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Introduction: Bile acid diarrhoea (BAD) can occur due to disruption to the enterohepatic circulation such as following cholecystectomy. However, the mechanism behind this is as yet unknown. The aim of this study was to determine the rate of post-cholecystectomy diarrhoea and to assess whether FGF19 within the gallbladder was associated with the development of BAD. Methods: This was a prospective case-control study in which patients were assessed pre- and post- cholecystectomy (study group) and compared with patients also having laparoscopic surgery but not cholecystectomy (control group). Their bowel habits and a GIQLI questionnaire was performed to compare the pre- and post-operative condition of the two groups. Gallbladder tissue sample was tested for FGF19 and PPARα in the study group patients. A subset had serum lipid levels, FGF19 and C4 measurements. Results: Gallbladder PPAR α was found to have a significant correlation with stool consistency, with the lower the PPARα concentration the higher the Bristol stool chart number (i.e. looser stool). There were no significant correlation when assessing the effect of gallbladder FGF19 concentration on bowel habit, stool consistency, lipid levels, BMI or smoking. The study group showed a significant increase in triglycerides post-operatively, however there were no changes in cholesterol, HDL and LDL levels. Correlation of the increased triglyceride levels with stool consistency and frequency showed no significant results Discussion and conclusion: We did not find any direct evidence that FGF19 levels within the gallbladder impact the development of post-cholecystectomy diarrhoea. There was however a significant increase in triglycerides postoperatively. There was also no correlation of bowel habits with PPARα suggesting the observed rise is independent of this pathway. Further work is required particularly relating to the gut microbiome to further investigate this condition. [ABSTRACT FROM AUTHOR]

Cenerimod is a sphingosine‐1‐phosphate receptor 1 modulator that reduces tissue availability of circulating lymphocytes. The compound is in Phase 3 development for the treatment of systemic lupus erythematosus. Its pharmacokinetic properties are characterized by slow absorption and multiphasic elimination with a long terminal half‐life (t½), potentially caused by enterohepatic circulation (EHC). In this trial in healthy participants, oral cenerimod 0.5 and 4 mg once daily was administered for 50 days, followed by oral administration of activated charcoal (ie, 50 mg every 12 h for 11 days, starting 24 h after the last cenerimod dose), to investigate the potential EHC of cenerimod and assess whether elimination of cenerimod can be accelerated. The multiple‐dose pharmacokinetics, pharmacodynamics, safety, and tolerability of cenerimod were also evaluated. For both doses, peak plasma concentrations were reached 6 and 7 h after dosing. Cenerimod accumulated approximately eightfold and (near) steady‐state conditions were reached after 50 doses, resembling clinically meaningful exposure to cenerimod. The t½ following 0.5 and 4 mg of cenerimod was 767 and 799 h (ie, 32 and 33 days) and 720 and 780 h (ie, 30 and 33 days) with or without administration of charcoal, respectively, indicating no statistically significant difference. Therefore, charcoal did not accelerate cenerimod elimination suggesting that there is no EHC of cenerimod. A reversible, dose‐dependent decrease in total lymphocyte count was observed. No safety concerns were identified; administration of charcoal was well tolerated. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease is liver disease caused by heavy and/or chronic alcohol consumption. Bile acids are synthesized in the liver and regulate the body through liver-intestinal circulation. Many studies have shown that bile acid is closely related to alcoholic liver disease. Alcohol intake can cause liver damage by affecting bile acid synthesis, hepato-enteric circulation and intestinal flora. This article summarizes the mechanism of action of bile acids in alcoholic liver disease and the current research status of improving alcoholic liver disease based on bile acid regulation, in order to provide new ideas for future research on the prevention and treatment of alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Roux‐en‐Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic–pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed‐effect modeling approach. A parent–metabolite model with first‐order absorption, 2‐compartments for SV and 1‐compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL‐cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low‐intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post‐RYGB patients to maintain a comparable response to that of non‐operated subjects. Moderate‐intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non‐statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post‐RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non‐statin drugs to attain equivalent responses and mitigate potential adverse events. [ABSTRACT FROM AUTHOR]

The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment. [ABSTRACT FROM AUTHOR]

Enterohepatic circulation (EHC) is a complex process where drugs undergo secretion and reabsorption from the intestinal lumen multiple times, resulting in pharmacokinetic profiles with multiple peaks. The impact of EHC on area under the curve (AUC) has been a topic of extensive debate, questioning the suitability of conventional AUC estimation methods. Moreover, a universal model for accurately estimating AUC in EHC scenarios is lacking. To address this gap, we conducted a simulation study evaluating five empirical models under various sampling strategies to assess their performance in AUC estimation. Our results identify the most suitable model for EHC scenarios and underscore the critical role of meal-based sampling strategies in accurate AUC estimation. Additionally, we demonstrate that while the trapezoidal method performs comparably to other models with a large number of samples, alternative models are essential when sample numbers are limited. These findings not only illuminate how EHC influences AUC but also pave the way for the application of empirical models in real-world drug studies. [ABSTRACT FROM AUTHOR]

