The human gut microbiome plays a pivotal role in health and disease, notably through its interaction with bile acids (BAs). BAs, synthesized in the liver, undergo transformation by the gut microbiota upon excretion into the intestine, thus influencing host metabolism. However, the potential mechanisms of dicaffeoylquinic acids (DiCQAs) from Ilex kudingcha how to modulate lipid metabolism and inflammation via gut microbiota remain unclear.

The objectives of the present study were to investigate the regulating effects of DiCQAs on diabetes and the potential mechanisms of action. Two mice models were utilized to investigate the anti-diabetic effects of DiCQAs. Additionally, analysis of gut microbiota structure and functions was conducted concurrently with the examination of DiCQAs' impact on gut microbiota carrying the bile salt hydrolase (BSH) gene, as well as on the enterohepatic circulation of BAs and related signaling pathways.

Our findings demonstrated that DiCQAs alleviated diabetic symptoms by modulating gut microbiota carrying the BSH gene. This modulation enhanced intestinal barrier integrity, increased enterohepatic circulation of conjugated BAs, and inhibited the farnesoid X receptor-fibroblast growth factor 15 (FGF15) signaling axis in the ileum. Consequently, the protein expression of hepatic FGFR4 fibroblast growth factor receptor 4 (FGFR4) decreased, accompanied by heightened BA synthesis, reduced hepatic BA stasis, and lowered levels of hepatic and plasma cholesterol. Furthermore, DiCQAs upregulated glucolipid metabolism-related proteins in the liver and muscle, including v-akt murine thymoma viral oncogene homolog (AKT)/glycogen synthase kinase 3-beta (GSK3β) and AMP-activated protein kinase (AMPK), thereby ameliorating hyperglycemia and mitigating inflammation through the down-regulation of the MAPK signaling pathway in the diabetic group.

Our study elucidated the anti-diabetic effects and mechanism of DiCQAs from I. kudingcha, highlighting the potential of targeting gut microbiota, particularly Acetatifactor sp011959105 and Acetatifactor muris carrying the BSH gene, as a therapeutic strategy to attenuate FXR-FGF15 signaling and ameliorate diabetes.

Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation.

This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed.

In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.

Bile acids in the ileum act as a feedback regulator of their own synthesis by inducing the release of ileal fibroblast growth factor 19 (FGF19), which inhibits the cholesterol-7-alpha hydroxylase enzyme. In cholestasis, this feedback mechanism is dysregulated. FGF19 is not expressed in the healthy liver. We aimed to assess the hepatic expression of FGF19 in neonatal cholestasis (NC) and its relation to serum bile acids.

The study included 41 patients with NC. FGF19 immunohistochemical staining in liver tissue (hepatocytes, endothelial cells, bile ducts, and bile canaliculi) was evaluated as negative, weak, moderate, and strong staining. FGF19 staining in 6 liver samples from explants of children with Crigler-Najjar syndrome type-1 served as controls.

Hepatocyte, endothelial, and canalicular FGF19 expression was significantly higher in cholestasis group compared to controls (P = .039, .006, and .028 respectively). Serum bile acids had significant correlation with hepatocyte FGF19, endothelial, and bile duct FGF19 expressions (P = .002, .003, and .01, respectively) but not with canalicular FGF19 expression. Hepatocyte FGF19 expression significantly associated with cholestasis severity in terms of serum total bilirubin, direct bilirubin, and aspartate transaminase levels (P = .01, .02, and .02, respectively).

Hepatic FGF19 expression significantly upregulated in NC and correlated with cholestasis severity.

Bile acids (BA) are C24 steroids synthesized from cholesterol in liver. Hardly any data exist on BA in the most accessible human biofluid urine. As bile acids bear great potential as future biomarkers in diagnosis and monitoring of metabolic diseases, we aimed at developing and implementing a new method for the quantification of urinary bile acids using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). A second goal consisted in creating first reference values of urinary bile acids during childhood and to investigate their excretion patterns in obese children and adolescents. Our method required 2 mL of urine and sample preparation consisting of protein precipitation and solid phase extraction. Stable isotopes of BA were included as internal standards (IS). Our method is capable of simultaneously determining 18 BA: the primary BA cholic acid (CA) and chenodeoxycholic acid (CDCA), and the secondary BA deoxycholic acid (DCA) and lithocholic acid (LCA) as well as glycine and taurine conjugates of these four BA. Furthermore, ursodeoxycholic acid (UDCA) and five BA in their sulfated forms (LCA-S, GLCA-S, TLCA-S, GCDCA-S, GDCA-S) were analyzed. After successful validation (intra-day precision 1.02 % - 11.07 %; inter-day precision 0.42-11.47 %.; intra-day accuracy 85.75 % - 108.90 %; inter-day accuracy 86.76 % - 110.99 %; no significant matrix effect; recovery 90.49 % - 113.99 %)., the method was applied to samples of 80 healthy children as well as 237 obese children of various age groups. Sulfated BA showed the highest concentrations, with GCDCA-S (nmol/L, medians, controls vs. obese 588.4 vs. 360.2) being the most abundant among all BA, followed by GLCA-S (353.9 vs. 344.8) and GDCA-S (319,3 vs. 323.9). CA (135.1 vs. 174.6) and GCA (100.2 vs. 92.4) were the two dominant non-sulfated BA. In conclusion, we developed a LC-MS/MS method for the simultaneous determination of 18 urinary bile acids in children and adolescents. We created reference values and investigated obese children. Sulfated bile acids dominated in both study groups. Lower bile acid sulfation and amidation in obese children point to limitations in their hepatic metabolic capacity.

