, p=0.004; 30.3%, p=0.015) increased one-year post-SG. For 20 BA: Δ15 DCA and total 20 BAs (212.5%, p≤0.011; 195.2%, p=0.004), and AUC DCA and total 20 BAs (95.0%, p=0.031; 59.4%, p=0.035) increased. Δ15 and AUC total BA also increased (100%, p=0.002; 1060.9%, p≤0.0001). Insulin resistance (HOMA-IR) (58.6%), low-density lipoprotein (LDL) (11.2%), triglyceride (14.6%), and ALT (26.9%) decreased (p<0.05), while high-density lipoprotein (HDL) levels (10.2%, p=0.04) increased. Decreases in AUC insulin were associated with increases in AUC 20/10 BA (ρ=-0.687, p=0.009). HBA1C decreases were associated with increases in AUC total BAs (ρ=-0.531, p=0.034). Increases in the insulinogenic index (Δ30 Insulin/ Δ30 glucose) correlated positively with fasting DCA (ρ=0.567, p=0.028). Increases in HDL were associated with increases in fasting CA (ρ=0.580, p=0.018) and UDCA (ρ=0.592, p=0.016). Conclusion: Total, 10, and 20 bile acids increase after SG in youth associated with improvements in metabolic profile. Presentation: Thursday, June 15, 2023

Ileal Bile Acid Transporter Blockers for Cholestatic Liver Disease in Pediatric Patients with Alagille Syndrome: A Systematic Review and Meta-Analysis.

Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic review and meta-analysis presents the latest evidence for ileal bile acid transport (IBAT) blockers in AGLS patients in order to improve their efficacy. This study adhered to PRISMA 2020 Statement guidelines. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane library was conducted from inception until 23 October 2022. A combination of the following keywords was used: Alagille syndrome, therapeutics, treatment, therapy. Meta-analytical outcomes included effect directions of end-line changes in serum bile acids (sBAs), Itch Scale scores (ItchRO), Multidimensional Fatigue Scale scores, pediatric quality of life (QL), alanine aminotransferase (ALT), and total bilirubin. A total of 94 patients across four trials were enrolled and received maralixibat, odevixibat, or a placebo. There was a significant reduction in ItchRO scores by 1.8 points, as well as in sBAs by 75.8 μmol/L. Both the Multidimensional Fatigue Scale and Pediatric QL scale were also improved by 11.4 and 8.3 points, respectively. However, ALT levels were raised by 40 U/L. The efficacy of IBAT inhibitors across current trials was noted. Future trials may focus on the optimization of dosing regimens, considering gastrointestinal side effects and drug-induced ALT elevation in AGLS patients.

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

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

Evidence That the Length of Bile Loop Determines Serum Bile Acid Concentration and Glycemic Control After Bariatric Surgery

BackgroundBariatric surgery contributes to the improvement in glucose metabolism that may be related to a postoperative increase in serum bile acids (BAs). Three commonly used types of bariatric procedures, laparoscopic sleeve gastrectomy (LSG) (without creation of a bile loop), Roux-en-Y gastric bypass (RYGB), and omega-loop gastric bypass (OLGB) (with creation of shorter 100–150 cm and longer 200–280 cm bile loops, respectively), differ in their effects on glycemic control. The aim of the study was to compare the effects of various bariatric procedures on serum BA concentration and glucose homeostasis.MethodsSerum BAs in 26 obese patients were determined by liquid chromatography-mass spectrometry prior to bariatric surgery, as well as 4 days and 3 months thereafter.ResultsFour days after the surgery, serum concentrations of BAs in LSG and OLGB groups were similar as prior to the procedure, and a slight decrease in serum BAs was observed in the RYGB group. Serum BA level in the LSG group remained unchanged also at 3 months after the surgery, whereas a significant 0.5- and 3-fold increase in this parameter was noted in the RYGB and OLGB groups, respectively. Serum concentration of BAs correlated positively with the length of the bile loop (R = 0.47, p < 0.05).ConclusionThe evident improvement of glycemic control observed 3 months after OLGB might be associated with a postoperative increase in serum BAs, resulting from their better absorption from the longer bile loop. However, the changes in serum BAs probably had little or no impact on insulin sensitivity improvement at 4 days post-surgery.

Antibiotic effects on gut microbiota and metabolism are host dependent.

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential.

Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities

Surgical interposition of distal ileum into the proximal jejunum is a bariatric procedure that improves the metabolic syndrome. Changes in intestinal and hepatic physiology after ileal interposition (transposition) surgery (IIS) are not well understood. Our aim was to elucidate the adaptation of the interposed ileum, which we hypothesized, would lead to early bile acid reabsorption in the interposed ileum, thus short circuiting enterohepatic bile acid recycling to more proximal bowel segments. Rats with diet-induced obesity were randomized to IIS, with 10 cm of ileum repositioned distal to the duodenum, or sham surgery. A subgroup of sham rats was pair-fed to IIS rats. Physiological parameters were measured until 6 wk postsurgery. IIS rats ate less and lost more weight for the first 2 wk postsurgery. At study completion, body weights were not different, but IIS rats had reversed components of the metabolic syndrome. The interposed ileal segment adapted to a more jejunum-like villi length, mucosal surface area, and GATA4/ILBP mRNA. The interposed segment retained capacity for bile acid reabsorption and anorectic hormone secretion with the presence of ASBT and glucagon-like-peptide-1-positive cells in the villi. IIS rats had reduced primary bile acid levels in the proximal intestinal tract and higher primary bile acid levels in the serum, suggesting an early and efficient reabsorption of primary bile acids. IIS rats also had increased taurine and glycine-conjugated serum bile acids and reduced fecal bile acid loss. There was decreased hepatic Cyp27A1 mRNA with no changes in hepatic FXR, SHP, or NTCP expression. IIS protects against the metabolic syndrome through short-circuiting enterohepatic bile acid recycling. There is early reabsorption of primary bile acids despite selective "jejunization" of the interposed ileal segment. Changes in serum bile acids or bile acid enterohepatic recycling may mediate the metabolic benefits seen after bariatric surgery.

Selectivity and sensitivity of changes in serum bile acids during induction of cirrhosis in ratsselectivity and sensitivity of changes in serum bile acids during induction of cirrhosis in rats

Because some patients with cirrhosis have serum transaminase levels within the normal range, a prospective study was undertaken to determine whether the concentration of individual serum bile acids would be a sensitive indicator of development of cirrhosis. The choline-deficient rat has been used as a model for study of these changes. Using high-performance liquid chromatography, we measured the concentrations of individual serum bile acids at 3, 6, 10, 20 and 30 wk of dietary intake. Serum levels of total glycine- and taurine-conjugated bile acids were elevated at all stages tested as compared with levels in control groups (choline supplemented). Similarly, unconjugated bile acids and, particularly, cholic acid showed significantly higher levels at all stages except with the occurrence of cirrhosis at 30 wk, at which time there was a significantly lower level for unconjugated bile acids (0.48 ± 0.11 vs. 1.40 ± 0.36 in controls) and for cholic acid (0.17 ± 0.05 vs. 0.91 ± 0.39 in controls). The ratio of serum cholic acid to serum chenodeoxycholic acid changed in temporal relationship to progression in the histological lesions in livers of these rats. The ratio was at its highest at 78 ± 3 at 3 wk (no histological change) and decreased with increasing time and changes in histological appearance until 30 wk, at which time it was down to 1.6 ± 0.6. The routinely used markers of liver injury (serum ALT, alkaline phosphatase and bilirubin), however, did not match the progression of hepatic histological changes. The relationship of the increase in serum bile acids to the cirrhotic process is supported by qualitatively similar findings in a second rat model. Thus the hepatic pathological changes in cirrhotic rats were reflected by the changes in the individual serum bile acids together with the ratio of serum cholic acid to serum chenodeoxycholic acid, but not with other standard tests of liver function. (HEPATOLOGY 1993;18:1224-1231).

Selectivity and sensitivity of changes in serum bile acids during induction of cirrhosis in rats, ,