Males and females have long shown disparities in body weight and height; yet, the underlying mechanisms influencing growth and development remain unclear. Male and female Zhedong White Geese (ZDW) geese have long been selected for large body size and egg production, respectively. This led to a large difference in body weight between males and females, making them a unique model for studying the effects of sex on growth and development. This study aimed to elucidate these mechanisms by comparing the transcriptomes of muscle and pituitary tissues in male and female ZDW geese to identify the critical genes responsible for the effects of sex on growth performance. Our analysis revealed 1101 differentially expressed genes (DEGs) in leg musculature (507 upregulated, 594 downregulated), 773 DEGs in breast musculature (311 upregulated, 462 downregulated), and 517 DEGs in the pituitary gland (281 upregulated, 236 downregulated) between male and female geese. These DEGs were significantly enriched in gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with endocrine metabolism (e.g., hormonal activities), muscle formation (e.g., sarcomere and myofibril), and bone formation (e.g., bone morphogenesis and cartilage formation). The upregulated genes in males were enriched in KEGG pathways involving nutrient digestion and absorption (vitamin and protein), as well as the secretion of digestive juices (gastric acid and bile). Through protein–protein interaction analyses, we also observed high-density gene networks related to muscle fiber development, calcium ion metabolism, mitochondrial respiratory chain, and bone development. Therefore, our multi-tissue transcriptome analysis provides a deeper understanding of the complex and systematic gender-driven effects on growth and development in geese. IGF1, GHRHR, and NCAPG-LCORL and pathways related to myogenesis might play vital roles in gender differences before hormones exert their effect. [ABSTRACT FROM AUTHOR]

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)--protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD. [ABSTRACT FROM AUTHOR]

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson's disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49–97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3–83.7%. Secondary peaks were observed at approximately 4–8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic–pharmacodynamic correlation of 2-QBA to assess its potential as a drug. [ABSTRACT FROM AUTHOR]

Objectives: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. Methods: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. Key findings: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. Conclusions: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways. [ABSTRACT FROM AUTHOR]

• Bile acid malabsorption (BAM) can generate functional chronic diarrhea. • Derangement of the gut-liver axis is involved in BAM. • BAM is frequently underdiagnosed but specific tests are available. • Therapies target enterohepatic BAs circulation by sequestrants and novel approaches. Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM. [ABSTRACT FROM AUTHOR]

Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver, through the intestine, to virtually any organ, thus encouraging their pleiotropic physiological effects. Aging is a complex natural process defined as a progressive decline in cellular and organismal functions. A causal link between bile acids and the aging process is emerging. However, there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging process. Intestinal barrier dysfunction leads to endotoxemia, systemic inflammation, insulin resistance, diabetes, lipid accumulation, obesity and fatty liver diseases, and health decline and death. In fact, intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of aging. Bile acids may modulate the aging process by regulating intestinal barrier integrity.

Introduction: In infants with cholestasis, variations in the enterohepatic circulation of bile acids and the gut microbiota (GM) characteristics differ between those with biliary atresia (BA) and non-BA, prompting a differential analysis of their respective GM profiles. Methods: Using 16S rDNA gene sequencing to analyse the variance in GM composition among three groups: infants with BA (BA group, n=26), non-BA cholestasis (IC group, n=37), and healthy infants (control group, n=50). Additionally, correlation analysis was conducted between GM and liver function-related indicators. Results: Principal component analysis using Bray-Curtis distance measurement revealed a significant distinction between microbial samples in the IC group compared to the two other groups. IC-accumulated co-abundance groups exhibited positive correlations with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, and total bile acid serum levels. These correlations were notably reinforced upon the exclusion of microbial samples from children with BA. Conclusion: The varying "enterohepatic circulation" status of bile acids in children with BA and non-BA cholestasis contributes to distinct GM structures and functions. This divergence underscores the potential for targeted GM interventions tailored to the specific aetiologies of cholestasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Body metabolism and colonic microbiota collectively controlled lipid metabolism in finishing pigs. Diminishing standardized ileal digestible lysine to net energy ratio in high-wheat diets may regulate lipid metabolism via AMP-activated protein kinase α1/sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator-1α pathway and farnesol X receptor/small heterodimer partner pathway, ultimately increased the marbling score of longissimus dorsi muscle. The present study aimed to investigate the impacts of dietary standardized ileal digestible lysine to net energy (SID Lys:NE) ratio on lipid metabolism in pigs fed high-wheat diets. Thirty-six crossbred growing barrows (65.20 ± 0.38 kg) were blocked into two treatment groups, fed high-wheat diets with either a high SID Lys:NE ratio (HR) or a low SID Lys:NE ratio (LR). Each treatment group consisted of three replicates, with six pigs per pen in each replicate. The diminishing dietary SID Lys:NE ratio exhibited no adverse impacts on the carcass trait (p > 0.05) but increased the marbling score of the longissimus dorsi muscle (p < 0.05). Meanwhile, LR diets tended to increase the serum triglyceride concentration (p < 0.1). LR diets upregulated fatty acid transport protein 4 and acetyl-coA carboxylase α expression levels and downregulated the expression level of adipose triglyceride lipase (p < 0.05). LR diets improved energy metabolism via decreasing the expression levels of AMP-activated protein kinase (AMPK) α1, sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (p < 0.05). Additionally, LR diets stimulated hepatic bile acid synthesis via upregulating the expression levels of cytochrome P450 family 7 subfamily A member 1 and cytochrome P450 family 27 subfamily A member 1, and downregulating farnesol X receptor (FXR) and small heterodimer partner (SHP) expression levels (p < 0.05). A lowered SID Lys:NE ratio affected the colonic microbial composition, characterized by increased relative abundances of YRC22, Parabacteroides, Sphaerochaeta, and Bacteroides, alongside a decreased in the proportion of Roseburia, f_Lachnospiraceae_g_Clostridium, Enterococcus, Shuttleworthia, Exiguobacterium, Corynebacterium, Subdoligranulum, Sulfurospirillum, and Marinobacter (p < 0.05). The alterations in microbial composition were accompanied by a decrease in colonic butyrate concentration (p < 0.1). The metabolomic analysis revealed that LR diets affected primary bile acid synthesis and AMPK signaling pathway (p < 0.05). And the mantel analysis indicated that Parabacteroides, Sphaerochaeta, f_Lachnospiraceae_g_Clostridium, Shuttleworthia, and Marinobacter contributed to the alterations in body metabolism. A reduced dietary SID Lys:NE ratio improves energy metabolism, stimulates lipogenesis, and inhibits lipolysis in finishing pigs by regulating the AMPKα/SIRT1/PGC-1α pathway and the FXR/SHP pathway. Parabacteroides and Sphaerochaeta benefited bile acids synthesis, whereas f_Lachnospiraceae_g_Clostridium, Shuttleworthia, and Marinobacter may contribute to the activation of the AMPK signaling pathway. Overall, body metabolism and colonic microbiota collectively controlled the lipid metabolism in finishing pigs. [ABSTRACT FROM AUTHOR]