Cholestasis, a condition characterized by impaired bile flow, can lead to severe liver damage if left untreated. Current therapeutic options are limited, necessitating the development of novel treatment strategies. This study investigated the synergistic action of cilnidipine, a calcium channel blocker, and bexarotene, a retinoid X receptor (RXR) agonist, in mitigating cholestatic liver damage induced by alpha-naphthyl isothiocyanate (ANIT) in rats. The study aimed to elucidate the role of the farnesoid X receptor (FXR) signaling cascade in the protective effects of the combined treatment. Rats were divided into three groups: a negative control group, an ANIT-treated group, and a group pretreated with cilnidipine and bexarotene before ANIT administration. Biochemical markers of liver function, oxidative stress, and inflammation were assessed, along with histological examination of liver tissue. The expression of genes related to the FXR signaling pathway was also evaluated using quantitative polymerase chain reaction (qPCR). The results demonstrated that pretreatment with cilnidipine and bexarotene significantly attenuated ANIT-induced cholestatic liver damage, as evidenced by improved liver function markers, reduced oxidative stress and inflammation, and ameliorated histological changes. Furthermore, the combined treatment upregulated the expression of FXR and its target genes, suggesting that the protective effects may be mediated through the activation of the FXR signaling cascade. These findings highlight the potential of cilnidipine and bexarotene as a novel therapeutic approach for the management of cholestatic liver disorders and provide insights into the underlying molecular mechanisms involving the FXR signaling pathway.

Recent studies have indicated that Lactococcus petauri LZys1 (L. petauri LZys1), isolated from healthy human feces, exhibits a promising probiotic profile in vitro. However, its impact on the physiological status of the host in vivo remains uncertain. The objective of our study was to investigate the effects and mechanisms of orally administering L. petauri LZys1 on gut microbiota and liver function in mice. We administered L. petauri LZys1 through daily oral gavage to C57BL/6 male mice. Subsequently, we analyzed changes in gut microbiota composition using 16S rRNA sequencing and quantified alterations in hepatic-intestinal bile acid (BA) profile. Serum biochemical parameters were assessed to evaluate liver function. Our findings revealed that L. petauri LZys1 led to an increase in body weight, liver mass, and serum aminotransferase levels. Oral administration altered the gut microbiota composition, resulting in reduced diversity and abundance of intestinal bacteria. Additionally, the profiles of BAs were suppressed across organs, associated with the downregulation of the ileum's farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15) signaling pathway. The decrease in circulating FGF15 mediated the downregulation of hepatic fibroblast growth factor receptor 4 (FGFR4)/FXR, disrupting BA metabolism and fatty acid oxidation. Our findings suggest that L. petauri LZys1 may impact liver function by influencing the gut microbiota-mediated ileal FXR-FGF15 axis and inhibiting hepatic bile acid metabolism.

This work elucidated the impact of L. petauri LZys1 on host gut microbiota metabolism and hepatic physiological metabolism. We observed that L. petauri LZys1 administration induced liver weight gain and biochemical parameters changes, in addition to a altered gut microbiota and suppressed bile acid (BA) profiles. Furthermore, we propose that changes in liver status are related to the enterohepatic farnesoid X receptor-fibroblast growth factor axis, which alters bile acid metabolism and disrupts liver function. The above findings suggest that attention should be paid to the effect of probiotics on liver function.

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive form of non-Hodgkin lymphoma, primarily confined to the central nervous system. In recent years, growing evidence has indicated that dysbiosis of the gut microbiota is closely associated with the development of various malignancies. This study aims to systematically explore the potential role of gut microbiota and their metabolic pathways in the pathogenesis of PCNSL by integrating metagenomic and metabolomic approaches.

A total of 33 PCNSL patients and 32 healthy controls were enrolled in this study, and fecal samples were collected from each participant. The fecal samples were analyzed using metagenomic and metabolomic techniques, followed by KEGG pathway enrichment analysis to investigate the biological pathways enriched by the differential gut microbiota and metabolites.

Significant differences were observed in the composition of gut microbiota and metabolites between PCNSL patients and healthy controls. In the gut microbiota of PCNSL patients, the abundance of the phylum Proteobacteria was markedly increased, while the Firmicutes/Bacteroidetes (F/B) ratio was significantly elevated. Metabolomic analysis revealed that the abundance of oleamide was significantly reduced in the PCNSL group, while the relative abundance of deoxycholic acid was significantly elevated. KEGG pathway analysis indicated that the differential gut microbiota and metabolites were primarily involved in key metabolic pathways such as nitrogen metabolism, phenylalanine metabolism, purine metabolism, and pyrimidine metabolism, with these pathways being more active in PCNSL patients.

