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1.
Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.
Stepien, M, Lopez-Nogueroles, M, Lahoz, A, Kühn, T, Perlemuter, G, Voican, C, Ciocan, D, Boutron-Ruault, MC, Jansen, E, Viallon, V, et al
International journal of cancer. 2022;(8):1255-1268
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Abstract
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
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2.
The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism.
Li, X, Xin, Y, Mo, Y, Marozik, P, He, T, Guo, H
Molecules (Basel, Switzerland). 2022;(2)
Abstract
Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5-2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.
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Novel Bile Acid-Dependent Mechanisms of Hepatotoxicity Associated with Tyrosine Kinase Inhibitors.
Saran, C, Sundqvist, L, Ho, H, Niskanen, J, Honkakoski, P, Brouwer, KLR
The Journal of pharmacology and experimental therapeutics. 2022;(2):114-125
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Abstract
Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the bile salt export pump (BSEP) is one mechanism of DILI. Dasatinib, pazopanib, and sorafenib are tyrosine kinase inhibitors (TKIs) that competitively inhibit BSEP and increase serum biomarkers for hepatotoxicity in ∼25-50% of patients. However, the mechanism(s) of hepatotoxicity beyond competitive inhibition of BSEP are poorly understood. This study examined mechanisms of TKI-mediated hepatotoxicity associated with altered bile acid homeostasis. Dasatinib, pazopanib, and sorafenib showed bile acid-dependent toxicity at clinically relevant concentrations, based on the C-DILI assay using sandwich-cultured human hepatocytes (SCHH). Among several bile acid-relevant genes, cytochrome P450 (CYP) 7A1 mRNA was specifically upregulated by 6.2- to 7.8-fold (dasatinib) and 5.7- to 9.3-fold (pazopanib), compared with control, within 8 hours. This was consistent with increased total bile acid concentrations in culture medium up to 2.3-fold, and in SCHH up to 1.4-fold, compared with control, within 24 hours. Additionally, protein abundance of sodium taurocholate co-transporting polypeptide (NTCP) was increased up to 2.0-fold by these three TKIs. The increase in NTCP protein abundance correlated with increased function; dasatinib and pazopanib increased hepatocyte uptake clearance (CLuptake) of taurocholic acid, a probe bile acid substrate, up to 1.4-fold. In conclusion, upregulation of CYP7A1 and NTCP in SCHH constitute novel mechanisms of TKI-associated hepatotoxicity. SIGNIFICANCE STATEMENT Understanding the mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors (TKIs) is fundamental to development of effective and safe intervention therapies for various cancers. Data generated in sandwich-cultured human hepatocytes, an in vitro model of drug-induced hepatotoxicity, revealed that TKIs upregulate bile acid synthesis and alter bile acid uptake and excretion. These findings provide novel insights into additional mechanisms of bile acid-mediated drug-induced liver injury, an adverse effect that limits the use and effectiveness of TKI treatment in some cancer patients.
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Effect of Lactobacillus rhamnosus Probiotic in Early Pregnancy on Plasma Conjugated Bile Acids in a Randomised Controlled Trial.
Chen, Y, Lu, J, Wickens, K, Stanley, T, Maude, R, Stone, P, Barthow, C, Crane, J, Mitchell, EA, Merien, F, et al
Nutrients. 2021;(1)
Abstract
We have previously shown that probiotic supplementation with Lactobacillus rhamnosus HN001 (HN001) led to a reduced incidence of gestational diabetes mellitus (GDM). Here we investigate whether HN001 supplementation resulted in alterations in fasting lipids, insulin resistance, or bile acids (BAs) during pregnancy. Fasting plasma samples collected at 24-30 weeks' gestation, from 348 women randomised at 14-16 weeks' gestation to consume daily probiotic HN001 (n = 172) or a placebo (n = 176) were analysed for lipids, insulin, glucose and BAs. Women supplemented with HN001 had lower fasting glucose compared with placebo (p = 0.040), and lower GDM. Significant differences were found in fasting insulin, HOMA-IR, low density lipoprotein-cholesterol (LDL-c), high density lipoprotein (HDL)-c, triglycerides, total cholesterol, and BAs by GDM status. Lower fasting conjugated BAs were seen in women receiving HN001. A significant decrease of glycocholic acid (GCA) was found in older (age ≥ 35) women who received HN001 (p = 0.005), while GDM women showed significant reduced taurodeoxycholic acid (TDCA) (p = 0.018). Fasting conjugated BA was positively correlated with fasting glucose (r = 0.136, p = 0.020) and fasting insulin (r = 0.113, p = 0.036). Probiotic HN001 supplementation decreases conjugated BAs and might play a role in the improvement of glucose metabolism in women with pregnancy.
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Effect of Standardized Grape Powder Consumption on the Gut Microbiome of Healthy Subjects: A Pilot Study.
Yang, J, Kurnia, P, Henning, SM, Lee, R, Huang, J, Garcia, MC, Surampudi, V, Heber, D, Li, Z
Nutrients. 2021;(11)
Abstract
Grapes provide a rich source of polyphenols and fibers. This study aimed to evaluate the effect of the daily consumption of 46 g of whole grape powder, providing the equivalent of two servings of California table grapes, on the gut microbiome and cholesterol/bile acid metabolism in healthy adults. This study included a 4-week standardization to a low-polyphenol diet, followed by 4 weeks of 46 g of grape powder consumption while continuing the low-polyphenol diet. Compared to the baseline, 4 weeks of grape powder consumption significantly increased the alpha diversity index of the gut microbiome. There was a trend of increasing Verrucomicrobia (p = 0.052) at the phylum level, and a significant increase in Akkermansia was noted. In addition, there was an increase in Flavonifractor and Lachnospiraceae_UCG-010, but a decrease in Bifidobacterium and Dialister at the genus level. Grape powder consumption significantly decreased the total cholesterol by 6.1% and HDL cholesterol by 7.6%. There was also a trend of decreasing LDL cholesterol by 5.9%, and decreasing total bile acid by 40.9%. Blood triglyceride levels and body composition were not changed by grape powder consumption. In conclusion, grape powder consumption significantly modified the gut microbiome and cholesterol/bile acid metabolism.