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL‐induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL‐induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down‐regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down‐regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice. Not only does colchicine exert its toxic effects within bile acid biosynthesis in the liver but also in the biological transport of bile acids. Colchicine treatment can cause defects in the reabsorption and reuptake system of bile acids in mice, resulting in a large accumulation of bile acids in the gut, thereby disrupting bile acid metabolism in mice and possibly contributing to the adverse intestinal reactions observed in humans treated with the drug. [ABSTRACT FROM AUTHOR]

Background: Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored. Results: Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells. Conclusions: In conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets. [ABSTRACT FROM AUTHOR]

Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress cell proliferation, inhibit hepatocyte differentiation, and promote cholangiocyte differentiation in the fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in the fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage and sex differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0–18), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway. [ABSTRACT FROM AUTHOR]

Intestinal failure-associated liver disease (IFALD) is a relatively common complication in individuals receiving parenteral nutrition (PN). IFALD can be manifested as different types of liver injury, including steatosis, cholestasis, and fibrosis, and could result in liver failure in some cases. The onset and progression of IFALD are highly dependent on various patient and PN-related risk factors. Despite still being under investigation, several mechanisms have been proposed. Liver injury can originate due to caloric overload, nutrient deficiency, and toxicity, as well as phytosterol content, and omega-6 to omega-3 fatty acids ratio contained in lipid emulsions. Additional mechanisms include immature or defective bile acid metabolism, acute heart failure, infections, and sepsis exerting negative effects via Toll-like receptor 4 and nuclear factor κB inflammatory signaling. Furthermore, lack of enteral feeding, gut dysbiosis, and altered enterohepatic circulation that affect the farnesoid x receptor-fibroblast growth factor 19 axis can also contribute to IFALD. Various best practices can be adopted to minimize the risk of developing IFALD, such as prevention and management of central line infections and sepsis, preservation of intestine's length, a switch to oral and enteral feeding, cyclic PN, avoidance of overfeeding and soybean oil-based lipid formulations, and avoiding hepatotoxic substances. The present review thus provides a comprehensive overview of all relevant aspects inherent to IFALD. Further research focused on clinical observations, translational models, and advanced toxicological knowledge frameworks is needed to gain more insight into the molecular pathogenesis of hepatotoxicity, reduce IFALD incidence, and encourage the safe use of PN. [ABSTRACT FROM AUTHOR]

Background: Altered prandial glycemic response after Roux‐en‐Y gastric bypass (RYGB) is exaggerated in patients with post‐RYGB hypoglycemia. Increased contribution of glucagon‐like peptide 1 (GLP‐1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls. Methods: Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB‐treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal‐tolerance test with (MTT‐Sham) and without (MTT) preceding modified sham feeding (chew and spit). Key Results: Meal ingestion raised serum total BAs in RYGB‐treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal‐induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = −0.75, p < 0.05) and were directly associated with ISR and GLP‐1 during MTT‐Sham. Conclusions & Inferences: In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post‐RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB. [ABSTRACT FROM AUTHOR]

Formula feeding, obesity and the gut microbiota are closely related. The present investigation explored the profiles of the intestinal microbiota in obese children over 5 years old with formula feeding in early life. We identified functional bacteria with anti-obesity potential through in vitro and in vivo experiments, elucidating their mechanisms. The results indicated that, in the group of children over 5 years old who were fed formula in early life, obese children exhibited distinct gut microbiota, which were characterized by diminished species diversity and reduced Bifidobacterium levels compared to normal-weight children. As a result, Lactobacillus acidophilus H-68 (H-68) was isolated from the feces of the N-FF group and recognized as a promising candidate. H-68 demonstrated the ability to stimulate cholecystokinin (CCK) secretion in STC-1 cells and produce bile salt hydrolase. In vivo, H-68 promoted CCK secretion, suppressing food intake, and regulated bile acid enterohepatic circulation, leading to increased deoxycholic acid and lithocholic acid levels in the ileum and liver. This regulation effectively inhibited the diet-induced body weight and body fat gain, along with the liver fat deposition. In conclusion, H-68 was recognized for its prospective anti-obesity impact, signifying an auspicious pathway for forthcoming interventions targeted at averting pediatric obesity in formula-fed children. [ABSTRACT FROM AUTHOR]