This study is the first to systematically investigate the differences in gut microbiota and their metabolites between PCNSL patients and healthy individuals, highlighting the potential role of gut microbiota alterations in the pathogenesis of PCNSL.

Yinchenhao decoction (YCHD) is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice (OJ). Although YCHD has demonstrated protective effects against liver damage, reduced apoptosis, and mitigated oxidative stress in OJ, the precise molecular mechanisms involved remain poorly understood.

To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.

The active constituents of YCHD were identified using liquid chromatography-tandem mass spectrometry, and their potential targets for OJ treatment were predicted through network pharmacology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. An OJ rat model was established by common bile duct ligation. Rats were divided into three groups: Sham surgery (S Group), model (O Group), and YCHD (Y Group). YCHD was administered to Group Y for one week. Bilirubin levels, liver function parameters, and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay. The bile acid renal clearance rate (Clr) was calculated. Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining. Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues. The expression of the constitutive androstane receptor (CAR) and its nuclear localization were evaluated by immunohistochemistry. Molecular docking studies identified the epidermal growth factor receptor (EGFR) as a potential target of YCHD's active components. An OJ cell model was created using human liver (L02) and renal tubular epithelial (HK-2) cells, which were treated with YCHD-containing serum. Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.

Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ. In vivo experiments showed that YCHD improved liver function, reduced OJ-induced pathology in liver and kidney tissues, and decreased serum bile acid content by enhancing bile acid Clr and urine output. YCHD also increased CAR expression and nuclear heterotopy, upregulating proteins involved in bile acid metabolism and transport, including CYP3A4, UGT1A1, MRP3, and MRP4 in the liver, and MRP2 and MRP4 in the kidneys. In vitro, YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells, an effect that was reversed by EGFR agonists.

YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys, ameliorating liver damage caused by OJ. These effects are likely mediated by the upregulation of CAR and its nuclear translocation.

The gut microbiota exerts a critical influence on energy metabolism homeostasis and productive performance in avian species. Given the diminishing availability of arable land and intensifying competition for finite resources between livestock production and human populations, the agricultural sector faces dual imperatives to enhance productive efficiency while mitigating ecological footprints. Within this paradigm, optimizing nutrient assimilation efficiency in commercial waterfowl operations emerges as a strategic priority. This investigation employs an integrated multi-omics approach framework (metagenomic, metabolomic, and transcriptomic analyses) to elucidate the mechanistic relationships between cecal microbial consortia and feed conversion ratios in Shan Partridge ducks.

Based on the analysis of metagenome data, a total of 34 phyla, 1033 genera and 3262 species of bacteria were identified by metagenomic sequencing analysis. At the phylum level, 31 phylums had higher mean abundance in the low residual feed intake ( LRFI) group than in the high residual feed intake (HRFI) group. Among them, the expression of microbiome Elusimicrobiota was significantly higher in the LRFI group than in the HRFI group (P < 0.05). And we also found a significant differences in secondary metabolites biosynthesis, transport, and catabolism pathways between the two groups in microbial function (P < 0.05). Based on metabolomic analysis, 17 different metabolites were found. Among them, Lipids and lipid molecules accounted for the highest proportion. Whereas the liver is very closely related to lipid metabolism, we are close to understanding whether an individual's energy utilization efficiency is related to gene expression in the liver. We selected six ducks from each group of six ducks each for liver transcriptome analysis. A total of 322 differential genes were identified in the transcriptome analysis results, and 319 genes were significantly down-regulated. Among them, we found that prostaglandin endoperoxide synthase 2 (PTGS2) might be a key hub gene regulating RFI by co-occurrence network analysis. Interestingly, the differential gene PTGS2 was enriched in the arachidonic acid pathway at the same time as the differential metabolite 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2). In addition, the results of the association analysis of differential metabolites with microorganisms also revealed a significant negative correlation between 15d-PGJ2 and Elusimicrobiota.

Based on comprehensive analysis of the research results, we speculate that the Elusimicrobiota may affect the feed utilization efficiency in ducks by regulating the expression of the PTGS2 gene.

FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro, however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX's therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX's anti-colon cancer effects in vivo. Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.

While it is currently assumed that liver assessment is only possible during normothermic machine perfusion, there is uncertainty regarding a reliable and quick prediction of graft injury during ex situ hypothermic oxygenated perfusion (HOPE). We therefore intended to test, in an international liver transplant cohort, recently described mitochondrial injury biomarkers measured during HOPE before liver transplantation.

Perfusate samples of human livers from ten centers in seven countries with HOPE experience were analyzed for released mitochondrial compounds, i.e. flavin mononucleotide (FMN), NADH, purine derivatives and inflammatory markers. Livers deemed unsuitable for transplantation served as negative controls.