Because some patients with cirrhosis have serum transaminase levels within the normal range, a prospective study was undertaken to determine whether the concentration of individual serum bile acids would be a sensitive indicator of development of cirrhosis. The choline-deficient rat has been used as a model for study of these changes. Using high-performance liquid chromatography, we measured the concentrations of individual serum bile acids at 3, 6, 10, 20 and 30 wk of dietary intake. Serum levels of total glycine- and taurine-conjugated bile acids were elevated at all stages tested as compared with levels in control groups (choline supplemented). Similarly, unconjugated bile acids and, particularly, cholic acid showed significantly higher levels at all stages except with the occurrence of cirrhosis at 30 wk, at which time there was a significantly lower level for unconjugated bile acids (0.48 +/- 0.11 vs. 1.40 +/- 0.36 in controls) and for cholic acid (0.17 +/- 0.05 vs. 0.91 +/- 0.39 in controls). The ratio of serum cholic acid to serum chenodeoxycholic acid changed in temporal relationship to progression in the histological lesions in livers of these rats. The ratio was at its highest at 78 +/- 3 at 3 wk (no histological change) and decreased with increasing time and changes in histological appearance until 30 wk, at which time it was down to 1.6 +/- 0.6. The routinely used markers of liver injury (serum ALT, alkaline phosphatase and bilirubin), however, did not match the progression of hepatic histological changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of Trichloroethylene-Induced Elevation of Individual Serum Bile Acids: II. In Vitro and in Vivo Interference by Trichloroethylene with Bile Acid Transport in Isolated Rat Hepatocytes

The effects of trichloroethylene (TRI) on bile acid transport in isolated rat hepatocytes have been studied using doses ranging from 0.5 to 4.0 μl/flask and a 20-min equilibration period. It was found that TRI caused a dose-related suppression of initial rates of uptake of cholic acid (CA) and taurocholic acid (TC) with no significant effect on enzyme leakage and intracellular potassium ion contents. Accumulation over 30 min for each of those two bile acids was also inhibited. A noncompetitive inhibition of bile acid uptake was shown as indicated by a decrease in maximum velocity ( V max) and unchanged Michaelis constant ( K m ). Thirty minutes after cessation of TRI exposure in vitro the uptake of bile acids had gradually returned to normal levels. No significant interference of efflux was found in cells preloaded with either CA or TC. After dosing rats with 1 mmol/kg TRI in vivo the inhibition of uptake of CA and TC by subsequently isolated hepatocytes was not detected until 4 hr. By 16 hr uptake had returned to normal. The accumulation of bile acids was also suppressed at 4 and 8 hr. The inhibition of uptake after in vivo treatment was also noncompetitive. The data are consistent with the reversible increase of serum bile acids (SBA) in experimental animals after exposure to TRI. Furthermore, they support the contention that it is an interference with bile acid uptake, rather than actual cell damage, that is responsible for TRI induced increases in SBA. Thus, the changes in SBA seem to be the result of interference with a physiological process rather than an event associated with significant pathological consequences.

Effects of carbon tetrachloride and chloroform on bile acid transport in isolated rat hepatocytes: Relationship to elevated serum bile acids

The hepatotoxic effects of chlorinated hydrocarbon solvents have been well recognized for many years. More recently serum bile acids (SBA) have been considered as a sensitive indicator for the determination of liver dysfunction. However, changes in SBA could result from interference with hepatic transport processes. In this study, the effects of carbon tetrachloride (CCl 4) and chloroform (CHCl 3) on uptake and efflux of bile acids were examined in isolated rat liver cells to determine whether this may play a role in elevated SBA after CCl 4 or CHCl 3 treatment. Cholic acid (CA) and taurocholic acid (TC) were selected as representative bile acids known to enter hepatocytes by active transport. At none of the doses of CCl 4 and CHCl 3 investigated was there a significant change in cytoplasmic enzymes or intracellular K + release. CCl 4 and CHCl 3 were both found to cause a dose-related inhibition of uptake of CA and TC. Furthermore, CCl 4 and CHCl 3 were shown to increase the Michaelis constant ( K m ) but leave maximum velocity ( V max ) unchanged thus indicating competitive inhibition. The lowest doses of CCl 4 and CHCl 3 at which inhibition of initial uptake rate (V 0) occurred for CA or TC were found to be 0.5 μl/flask (0.07 m m) or 1.0 μl/flask (0.17 m m) in cell suspensions, respectively. The inhibition of uptake could be reversed 30 min after cessation of exposure to CCl 4. No chemical-induced interference of efflux for CA or TC was found in preloaded cells. These findings indicate that interference in bile acid uptake may be involved, at least in part, in the increases in SBA in dosed animals, or workers exposed to CCl 4, CHCl 3 and perhaps other chlorinated solvents.

Conjugated bile acids in serum and secretions in response to cholecystokinin/secretin stimulation in children with cystic fibrosis.