Introduction: Duodenal-jejunal bypass (DJB) is an experimental procedure in metabolic surgery that does not have a restrictive component. Changes in bile acid (BA) dynamics and intestinal microbiota are possibly related to metabolic improvement after DJB. Our previous studies involving obese diabetic rats showed the crucial role of the biliopancreatic limb (BPL) in metabolic improvement after DJB caused by BA reabsorption. We established a new DJB procedure to prevent bile from flowing into the BPL and aimed to elucidate the importance of bile in the BPL after DJB. Methods: Otsuka Long-Evans Tokushima Fatty rats with diabetes were divided into three groups: two DJB groups and a sham group (n = 11). Duodenal-jejunal anastomosis was performed proximal to the papilla of Vater in the DJB group (n = 11). However, the DJB-D group (n = 11) underwent a new procedure with duodenal-jejunal anastomosis distal to the papilla of Vater for preventing bile flow into the BPL. Results: Glucose metabolism improved and weight gain was suppressed in the DJB group, but not in the DJB-D and sham groups. Serum BA level and conjugated BA concentration were elevated in the DJB group. The gut microbiota was altered only in the DJB group; the abundance of Firmicutes and Bacteroidetes decreased and that of Actinobacteria increased. However, the DJB-D group exhibited no apparent change in the gut microbiota, similar to the sham group. Conclusion: BAs are essential in the BPL for metabolic improvement after DJB; they can improve the gut microbiota in these processes. [ABSTRACT FROM AUTHOR]

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High temperature and humidity in the environment are known to be associated with discomfort and disease, yet the underlying mechanisms remain unclear. We observed a decrease in plasma glucagon-like peptide-1 levels in response to high-temperature and humidity conditions. Through 16S rRNA gene sequencing, alterations in the gut microbiota composition were identified following exposure to high temperature and humidity conditions. Notably, changes in the gut microbiota have been implicated in bile acid synthesis. Further analysis revealed a decrease in lithocholic acid levels in high-temperature and humidity conditions. Subsequent in vitro experiments demonstrated that lithocholic acid increases glucagon-like peptide-1 secretion in NCI-H716 cells. Proteomic analysis indicated upregulation of farnesoid X receptor expression in the ileum. In vitro experiments revealed that the combination of lithocholic acid with farnesoid X receptor inhibitors resulted in a significant increase in GLP-1 levels compared to lithocholic acid alone. In this study, we elucidate the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature and humidity condition. This study elucidates the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature-and-humidity condition. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut–liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota–bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. Methods: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. Results: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. Conclusion: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction. [ABSTRACT FROM AUTHOR]

The novel anti-Parkinson disease drug, FLZ, had a complicated drug absorption and metabolise process reported in single-dose studies. A multi-peak absorption peak phenomenon was found. This study focused on the multi-dose pharmacokinetics (PK) characteristics of FLZ, T1, and T2 in cynomolgus monkeys and raised discussion on its multi-peak absorption situation. Different doses of FLZ ranging from 75 to 300 mg/kg were administered orally to 16 cynomolgus monkeys. The whole treatment period lasted for 42 days with FLZ once a day. The primary metabolites of FLZ were Target1 (T1) and Target2 (T2), which had plasma exposure (calculated as AUC0–24, day 42) approximately 2 and 10 times higher than the parent drug. The proportion of plasma exposure increase was lower than the proportion of dose increase in FLZ, T1, and T2. Gender influenced its exposure (AUC0–24) with approximately 3-fold higher in males than females. There was no significant accumulation of T1 and T2. Enterohepatic Circulation (EHC) and gastrointestinal (GI) tract absorption may be involved in the mechanism of multi-peak characteristics. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the present study was to investigate the effect of Rhubarb anthraquinone (RA) on a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) rat model, and explore potential biomarker and metabolic pathways by using the metabolomics method. Materials and methods: We established HFD rats as the NAFLD model. Forty Sprague–Dawley rats were randomly divided into a control group, model group, RA low-dose group, RA medium-dose group, and RA high-dose group, and evaluated the protective effect of RA on NAFLD by detecting biochemical indicators of serum and pathological changes of liver tissue. Investigating potential biomarkers and metabolic pathways connected with RA's protective effects against NAFLD by UHPLC–Q-TOF-MS untargeted metabolomics. Results: The results showed that RA significantly reversed the increase of TG, TC, ALT, AST, and ALP (P <.05), the decrease of HDL-C (P <.05), and alleviated pathological conditions in NAFLD rats. Based on potential biomarker analysis, RA affected metabolic pathways such as fatty acids biosynthesis, bile acids biosynthesis, and pentose phosphate pathway, delaying the progression of NAFLD. Conclusion: RA improved blood lipid levels, liver function, and pathological conditions of NAFLD rats. Meanwhile, affected the metabolic pathways and regulated the synthesis of fatty acids and bile acids in NAFLD rats. Rhubarb anthraquinone affects the metabolic pathways of fatty acids biosynthesis, bile acids biosynthesis, and pentose phase pathway, thereby regulating the function of synthesis of fatty acids and bile acids in NAFLD rats. Rhubarb anthraquinone has the potential to prevent and treat NAFLD. [ABSTRACT FROM AUTHOR]

The comprehensive examination of bile acids is of paramount importance across various fields of health sciences, influencing physiology, microbiology, internal medicine, and pharmacology. While enzymatic reaction-based photometric methods remain fundamental for total BA measurements, there is a burgeoning demand for more sophisticated techniques such as liquid chromatography–tandem mass spectrometry (LC-MS/MS) for comprehensive BA profiling. This evolution reflects a need for nuanced diagnostic assessments in clinical practice. In canines, a BA assessment involves considering factors, such as food composition, transit times, and breed-specific variations. Multiple matrices, including blood, feces, urine, liver tissue, and gallbladder bile, offer insights into BA profiles, yet interpretations remain complex, particularly in fecal analysis due to sampling challenges and breed-specific differences. Despite ongoing efforts, a consensus regarding optimal matrices and diagnostic thresholds remains elusive, highlighting the need for further research. Emphasizing the scarcity of systematic animal studies and underscoring the importance of ap-propriate sampling methodologies, our review advocates for targeted investigations into BA alterations in canine pathology, promising insights into pathomechanisms, early disease detection, and therapeutic avenues. [ABSTRACT FROM AUTHOR]