We collected 473 perfusate samples of human donation after cardiac death (n = 315) and donation after brain death (n = 158) livers. Fluorometric assessment of FMN in perfusate was validated by mass spectrometry (R = 0.7011, p <0.0001). Graft loss due to primary non-function or cholangiopathy was predicted by perfusate FMN values (c-statistic mass spectrometry 0.8418, 95% CI 0.7466-0.9370, p <0.0001; c-statistic fluorometry 0.7733, 95% CI 0.7006-0.8461, p <0.0001). Perfusate FMN values were also significantly correlated with symptomatic non-anastomotic strictures and kidney failure, and superior for the prediction of graft loss than conventional scores derived from donor and recipient parameters, such as the donor risk index and the balance of risk score. Mitochondrial FMN values in liver tissues of non-utilized livers were low, and inversely correlated to high perfusate FMN values and purine metabolite release.

This first international study validates the predictive value of the mitochondrial cofactor FMN, released from complex I during HOPE, and may therefore contribute to a better risk stratification of injured livers before implantation.

Analysis of 473 perfusates, collected from ten international centers during HOPE (hypothermic oxygenated perfusion), revealed that mitochondria-derived flavin mononucleotide values in perfusate are predictive of graft loss, cholangiopathy, and kidney failure after liver transplantation. This result is of high clinical relevance, as recognition of graft quality is urgently needed to improve the safe utilization of marginal livers. Ex situ machine perfusion approaches, such as HOPE, are therefore likely to increase the number of useable liver grafts.

Understanding the kinetics of hepatic processes, such as bile acid (BA) handling and cellular aerobic metabolism, is crucial for advancing our knowledge of liver toxicity, particularly drug-induced cholestasis (DiCho). This article aimed to construct interpretable models with parameter estimations serving as reference values when investigating these cell metrics. Longitudinal datasets on BA disposition and oxygen consumption rates were collected using sandwich-cultured human hepatocytes. Chenodeoxycholic acid (CDCA), lithocholic acid (LCA), as well as their amidated and sulfate-conjugated metabolites were quantified with liquid chromatography-mass spectrometry. The bile salt export pump (BSEP) abundance was monitored with targeted proteomics and modelled for activity assessment. Oxygen consumption was measured using Seahorse XFp analyser. Ordinary differential equation-based models were solved in R. The basolateral uptake and efflux clearance of glycine-conjugated CDCA (GCDCA) were estimated at 1.22 µL/min/106 cells (RSE 14%) and 0.11 µL/min/106 cells (RSE 10%), respectively. The GCDCA clearance from canaliculi back to the medium was 2.22 nL/min/106 cells (RSE 17%), and the dissociation constant between (G)CDCA and FXR for regulating BSEP abundance was 25.73 nM (RSE 11%). Sulfation clearance for LCA was 0.19 µL/min/106 cells (RSE 11%). Model performance was further demonstrated by a maximum two-fold deviation of the 95% confidence boundaries from parameter estimates. These in vitro-in silico models provide a quantitative framework for exploring xenobiotic impacts on BA disposition, BSEP activity, and cellular aerobic metabolism in hepatocytes. Model simulations were consistent with reported in vivo data in progressive familial intrahepatic cholestasis type II patients.

The liver is vital for metabolism, detoxification, storage, and secretion. Cholestasis, in which bile flow is hindered, can cause serious harm to the liver. This study examines the potential of ellagic acid to prevent cholestasis in male rats that has been caused by alpha-naphthyl isothiocyanate (ANIT).

Male rats were divided into four groups for an 8-day study. The control group received 5 % dimethyl sulfoxide (DMSO) orally for eight days and maize oil (1 mL/kg, orally) 48 h before sacrifice. The ANIT Group received 5 % DMSO orally for 8 days, the ANIT (100 mg/kg, orally) administered on the 6th day, 48 h before sacrifice. The low-Dose Ellagic Acid + ANIT Group was given ellagic acid (5 mg/kg, orally) for eight days, with ANIT (100 mg/kg, orally) on the 6th day, 48 h prior to sacrifice. The high-Dose Ellagic Acid + ANIT Group received ellagic acid (10 mg/kg, orally) for eight days, the ANIT (100 mg/kg, orally) on the 6th day, 48 h before sacrifice. Different biochemical and histopathological analyses were conducted to assess the protective effects of ellagic acid on ANIT-induced liver injury.

ANIT significantly elevated serum of liver enzymes. It caused severe bile duct inflammation and reduced bile salt export pump (BSEP) and Na+-taurocholate cotransporting polypeptide (NTCP) expression, indicating liver injury. Ellagic acid treatment mitigated these changes, improving biochemical parameters and reducing liver damage. ANIT-induced cholestasis results in bile acid accumulation due to decreased BSEP and NTCP expression linked to impaired farnesoid X receptor (FXR) signaling. Ellagic acid restored BSEP and NTCP levels via FXR activation, reducing bile acids and inflammatory markers IL-1β and TNF-α. Ellagic acid also enhanced SIRT1 activity, further improving FXR function and bile acid homeostasis.