More than 80% of patients with cystic fibrosis have poor pancreatic function, and have large daily faecal bile acid losses. This has been postulated to lower luminal bile acid concentrations and adversely affect fat absorption. We studied, for the first time, quantitative individual conjugated duodenal bile acid secretion rates into the duodenum during cholecystokinin/secretin infusion in 55 cystic fibrosis patients and six controls, using a quantitative non-absorbable marker technique. We were able to show adequate duodenal total bile acid concentrations and normal secretion rates in these children. The bile acid secretion pattern in cystic fibrosis patients showed a marked increase in bile acid concentration during cholecystokinin/secretin infusion, to levels which were above the critical micellar concentration indicating that the gall bladder is a functional organ in this disease. The subsequent fall in secretion rate was similar to controls. We have documented a significantly raised glycine/taurine bile acid conjugation ration in duodenal juice from cystic fibrosis patients and suggest that the combined effects of lowered ileal pH and increased glycine conjugated proportion of bile acids may cause precipitation of bile acids leading to decreased fat absorption and large faecal bile acid losses. To further investigate bile acid secretion in children with cystic fibrosis, we modified the high performance thin layer chromatography/densitometry method to enable measurement of individual glycine and taurine conjugates in serum. In comparing cystic fibrosis patients and controls, we were able to determine a group of 18 (36%) with bile acid evidence of liver damage who also showed reduced bile acid secretion into the duodenum. We were unable to study changes in serum bile acids during cholecystokinin/secretin infusion because of the high level of bile acid contamination in Boots Secretin. Some patients showed raised fasting serum bile acid concentrations more than two years before changes in conventional liver function tests or clinically evident liver disease. We have shown fasting serum bile acids to be a sensitive measure of liver dysfunction in cystic fibrosis and postulate that raised proportions of glycine conjugated bile acids may be responsible for the high incidence of liver disease in cystic fibrosis.

Serum bile acids as related to bile acid secretion in liver disease.

The level of serum bile acids and their rate of secretion into the duodenum were measured in normal subjects and patients with cholesterol gallstones and hepatobiliary disease. These studies were undertaken to determine if changes in serum bile acids reflected alterations in bile acid secretion within the enterohepatic circulation, especially in association with disordered bile acid metabolism and liver dysfunction. To quantitate bile acid secretion, an intestinal marker-perfusion technique was used which measured duodenal output under stimulated but steady-state conditions. During these perfusion studies, serum bile acids were determined at hourly intervals. In normal subjects, serum bile acids during fasting were low (6.6±0.7 μM) with only a modest rise occurring after a fat meal (7.6±0.7 μM). The average bile acid secretion rate in these subjects was 1321 μmol/hr, and little fluctuation was noted in the serum levels (7.5±0.8 μM) during the perfusion studies. Patients with cholesterol galistones demonstrated a decreased rate of bile acid secretion at 714 μmol/hr but had normal serum values. After cholecystectomy, their bile acid secretion rate increased without any corresponding change in serum levels. In patients with liver disease, however, serum bile acids were elevated while bile acid secretion was reduced. Thus, in normal subjects the liver is quite capable of handling an increased endogenous bile acid return with only a small rise in serum levels. In liver disease, bile acid secretion is reduced while serum concentrations are increased, implying a defect in bile acid handling by the liver. In cholesterol gallstone disease, serum levels do not reflect the abnormality in bile acid metabolism. The relation between bile acid concentration in the serum and secretion rate into the enterohepatic circulation is therefore complex, depending on whether or not hepatic dysfunction is present or if bile acid metabolism is abnormal.

12 - Diagnostic Value of Serum Bile Acids

With the development of simplified methods of bile acid analysis, a new era has drawned in the evaluation of hepatobiliary disease. 1. A total serum bile acid particularly in the postprandial periods is more sensitive than either BSP or ICG for the detection of minimal liver disease and will become a useful screening method. 2. The ratio of chenodeoxycholate to cholate in serum together with the total concentration can often distinguish hepatitis and cirrhosis from intrahepatic and extrahepatic cholestasis with normal liver cell parenchyma. However, in practice this is usually of less value than the total serum bile acid level. 3. Changes in serum bile acids throughout a 24 hour cycle reflect the enterohepatic circulation of bile acids and the capacity of the liver to transport them. These patterns are most useful in judging the severity of cholestasis and response to resin therapy. They also provide new insights into the pathophysiology of bile acid metabolism and excretion in different diseases of the liver.