Hyperlipidemia, characterized by elevated serum lipid concentrations resulting from lipid metabolism dysfunction, represents a prevalent global health concern. Ginsenoside Rb1, compound K (CK), and 20(S)-protopanaxadiol (PPD), bioactive constituents derived from Panax ginseng, have shown promise in mitigating lipid metabolism disorders. However, the comparative efficacy and underlying mechanisms of these compounds in hyperlipidemia prevention remain inadequately explored. This study investigates the impact of ginsenoside Rb1, CK, and PPD supplementation on hyperlipidemia in rats induced by a high-fat diet. Our findings demonstrate that ginsenoside Rb1 significantly decreased body weight and body weight gain, ameliorated hepatic steatosis, and improved dyslipidemia in HFD-fed rats, outperforming CK and PPD. Moreover, ginsenoside Rb1, CK, and PPD distinctly modified gut microbiota composition and function. Ginsenoside Rb1 increased the relative abundance of Blautia and Eubacterium, while PPD elevated Akkermansia levels. Both CK and PPD increased Prevotella and Bacteroides, whereas Clostridium-sensu-stricto and Lactobacillus were reduced following treatment with all three compounds. Notably, only ginsenoside Rb1 enhanced lipid metabolism by modulating the PPARγ/ACC/FAS signaling pathway and promoting fatty acid β-oxidation. Additionally, all three ginsenosides markedly improved bile acid enterohepatic circulation via the FXR/CYP7A1 pathway, reducing hepatic and serum total bile acids and modulating bile acid pool composition by decreasing primary/unconjugated bile acids (CA, CDCA, and β-MCA) and increasing conjugated bile acids (TCDCA, GCDCA, GDCA, and TUDCA), correlated with gut microbiota changes. In conclusion, our results suggest that ginsenoside Rb1, CK, and PPD supplementation offer promising prebiotic interventions for managing HFD-induced hyperlipidemia in rats, with ginsenoside Rb1 demonstrating superior efficacy. [ABSTRACT FROM AUTHOR]

Nivasorexant was the first orexin-1 selective receptor antagonist entering clinical development. Despite encouraging preclinical evidence in animal models, a proof-of-concept trial in binge-eating patients recently failed to demonstrate its clinical utility in this population. Across species, nivasorexant clearance was driven by metabolism along seven distinct pathways, five of which were hydroxylation reactions in various locations of the molecule. The exact sites of metabolism were identified by means of mass spectrometry, the use of deuterated analogues, and finally confirmed by chemical references. CYP3A4 was the main cytochrome P450 enzyme involved in nivasorexant metabolism in vitro and accounting for about 90% of turnover in liver microsomes. Minor roles were taken by CYP2C9 and CYP2C19 but individually did not exceed 3–7%. In the rat, nivasorexant was mostly excreted via the bile after extensive metabolism, while urinary excretion was negligible. Only traces of the parent drug were detected in urine, bile, or faeces. [ABSTRACT FROM AUTHOR]

The altered circulating bile acids (BAs) modulate gut microbiota, energy metabolism and various physiological functions. BA profiles in liver, serum, ileum and feces of HFD-fed mice were analyzed with normal chow diet (NCD)-fed mice after 16-week feeding. Furthermore, gut microbiota was analyzed and its correlation analysis with BA was performed. The result showed that long-term HFD feeding significantly decreased hepatic and serum BA levels, mainly attributed to the inhibition of hepatic BA synthesis and the reduced reabsorption efficiency of BAs in enterohepatic circulation. It also significantly impaired glucose and lipid homeostasis and gut microbiota in mice. We found significantly higher bile salt hydrolase activity in ileal microbes and a higher ratio of free BAs to conjugated BA content in ileal contents in HFD groups compared with NCD group mice, which might account for the activated intestinal farnesoid X receptor signaling on liver BA synthesis inhibition and reduced ileal reabsorption. The decreased circulating BAs were associated with the dysregulation of the lipid metabolism according to the decreased TGR5 signaling in the ileum and BAT. In addition, it is astonishing to find extremely high percentages of taurocholate and 12-OH BAs in liver and serum BA profiles of both groups, which was mainly attributed to the high substrate selectivity for 12-OH BAs of the intestinal BAs transporter during the ileal reabsorption of enterohepatic circulation. This study revealed a significant effect of long-term HFD feeding on the decreased circulating BA pool in mice, which impaired lipid homeostasis and gut microbiota, and collectively resulted in metabolic disorders and obesity. [ABSTRACT FROM AUTHOR]

Immunosuppression management in transplant recipients is a critical component of pharmacotherapy. This becomes particularly crucial when patients are exposed to multiple medications that may lead to pharmacological interactions, potentially compromising the effectiveness of immunosuppression. We present the case of a 46-year-old patient diagnosed with cystic fibrosis in childhood at our hospital, who underwent bilateral lung transplantation and is undergoing immunosuppressive therapy. The patient was hospitalized due to an acute pulmonary exacerbation. During the hospitalization, the patient was administered various classes of antibiotics while continuing the standard antirejection regimen of everolimus and mycophenolate. Plasma concentrations of immunosuppressants, measured after antibiotic therapy, revealed significantly lower levels than the therapeutic thresholds, providing the basis for formulating the hypothesis of a drug–drug interaction phenomenon. This hypothesis is supported by the rationale of antibiotic-induced disruption of the intestinal flora, which directly affects the kinetics of mycophenolate. These levels increased after discontinuation of the antimicrobials. Patients with CF undergoing lung transplantation, especially prone to pulmonary infections due to their medical condition, considering the enterohepatic circulation of mycophenolate mediated by intestinal bacteria, necessitate routine monitoring of mycophenolate concentrations during and immediately following the cessation of antibiotic therapies, that could potentially result in insufficient immunosuppression. [ABSTRACT FROM AUTHOR]