Ellagic acid exhibits protective effects against cholestasis by enhancing the FXR signaling and ntcp and bsep expression with mitigating liver damage and inflammation.

Cytochrome P450 17A1 (CYP17A1) catalyzes two enzymatic reactions in the biosynthesis of dehydroepiandrosterone (DHEA) from pregnenolone. In pregnant humans, the adrenal gland is responsible for DHEA biosynthesis, which is then sulfated by SULT2A1 and released into the bloodstream. This sulfated DHEA is subsequently taken up by the placenta and deconjugated to serve as a precursor for estrogen biosynthesis. The expression of Cyp17a1 is regulated by methylation, typically showing marked interspecies differences, including repression of Cyp17a1 expression in the adrenal gland of rodents. This study focused on the liver, an extragonadal steroidogenic organ showing active sulfate conjugation, as a site for DHEA-sulfate (DHEA-S) biosynthesis during pregnancy in rodents, rather than the adrenal glands. Cyp17a1 expression in rat liver was significantly lower than in the testis, with no differences between sexes. However, Cyp17a1 expression increased significantly before parturition (gestational days [GD] 19-21) compared to late pregnancy (GD 15-18). The Sult2a family were expressed in the livers of both pregnant and non-pregnant rats. We also observed increased DHEA and DHEA-S levels in the liver of pregnant rats before parturition compared to non-pregnant rats, with DHEA-S concentrations being significantly higher at GD 19-21 than at days 15-18. These findings suggest that increased expression of Cyp17a1 in the last trimester enhances DHEA synthesis in the liver, and that DHEA is quickly conjugated by Sult2a. In rodents, the liver may be involved in DHEA-S biosynthesis before parturition, compensating for the repression of Cyp17a1 in the adrenal glands.

Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non-clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug-induced liver injury (DILI) and hepatic drug-drug interactions (DDIs). Systemic coproporphyrin-I (CP-I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B-mediated DDI risk in humans. In this clinical observational cohort-comparison study, bile acid profiles and CP-I concentrations in healthy volunteers and patients with ADPKD were compared.

Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP-I concentrations, were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Patients with ADPKD exhibited increased serum concentrations of total (1.3-fold) and taurine-conjugated (2.8-fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5-, 2.9-, 2.8-, 1.6-, 1.7- and 2.7-fold, respectively) in patients with ADPKD. Furthermore, serum CP-I concentrations were elevated and the renal clearance of CP-I was reduced in patients with ADPKD compared to healthy volunteers.

Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP-I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers.

The incidence of cholestatic liver disease (CLD), which is primarily marked by abnormal bile acids (BAs) metabolism and can result in significant hepatic injury, is rising. Nevertheless, there remains a lack of effective treatments and drugs in clinical practice. Silphium perfoliatum L. (SP) is rich in various structural types of caffeoylquinic acid (CQA) compounds, and it is a traditional herb of North American Indians with hepatobiliary therapy effects. However, its therapeutic effect and mechanism of action on CLD have never been studied.

To determine if SP-8, an extract rich in CQAs from SP, protects against cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) and to clarify its mechanism based on the farnesoid x receptor (FXR) signaling pathway and enterohepatic circulation of BAs.

The therapeutic efficacy of SP-8 was evaluated by assessing the serum biochemical indices, inflammatory factors, and liver histopathology. Targeted metabolomics of the BAs was studied in the feces, liver, serum, and bile using UPLC-MS/MS. Additionally, a Western blot analysis was used to examine the expression levels of the peroxisome proliferator-activated receptor γ (PPARγ), the FXR, and proteins related to the synthesis and transport of BAs. 16S rRNA gene sequencing was performed to evaluate the gut microbiota (GM). Finally, molecular docking simulations were conducted to assess the interaction between seven types of CQAs from SP-8 with FXR and PPARγ.

SP-8 significantly enhanced the health status of cholestatic mice induced by ANIT as evidenced by a notable reduction in the liver function indices and pro-inflammatory factors, restoration of liver pathological damage, and acceleration of BAs excretion through the feces. In addition, the levels of harmful secondary BAs in the liver and blood were significantly reduced by SP-8. Furthermore, the results of the study on the mechanism of action confirmed that SP-8 not only regulated FXR and PPARγ but also significantly ameliorated the GM structure, thereby promoting the enterohepatic circulation of BAs and achieving the homeostasis of the BAs in the blood and liver. In addition, SP-8 successfully reduced the inflammatory response by strongly suppressing the nuclear translocation of NF-κBp65. According to the molecular docking results, the extract's primary active ingredients could be the seven CQAs in SP-8, as they exhibited a strong affinity for both FXR and PPARγ. Finally, the Mantel test analysis revealed a significant correlation among cholestatic-associated parameters, the GM, and BAs.

It was confirmed for the first time that the SP-8 extract of Silphium perfoliatum L. that is rich in seven CQAs had a strong therapeutic effect on ANIT-induced CLD. Its mechanism may involve the regulation of the FXR signaling pathway and the amelioration of the GM structure to promote the homeostasis of BAs enterohepatic circulation. This study provides a potential candidate medicinal herb and its components for the development of CLD therapeutic drugs.

Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.

Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision-recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.

Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.

Since the gut microbiota plays a crucial role in host metabolism and homeostasis, its alterations induced by xenobiotics such as pesticides, could pose a risk to host health. The pyrethroid insecticides were frequently detected in surface water (up to 13 mg/L worldwide), sediments, and agricultural products; additionally, some previous studies indicated that pyrethroid insecticides could cause disruption of gut homeostasis. Hence herein, the normally used pyrethroid lambda-cyhalothrin (LCT) was selected and studied for its effects on the intestinal microbial community and its related bile acid metabolism using mice as the model species. Results showed that the total amount of bile acids in plasma and fecal samples from LCT treated mice markedly increased compared to controls, which could be mainly ascribed to the significantly raised proportions of taurine conjugated bile acids in plasma, and the increase in fecal secondary bile acids. In gut microbial profiles, a significantly increased richness of Prevotellacea and a depletion of Lachnospiraceae were found at the family level upon the treatment with lambda-cyhalothrin. In conclusion, results obtained on bacterial and bile acid profiles corroborate that the treatment of mice with LCT could affect gut microbial community with accompanying changes in bile acid homeostasis.

Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting.

Evidence indicates a close association between iron overload (IO) and the pathogenesis of chronic liver diseases, highlighting the potential for interventions targeted at IO to impede or decelerate the progression of chronic liver diseases. Diammonium glycyrrhizinate (DG), the medicinal form of glycyrrhizic acid, a principal constituent of licorice, has been clinically employed as a hepatoprotective agent; however, its protective effect against IO-induced liver injury and underlying molecular mechanisms remain elusive.

The aim of the present study is to investigate the hepatoprotective effect of DG against IO-induced liver injury with a focus on the gut-liver axis.

Animal models of IO-induced liver injury and DG treatment have been established in vivo. Iron deposition, liver injury, intestinal barrier damage, and liver inflammation were assessed in mice treated with iron dextran or DG. The microbiome composition in feces was analyzed using 16S rRNA full-length sequencing. Bile acids (BAs) profiles in feces were detected by UPLC-Q-TOF-MS technique, and the expression levels of receptors, enzymes or transporters involved in BAs metabolism were also determined.

DG partially reduced the iron deposition and the levels of ferrous ion in the livers of mice with IO, thereby mitigating oxidative damage. DG also improved gut microbiota dysbiosis, repaired intestinal barrier damage, inhibited endotoxin translocation to the liver, and subsequently suppressed TLR4/NF-κB/NLRP3 pathway-mediated liver inflammation caused by IO. Moreover, DG modulated BAs metabolism disorder in IO mice, reducing the accumulation of BAs in the liver.

DG alleviates IO-induced liver injury in mice by regulating the gut-liver axis. This study provides novel insights into the underlying mechanisms through which DG ameliorates liver injury caused by IO.

The pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 "Jing Tint 6" laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.

Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a "knockout placenta," lacks placental and maternal support, while maintaining a healthy extrauterine survival.

Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99-100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p < .05 deemed significant).

mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases.

A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.

The ATP-binding cassette (ABC) and solute carrier (SLC) transporters play pivotal roles in cellular transport mechanisms, influencing a wide range of physiological processes and impacting various medical conditions. Recent advancements in structural biology and computational modeling have provided significant insights into their function and regulation. This review provides an overview of the current knowledge of human ABC and SLC transporters, emphasizing their structural and functional relationships, transport mechanisms, and the contribution of computational approaches to their understanding. Current challenges and promising future research and methodological directions are also discussed.

The concentrations of fecal and serum bile acids (BAs) are known to be altered in human patients with chronic liver diseases (CLDs), especially those with biliary tract involvement (BTD). Scarce literature is available regarding fecal BA modifications during canine CLDs. This study aimed to evaluate fecal BAs in canine CLDs according to different clinical and clinicopathological variables. Forty-six dogs were enrolled. Canine feces were analyzed by HPLC. Cholic Acid (CA), Chenodeoxycholic Acid (CDCA), Ursodeoxycholic Acid (UDCA), Deoxycholic Acid (DCA), and Lithocholic Acid (LCA) were measured, and primary BAs (CA + CDCA), secondary BAs (UDCA + DCA + LCA), and the primary/secondary (P/S) ratio were calculated. Primary BAs (p < 0.0001), CA (p = 0.0003), CDCA (p = 0.003), the P/S ratio (p = 0.002), and total BAs (p = 0.005) were significatively higher in BTD dogs (n = 18) compared to in non-BTD dogs (n = 28). Fecal secondary BAs did not statistically differ between BTD and non-BTD dogs. Gastrointestinal clinical signs (p = 0.028) and diarrhea (p = 0.03) were significantly more prevalent in BTD dogs compared to in non-BTD dogs, supporting the hypothesis of some pathological mechanisms assimilable to bile acid diarrhea (BAD). Our results could reflect imbalances of the fecal BA metabolism in dogs with CLDs. Further studies involving gut microbiome and metabolomic assessment are needed to better understand the possible clinical implications of BA metabolism disruption and their potential role in canine CLDs.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Data on cholestasis and biliary injury in patients with COVID-19 are scarce. The primary aim of this study was to evaluate the prevalence of cholestasis and factors associated with its development and outcome in critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS). In this retrospective exploratory study, COVID-19 patients with ARDS admitted to an intensive care unit (ICU) at the Medical University of Vienna were evaluated for the development of cholestasis defined as an alkaline phosphatase level of 1.67x upper limit of normal for at least three consecutive days. Simple and multiple logistic regression analysis was used to evaluate parameters associated with development of cholestasis and survival. Of 225 included patients 119 (53%) developed cholestasis during ICU stay. Patients with cholestasis had higher peak levels of alkaline phosphatase, gamma-glutamyl transferase, bilirubin and inflammation parameters. Factors independently associated with cholestasis were extracorporeal membrane oxygenation support, ketamine use, high levels of inflammation parameters and disease severity. Presence of cholestasis and peak ALP levels were independently associated with worse ICU and 6-month survival. Development of cholestasis is a common complication in critically ill COVID-19 patients and represents a negative prognostic marker for survival. It is associated with disease severity and specific treatment modalities of intensive care.

Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.

Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.

Besides their lipid-digestive role, bile acids (BA) influence overall energy homeostasis, such as glucose and lipid metabolism. We hypothesized that BA along with their receptors, regulatory enzymes, and transporters are present in subcutaneous adipose tissue (scAT). In addition, we hypothesized that their mRNA abundance varies with the body condition of dairy cows around calving. Therefore, we analyzed BA in serum and scAT as well as the mRNA abundance of BA-related enzymes, transporters, and receptors in scAT during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into either a high (HBCS; n = 19) or normal BCS (NBCS; n = 19) group based on their BCS and back-fat thickness (BFT). Cows were fed different diets to achieve the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off at 7 wk antepartum. During the dry period and subsequent lactation, both groups were fed the same diets according to their energy demands. Using a targeted metabolomics approach via liquid chromatography-electrospray ionization-MS /MS, BA were analyzed in serum and scAT at wk -7, 1, 3, and 12 relative to parturition. In serum, 15 BA were observed: cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid, deoxycholic acid (DCA), lithocholic acid, glycodeoxycholic acid (GDCA), glycolithocholic acid, taurodeoxycholic acid, taurolithocholic acid, β-muricholic acid, tauromuricholic acid (sum of α and β), and glycoursodeoxycholic acid, whereas in scAT 7 BA were detected: CA, GCA, TCA, GCDCA, taurochenodeoxycholic acid, GDCA, and taurodeoxycholic acid. In serum and scAT samples, the primary BA CA and its conjugate GCA were predominantly detected. Increasing serum concentrations of CA, CDCA, TCA, GCA, GCDCA, DCA, and β-muricholic acid with the onset of lactation might be related to the increasing DMI after parturition. Furthermore, serum concentrations of CA, CDCA, GCA, DCA, GCDCA, TCA, lithocholic acid, and GDCA were lower in HBCS cows compared with NBCS cows, concomitant with increased lipolysis in HBCS cows. The correlation between CA in serum and scAT may point to the transport of CA across cell membranes. Overall, the findings of the present study suggest a potential role of BA in lipid metabolism depending on the body condition of periparturient dairy cows.

Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis.

Antituberculosis drugs induce pharmacologic cholestatic liver injury with long-term administration. Liver injury resulting from rifampicin is potentially related to the bile acid nuclear receptor Farnesoid X Receptor (FXR). To investigate this, cholestasis was induced in both wild-type (C57BL/6N) mice and FXR knockout (FXR-null) mice through administration of rifampicin (200 mg/kg) via gavage for 7 consecutive days. Compared with C57BL/6N mice, FXR-null mice exhibited more severe liver injury after rifampicin administration, characterized by enlarged liver size, elevated transaminases, and increased inflammation. Moreover, under rifampicin treatment, FXR knockout impairs lipid secretion and exacerbates hepatic steatosis. Significantly, the expression of metabolism molecules BSEP increased, while NTCP and CYP7A1 decreased following rifampicin administration in C57BL/6N mice, whereas these changes were absent in FXR knockout mice. Furthermore, rifampicin treatment in both C57BL/6N and FXR-null mice was associated with elevated c-Jun N-terminal kinase phosphorylation (p-JNK) levels, with a more pronounced elevation in FXR-null mice. Our study suggests that rifampicin-induced liver injury, steatosis, and cholestasis are associated with FXR dysfunction and altered bile acid metabolism, and that the JNK signaling pathway is partially implicated in this injury. Based on these results, we propose that FXR might be a novel therapeutic target for addressing drug-induced liver injury.