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Importance of Conjugation of the Bile Salt on the Mechanism of Lipolysis.
Łozińska, N, Jungnickel, C
Molecules (Basel, Switzerland). 2021;(19)
Abstract
We aim to advance the discussion on the significance of the conjugation of bile salts (BS) in our organism. We hypothesize that conjugation influences the rate of lipolysis. Since the rate of lipolysis is a compound parameter, we compare the effect of conjugation on four surface parameters, which contribute to the rate. Since deconjugation is due to gut microbiota, we hypothesize that microbiota may affect the rate of lipolysis. A meta-analysis of literature data of critical micelle concentration, β, aggregation number, and molar solubilization ratio has been performed for the first time. In addition, critical micelle concentration (CMC), interfacial tension, and lipolysis rate measurements were performed. It was found that the unconjugated BS in mixed micelles increases the antagonism between the BS, therefore, increasing the CMC. This correlated with the effect of unconjugated BS on the solubilization capacity of mixed micelles. The collected literature information indicates that the role of the BS and its conjugation in our organism is a key factor influencing the functioning of our organism, where too high levels of unconjugated BS may lead to malabsorption of fat-soluble nutrients. The experimental lipolysis results irrevocably showed that conjugation is a significant factor influencing the rate.
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Aberrant Gut-To-Brain Signaling in Irritable Bowel Syndrome - The Role of Bile Acids.
Ní Dhonnabháín, R, Xiao, Q, O'Malley, D
Frontiers in endocrinology. 2021;:745190
Abstract
Functional bowel disorders such as irritable bowel syndrome (IBS) are common, multifactorial and have a major impact on the quality of life of individuals diagnosed with the condition. Heterogeneity in symptom manifestation, which includes changes in bowel habit and visceral pain sensitivity, are an indication of the complexity of the underlying pathophysiology. It is accepted that dysfunctional gut-brain communication, which incorporates efferent and afferent branches of the peripheral nervous system, circulating endocrine hormones and local paracrine and neurocrine factors, such as host and microbially-derived signaling molecules, underpins symptom manifestation. This review will focus on the potential role of hepatic bile acids in modulating gut-to-brain signaling in IBS patients. Bile acids are amphipathic molecules synthesized in the liver, which facilitate digestion and absorption of dietary lipids. They are also important bioactive signaling molecules however, binding to bile acid receptors which are expressed on many different cell types. Bile acids have potent anti-microbial actions and thereby shape intestinal bacterial profiles. In turn, bacteria with bile salt hydrolase activity initiate the critical first step in transforming primary bile acids into secondary bile acids. Individuals with IBS are reported to have altered microbial profiles and modified bile acid pools. We have assessed the evidence to support a role for bile acids in the pathophysiology underlying the manifestation of IBS symptoms.
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Changes in fasting bile acid profiles after Roux-en-Y gastric bypass and sleeve gastrectomy.
Zhang, C, Zhang, J, Zhou, Z
Medicine. 2021;(3):e23939
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Abstract
BACKGROUND Bile acid is an essential factor that plays a role in metabolic regulation, but how bile acid is regulated after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) remains unclear. This meta-analysis aimed to investigate changes in the levels of fasting bile acids following RYGB and SG. METHODS A systematic literature search of the PubMed, EMBASE, Cochrane Library and Web of Science databases through July 2020 was performed in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The concentrations of bile acids were evaluated. RESULTS Thirteen studies with 289 patients were included. Our results showed that patients who underwent RYGB had increased levels of fasting total bile acids, primary bile acids, secondary bile acids, conjugated bile acids, and unconjugated bile acids, but no significant differences in all these bile acid levels were observed in patients who underwent SG. Furthermore, 12a-hydroxylated bile acid levels and the 12a-hydroxylated/non-12a-hydroxylated bile acid ratio also increased following RYGB. CONCLUSION In this study, we found that fasting bile acid levels, especially 12a-hydroxylated bile acids levels, were increased after RYGB. However, no differences in fasting bile acid levels were observed following SG.
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Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?
Dening, TJ, Douglas, JT, Hageman, MJ
Molecular pharmaceutics. 2021;(8):3086-3098
Abstract
Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.
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Bile acid sequestrants: a review of mechanism and design.
Feng, Y, Li, Q, Ou, G, Yang, M, Du, L
The Journal of pharmacy and pharmacology. 2021;(7):855-861
Abstract
OBJECTIVE Bile acid sequestrants (BAS) are used extensively in the treatment of hypercholesterolaemia. This brief review aimed to describe the design and evaluation of three types of BAS: amphiphilic copolymers, cyclodextrin/poly-cyclodextrin and molecular imprinted polymers. The mechanisms underlying the action of BAS are also discussed. KEY FINDINGS BAS could lower plasma cholesterol, improve glycemic control in patients with type 2 diabetes and regulate balance energy metabolism via receptors or receptor-independent mediated mechanisms. Different types of BAS have different levels of ability to bind to bile acids, different stability and different in-vivo activity. CONCLUSIONS A growing amount of evidence suggests that bile acids play important roles not only in lipid metabolism but also in glucose metabolism. The higher selectivity, specificity, stability and in-vivo activity of BAS show considerable potential for lipid-lowering therapy.