The document is a contents list for the journal "Lab on a Chip," which focuses on devices and applications at the micro- and nanoscale. It includes a range of papers on topics such as microfluidic droplet production, automated centrifugal microfluidic systems, and the modeling of leukocyte trafficking. The journal aims to connect the world with the chemical sciences and is published by The Royal Society of Chemistry. [Extracted from the article]

Simple Summary: Bile acids (BAs) play an essential role in nutrient absorption and intestinal development for piglets. However, there remains a lack of clarity on the metabolic changes in BAs in piglets after birth and their relationship with intestinal development. This study found significant changes in BA metabolism in piglets after birth. In comparison with newborn piglets (NPs), the total serum BA content was increased for suckling piglets (SPs). Furthermore, the metabolic changes in BAs were highly correlated with the expression of genes related to BA receptors and the regulation of intestinal proliferation and barrier integrity, thereby laying the groundwork for the nutritional regulation of suckling piglets. This can also provide more insights into how the economic benefits of pig farming could be increased. Bile acids (BAs) are crucial for maintaining intestinal epithelial homeostasis. However, the metabolic changes in BAs and the communication between intestinal epithelial cells (IECs) in infants after birth remain unclear. This study aims to elucidate the BA profiles of newborn piglets (NPs) and suckling piglets (SPs), and to investigate their regulatory effects on IEC proliferation and barrier integrity, as well as the potential underlying mechanisms. In this study, compared with NPs, there were significant increases in serum triglycerides, total cholesterol, glucose, and albumin levels for SPs. The total serum BA content in SPs exhibited an obvious increase. Moreover, the expression of BA synthase cytochrome P450 27A1 (CYP27A1) was increased, and the ileal BA receptor Takeda G-coupled protein receptor 5 (TGR5) and proliferation marker Ki-67 were upregulated and showed a strong positive correlation through a Spearman correlation analysis, whereas the expression of farnesoid X receptor (FXR) and occludin was markedly downregulated in SPs and also revealed a strong positive correlation. These findings indicate that the increased synthesis and metabolism of BAs may upregulate TGR5 and downregulate FXR to promote IEC proliferation and influence barrier function; this offers a fresh perspective and evidence for the role of BAs and BA receptors in regulating intestinal development in neonatal pigs. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a disease of chronic inflammatory conditions of the intestinal tract due to disturbance of the inflammation and immune system. Symptoms of IBD include abdominal pain, diarrhea, bleeding, reduced weight, and fatigue. In IBD, the immune system attacks the intestinal tract's inner wall, causing chronic inflammation and tissue damage. In particular, interlukin-6 and interlukin-17 act on immune cells, including T cells and macrophages, to amplify the immune responses so that tissue damage and morphological changes occur. Of note, excessive calorie intake and obesity also affect the immune system due to inflammation caused by lipotoxicity and changes in lipids supply. Similarly, individuals with IBD have alterations in liver function after sustained high-fat diet feeding. In addition, excess dietary fat intake, along with alterations in primary and secondary bile acids in the colon, can affect the onset and progression of IBD because inflammatory cytokines contribute to insulin resistance; the factors include the release of inflammatory cytokines, oxidative stress, and changes in intestinal microflora, which may also contribute to disease progression. However, interfering with de novo fatty acid synthase by deleting the enzyme acetyl-CoA-carboxylase 1 in intestinal epithelial cells (IEC) leads to the deficiency of epithelial crypt structures and tissue regeneration, which seems to be due to Lgr5+ intestinal stem cell function. Thus, conflicting reports exist regarding high-fat diet effects on IBD animal models. This review will focus on the pathological basis of the link between dietary lipids intake and IBD and will cover the currently available pharmacological approaches. [ABSTRACT FROM AUTHOR]

Introduction: Mycophenolate mofetil (MMF), an inactive prodrug of mycophenolic acid (MPA), is an immunosuppressive drug used widely in the treatment of lupus nephritis. In this case report, the area under the blood concentration time curve (AUC) of MPA was significantly decreased by the concomitant use of sacubitril/valsartan. Case Presentation: The patient was a man in his 40s with a diagnosis of lupus nephritis class IVa/c+V. MMF dose was 1.5 g/day at admission, and AUC of MPA on day 14 was 25.1 μg⋅h/mL. Owing to poor blood pressure control, sacubitril/valsartan was initiated at 97/103 mg/day on day 29. On day 37, AUC of MPA was significantly decreased to 8.7 μg⋅h/mL, suggesting drug interaction with the newly initiated sacubitril/valsartan. Sacubitril/valsartan was decreased to 49/51 mg/day, and AUC of MPA on day 67 was 37.6 μg⋅h/mL, achieving the target range. The final MMF dose was set at 1.75 g/day. A possible mechanism of drug interaction between sacubitril/valsartan and MPA involves an organic anion transporting polypeptide (OATP). The inhibition of OATPs by sacubitril may have interrupted the enterohepatic circulation of MPA, resulting in a lower plasma concentration. Conclusion: Since lupus nephritis is often associated with hypertension, the drug interaction observed in this report may also occur in other cases. However, it is impossible to conclude that the decrease in plasma MPA levels was due to the concomitant use of sacubitril/valsartan, and more cases and basic findings are needed. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is considered as one of the most common diseases of lipid metabolism disorders, which is closely related to bile acids disorders and gut microbiota disorders. Bile acids are synthesized from cholesterol in the liver, and processed by gut microbiota in intestinal tract, and participate in metabolic regulation through the enterohepatic circulation. Bile acids not only promote the consumption and absorption of intestinal fat but also play an important role in biological metabolic signaling network, affecting fat metabolism and glucose metabolism. Studies have demonstrated that exercise plays an important role in regulating the composition and function of bile acid pool in enterohepatic axis, which maintains the homeostasis of the enterohepatic circulation and the health of the host gut microbiota. Exercise has been recommended by several health guidelines as the first‐line intervention for patients with NAFLD. Can exercise alter bile acids through the microbiota in the enterohepatic axis? If so, regulating bile acids through exercise may be a promising treatment strategy for NAFLD. However, the specific mechanisms underlying this potential connection are largely unknown. Therefore, in this review, we tried to review the relationship among NAFLD, physical exercise, bile acids, and gut microbiota through the existing data and literature, highlighting the role of physical exercise in rebalancing bile acid and microbial dysbiosis. [ABSTRACT FROM AUTHOR]