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

Bile acids (BA) play a crucial role not only in lipid digestion but also in the regulation of overall energy homeostasis, including glucose and lipid metabolism. The aim of this study was to investigate BA profiles and mRNA expression of BA-related genes in the liver of high versus normal body condition in dairy cows. We hypothesized that body condition and the transition from gestation to lactation affect hepatic BA concentrations as well as the mRNA abundance of BA-related receptors, regulatory enzymes, and transporters. Therefore, we analyzed BA in the liver as well as the mRNA abundance of BA-related synthesizing enzymes, transporters, and receptors in the liver during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into groups with high body condition score (BCS) (HBCS; n = 19) or normal BCS (NBCS; n = 19) based on BCS and backfat thickness (BFT). Cows were fed diets aimed at achieving the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until they were dried off at wk 7 before parturition. Both groups were fed identical diets during the dry period and subsequent lactation. Liver biopsies were taken at wk -7, 1, 3, and 12 relative to parturition. For BA measurement, a targeted metabolomics approach with LC-ESI-MS/MS was used to analyze BA in the liver. The mRNA abundance of targeted genes related to BA-synthesizing enzymes, transporters, and receptors in the liver was analyzed using microfluidic quantitative PCR. In total, we could detect 14 BA in the liver: 6 primary and 8 secondary BA, with glycocholic acid (GCA) being the most abundant one. The increase of glycine-conjugated BA after parturition, in parallel to increasing serum glycine concentrations may originate from an enhanced mobilization of muscle protein to meet the high nutritional requirements in early lactating cows. Higher DMI in NBCS cows compared with HBCS cows was associated with higher liver BA concentrations such as GCA, deoxycholic acid (DCA), and cholic acid (CA). The mRNA abundance of BA-related enzymes measured herein suggests the dominance of the alternative signaling pathway in the liver of HBCS cows. Overall, BA profiles and BA metabolism in the liver depend on both, the body condition and lactation-induced effects in periparturient dairy cows.

This study evaluated effects of high starch (20%) on hematological variations, glucose and lipid metabolism, antioxidant ability, inflammatory responses, and histopathological lesions in largemouth bass. Results showed hepatic crude lipid and triacylglycerol (TAG) contents were notably increased in fish fed high starch. High starch could increase counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils and serum contents of TAG, TBA, BUN, and LEP (p < 0.05). There were increasing trends in levels of GLUT2, glycolysis, gluconeogenesis, and LDH in fish fed high starch through the AKT/PI3K signal pathway. Meanwhile, high starch not only triggered TAG and cholesterol synthesis, but mediated cholesterol accumulation by reducing ABCG5, ABCG8, and NPC1L1. Significant increases in lipid droplets and vacuolization were also shown in hepatocytes of D3-D7 groups fed high starch. In addition, high starch could decrease levels of mitochondrial Trx2, TrxR2, and Prx3, while increasing ROS contents. Moreover, high starch could notably increase amounts of inflammatory factors (IL-1β, TNF-α, etc.) by activating NLRP3 inflammasome key molecules (GSDME, caspase 1, etc.). In conclusion, high starch could not only induce metabolic disorders via gluconeogenesis and accumulation of glycogen, TAG, and cholesterol, but could disturb redox homeostasis and cause inflammatory responses by activating the NLRP3 inflammasome in largemouth bass.

Zearalenone (ZEN) is a mycotoxin that is harmful to humans and animals. In this study, female and male rats were exposed to ZEN, and the results showed that ZEN reduced the farnesoid X receptor (FXR) expression levels in the liver and disrupted the enterohepatic circulation of bile acids (BAs). A decrease in food intake induced by ZEN was negatively correlated with an increase in the level of total BAs. BA-targeted metabolomics revealed that ZEN increased glycochenodeoxycholic acid levels and decreased the ratio of conjugated BAs to unconjugated BAs, which further increased the hypothalamic FXR expression levels. Preventing the increase in total BA levels induced by ZEN via Lactobacillus rhamnosus GG intervention restored the appetite. In conclusion, ZEN disrupted the enterohepatic circulation of BAs to decrease the level of food intake. This study reveals a possible mechanism by which ZEN affects food intake and provides a new approach to decrease the toxic effects of ZEN.

Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.

Cellular entry of the hepatitis B and D viruses (HBV/HDV) requires binding of the viral surface polypeptide preS1 to the hepatobiliary transporter Na+-taurocholate co-transporting polypeptide (NTCP). This interaction can be blocked by bulevirtide (BLV, formerly Myrcludex B), a preS1 derivative and approved drug for treating HDV infection. Here, to elucidate the basis of this inhibitory function, we determined a cryo-EM structure of BLV-bound human NTCP. BLV forms two domains, a plug lodged in the bile salt transport tunnel of NTCP and a string that covers the receptor's extracellular surface. The N-terminally attached myristoyl group of BLV interacts with the lipid-exposed surface of NTCP. Our structure reveals how BLV inhibits bile salt transport, rationalizes NTCP mutations that decrease the risk of HBV/HDV infection, and provides a basis for understanding the host specificity of HBV/HDV. Our results provide opportunities for structure-guided development of inhibitors that target HBV/HDV docking to NTCP.