Summary: Background: Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75‐Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4) is inexpensive but lacks sensitivity. Aims: To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT. Methods: This diagnostic accuracy study was part of a randomised, placebo‐controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient‐reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation. Results: Ninety‐six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%–79%) sensitivity and 65% (47%–80%) specificity; C4 > 46 ng/mL had 47% (37%–57%) and 92% (87%–96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%–85%) sensitivity and 95% (83%–99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%–90%) sensitivity and 93% (80%–98%) specificity. Conclusions: Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4‐based testing, offering potential widely available diagnostics. Further validation is warranted. ClinicalTrials.gov: NCT03876717. [ABSTRACT FROM AUTHOR]

Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli. Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury. When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted. In summary, interruption of enterohepatic circulation via ileocecal resection abrogates the liver's exposure to toxic and inflammatory mediators while promoting physiological adaptations in bile acid metabolism and maintaining existing homeostatic pathways. [ABSTRACT FROM AUTHOR]

Bile salts have an established role in the emulsification and intestinal absorption of dietary lipids, and their homeostasis is tightly controlled by various transporters and regulators in the enterohepatic circulation. Notably, emerging evidence points toward bile salts as major modulators of cardiometabolic disease (CMD), an umbrella disease of disorders affecting the heart and blood vessels that is caused by systemic metabolic diseases such as Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), the latter encompassing also metabolic dysfunction-associated steatohepatitis (MASH). The underlying mechanisms of protective effects of bile salts are their hormonal properties, enabling them to exert versatile metabolic effects by activating various bile salt-responsive signaling receptors with the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled receptor 5 (TGR5) as most extensively investigated. Activation of FXR and TGR5 is involved in the regulation of glucose, lipid and energy metabolism, and inflammation. Bile salt-based therapies directly targeting FXR and TGR5 signaling have been evaluated for their therapeutic potential in CMD. More recently, therapeutics targeting bile salt transporters thereby modulating bile salt localization, dynamics, and signaling, have been developed and evaluated in CMD. Here, we discuss the current knowledge on the contribution of bile salt signaling in the pathogenesis of CMD and the potential of bile salt-based therapies for the treatment of CMD. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) are involved in the development of necrotizing enterocolitis (NEC), which mainly occurs in preterm infants. We aim to identify the change of BAs in preterm infants and validate its potential value in the detection of NEC. Targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) was performed to measure the plasma BAs in healthy preterm infants and patients with NEC. By analyzing the level of BAs in healthy preterm infants, we found that the plasma concentrations of BAs were related to sex, gestational/postnatal age, birth weight, mode of birth, and feeding type after birth. The plasma levels of TCA, GCA, TCDCA, GCDCA, primary BAs, and total BAs and the primary/secondary BA ratio were decreased, while DCA, UDCA, and secondary BAs were increased in NEC. The primary/secondary BA ratio (cutoff point 62.9) can effectively differentiate NEC from healthy preterm infants, with an AUC of 0.9, a sensitivity of 94.5%, and a specificity of 78.1%. Combining the ratio with high-risk factors of NEC can better distinguish between NEC and control, with an AUC of 0.95. Importantly, significantly lower levels of primary/secondary BA ratio were found in infants with surgical NEC than in nonsurgical NEC cases. The cutoff point of 28.7 identified surgical NEC from nonsurgical NEC with sensitivity and specificity of 76.9% and 100%. Thus, our study identified that the primary/secondary BA ratio in the plasma can differentiate NEC from healthy preterm infants and effectively differentiate the surgical NEC from nonsurgical NEC. Therefore, LC-MS/MS was expected to be a novel measurement platform used to distinguish infants who are most in need of close monitoring or early surgical intervention. [ABSTRACT FROM AUTHOR]

Hepatic impairment (HI) moderately (<5‐fold) affects the systemic exposure (i.e., area under the plasma concentration–time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10‐fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important in predicting the impact of HI on the AUC of dual OATP/CYP3A substrates. Because HI may reduce hepatic CYP3A‐mediated CL to a greater extent than biliary efflux CL, the greater the contribution of the former versus the latter, the greater the impact of HI on drug AUC ratio (AUCRHI). Using physiologically‐based pharmacokinetic modeling and simulation, we predicted relatively well the AUCRHI of OATP substrates that are not significantly metabolized (pitavastatin, rosuvastatin, valsartan, and gadoxetic acid). However, there was a trend toward underprediction of the AUCRHI of the dual OATP/CYP3A4 substrates fimasartan and atorvastatin. These predictions improved when the sinusoidal efflux CL of these two drugs was increased in healthy volunteers (i.e., before incorporating the effect of HI), and by modifying the directionality of its modulation by HI (i.e., increase or decrease). To accurately predict the effect of HI on AUC of hepatobiliary cleared drugs it is important to accurately predict all hepatobiliary pathways, including sinusoidal efflux CL. [ABSTRACT FROM AUTHOR]

This study was conducted to explore the potential effect of Yucca schidigera extract (YSE) on the metabolism of beef cattle. Thirty Angus crossbreed steers were selected, with an initial mean body weight of 506.6 ± 33.3 kg, and assigned to two treatments: a diet with no additives (CON group) and a diet supplemented with 1.75 g/kg of YSE (YSE group) (on a dry matter basis). The experiment lasted for 104 days, with 14 days for adaptation. The results showed that adding YSE could significantly improve the average daily gain (ADG) from 1 to 59 d (15.38%) (p = 0.01) and 1 to 90 d (11.38%) (p < 0.01), as well as dry matter digestibility (DMD) (0.84%) (p < 0.05). The contents of alanine aminotransferase, aspartate aminotransferase, and bilirubin and the total antioxidant capacity were increased and blood urea was reduced in the YSE group, compared to the CON group (p < 0.05). Both the glycerophospholipids and bile acids, including phosphocholine, glycerophosphocholine, PC(15:0/18:2(9Z,12Z)), PE(18:0/20:3(5Z,8Z,11Z)), PE(18:3(6Z,9Z,12Z)/P-18:0), LysoPC(15:0), LysoPC(17:0), LysoPC(18:0), LysoPC(20:5(5Z,8Z,11Z,14Z,17Z)), deoxycholic acid, glycocholic acid, and cholic acid, were upregulated by the addition of YSE. In summary, YSE may improve the ADG by increasing the blood total antioxidant capacity and glycerophospholipid synthesis, maintaining steers under a healthy status that is beneficial for growth. Furthermore, YSE may also increase the expression of bile acid synthesis, thereby promoting DMD, which, in turn, offers more nutrients available for growth. [ABSTRACT FROM AUTHOR]

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson’s disease. We developed an analytical method for 2-QBA using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49–97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3–83.7%. Secondary peaks were observed at approximately 4–8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic–pharmacodynamic correlation of 2-QBA to assess its potential as a drug.

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers (Abcc3 and Abcc4). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29, were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms. [ABSTRACT FROM AUTHOR]

Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of berberine in animals and humans. However, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine have not been reported. The present study aimed to investigate the pharmacokinetic parameters of demethyleneberberine by applying high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). After intragastric administration of demethyleneberberine in rats and mice, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine were comparatively studied for the first time. The plasma concentration of demethyleneberberine reached its peak within 5 min after intragastric administration in both rats and mice. Furthermore, its bioavailability was comparable, ranging from 4.47% to 5.94%, higher than that of berberine. The total excretion of demethyleneberberine in the urine, feces and bile was 7.28~9.77%. These findings provide valuable insights into the pharmacological and clinical research on demethyleneberberine. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effects of Chorum glandulosum Boiss. et Huet (CG) on the intestinal microbiota and serum bile acid (BA) in db/db mice. A total of 12 db/db mice were randomly divided into model (MOD), high‐dose CG (CGH), and control (CON) groups. The CON and MOD groups received distilled water by gavage for 8 weeks. Whereas, the CGH group received an alcohol extract of CG at a dose of 200 mg/kg/day. Results showed that CG can reduce blood lipid levels. It change the composition of the intestinal microbiota, and increase the relative abundances of Muribaculaceae, Prevotellaceae, Bifidobacterium_pseudolongum, Bacteroidaceae in db/db mice as well. LC–MS metabolomics results showed that CG adjusted the serum BA levels. The results reduced the levels of primary BAs, such as cholic acid (CA) and chenodeoxycholic acid (CDCA). The results decreased the primary BA/secondary BA (PSA/SBA) ratio in db/db mice. Correlation analysis showed that the abundances of Bifidobacterium_pseudolongum and Bacteroidaceae were positively correlated with acetic acid level and negatively correlated with ursocholic acid (UCA), α‐muricholic acid (αMCA), triglyceride (TG), and total cholesterol levels (TC), indicating an interaction between the intestinal microbiota and serum BAs. CG may play a positive role in the interaction between the intestinal microbiota and BAs in lipid metabolism. [ABSTRACT FROM AUTHOR]

Jiang-Zhi-Ning (JZN), a traditional Chinese medicinal formula, is used to treat hyperlipidemia in clinics. To screen the hypolipidemic "bioequivalent substance system (BSS)" of JZN and elucidate the potential hypolipidemic mechanism. In vitro, the TG content in HepG2 cells was determined after the intervention of the combination of advantageous components (CAC) by uniform design. In vivo, hyperlipidemia models were established by Triton WR-1339 (400 mg/kg; i.p.) in male ICR mice, and corresponding treatments were administered via oral administration once. The mice were divided into 12 groups (n = 5): control, hyperlipidemic model, simvastatin (positive control, 20 mg/kg), gradient doses of JZN granules (2, 4 and 8 g/kg) and the hypolipidemic effective extraction (HEE) of JZN (120, 240 and 480 mg/kg) and CAC groups (20, 40 and 160 mg/kg). Serum TC, TG, LDL-C and HDL-C were performed after 24 h. Transcriptomics and qRT–PCR technology were used to explore the mechanism of the "BSS" of JZN. In vitro, the ratio of CAC was determined. CAC could reduce the TG content in HepG2 cells (77.21%). Compared with the model group, the high dose of CAC could markedly decrease the levels of TC (61.86%), TG (105.54%) and LDL-C (39.38%) and increase the level of HDL-C (232.67%). CAC was proved to be the "BSS". Transcriptomics and qRT–PCR analysis revealed CAC regulated non-alcoholic fatty liver disease, bile secretion, PPAR and adipocytokine signalling pathway. These findings provided new feasible ideas and methods for the elucidation of the pharmacodynamic material basis. [ABSTRACT FROM AUTHOR]