Enterohepatic Circulation Of Bile Acids Research Articles

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets

BackgroundInfection 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.ResultsOur 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.ConclusionsIn 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.Graphical

Profiling the Gut Microbiota in Obese Children with Formula Feeding in Early Life and Selecting Strains against Obesity.

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.

Expression of bile acid receptors and transporters along the intestine of patients with type 2 diabetes and controls.

The enterohepatic circulation of bile acids depends on intestinal absorption by bile acid transporters and activation of bile acid receptors, which stimulates secretion of hormones regulating glucose and lipid metabolism and appetite. Distribution of bile acid transporters and receptors in the human gut and their potential involvement in type 2 diabetes (T2D) pathophysiology remain unknown. We explored the expression of genes involved in bile acid metabolism throughout the intestines of patients with T2D and matched healthy controls. Intestinal mucosa biopsies sampled along the intestinal tract in 12 individuals with T2D and 12 healthy controls were subjected to mRNA sequencing. We report expression profiles of apical sodium-dependent bile acid transporter (ASBT), organic solute transporter (OST) α/β, farnesoid X receptor (FXR), Takeda G receptor 5 (TGR5), fibroblast growth factor 19 (FGF19) and FGF receptor 4 (FGFR4). Expression of ASBT and OSTα/β was evident in the duodenum of both groups with increasing levels through the small intestine, and no (ASBT) or decreasing levels (OSTα/β) through the large intestine. The FXR expression pattern followed that of OSTα/β whereas FGFR4 were evenly expressed through the intestines. Negligible levels of TGR5 and FGF19 were evident. Patients with T2D exhibited lower levels of FGF19, FXR, ASBT and OSTα/β mRNAs compared with healthy controls, although the differences were not statistically significant after adjusting for multiple testing. We demonstrate distinct expression patterns of bile acid transporters and receptors through the intestinal tract with signs of reduced ASBT, OSTα/β, FXR and FGF19 mRNAs in T2D.

Zearalenone Decreases Food Intake by Disrupting the Gut-Liver-Hypothalamus Axis Signaling via Bile Acids.

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.

Ginsenoside Rb1, Compound K and 20(S)-Protopanaxadiol Attenuate High-Fat Diet-Induced Hyperlipidemia in Rats via Modulation of Gut Microbiota and Bile Acid Metabolism.

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.

High-Fat Diet-Induced Decreased Circulating Bile Acids Contribute to Obesity Associated with Gut Microbiota in Mice.

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.

Жовчнокам'яна хвороба в дітей

The prevalence of gallstone disease among children is 0.13-1.9%. Cholelithiasis in children is a multifactorial disorder. Scientific data analysis indicates a diversity of pathogenetic mechanism of gallstone formation. The purpose of the review is to summarize the scientific data about risk factors, clinical features, diagnosis and treatment of gallstone disease in children. Based on the literature data, the main factors for the disease are genetic, metabolic, low-calorie diet, nutritional disorders, liver and small intestine diseases. The main pathogenetic mechanisms of gallstone formation are liver dyscholia, disorders of enterohepatic circulation of bile acids, increased erythrocyte hemolysis and erythrocyte enzyme system insufficiency, a decrease in hepatic enzyme activity, impairment of gallbladder motility due to decreased sensitivity to cholecystokinin. Most children undergo asymptomatic gallstone disease: clinical features are absent, concrements in the gallbladder or bile ducts appear as accidental findings during ultrasound examination. The first stage of diagnosing cholelithiasis is an abdominal ultrasound examination. In case of absence of concrements during ultrasound examination and presence of typical clinical picture of cholelithiasis, endoscopic ultrasound and magnetic resonance cholangiopancreatography are prescribed. To reduce biliary pain, non-steroidal anti-inflammatory drugs and analgesics are required. The only way to treat symptomatic form of gallstone disease is cholecystectomy. The asymptomatic form is subject to observation without treatment. For the treatment and prevention of cholelithiasis, it is not recommended to take bile acid preparations due to the low effectiveness and frequency of relapses in the formation of stones after their complete dissolution. Conclusions. The incidence of gallstone disease among children and adolescents increases and more than half of patients has asymptomatic form. During the treatment of patients with cholelithiasis, cholecystectomy or observation tactics are used, depending on the clinical form of the disease. Prevention of gallstone disease relies on healthy lifestyle, weight loss for the obese children, physical activity, diet high in fiber and calcium. The authors declare that they have no conflicts of interest.

Polymethoxyflavones in citrus extract has a beneficial effect on hypercholesterolemia rats by promoting liver cholesterol metabolism

Ethnopharmacological relevanceHyperlipidemia is characterized by the disorder of lipid metabolism accompanied by oxidative stress damage, and low-grade inflammation, with the pathway of cholesterol and bile acid metabolic are an important triggering mechanism. Polymethoxyflavones (PMFs) are the active constituents of Aurantii Fructus Immaturus, which have many biological effects, including anti-inflammatory, antioxidant activities, anti-obesity, suppressing adipogenesis in adipocytes, and ameliorate type 2 diabetes, with potential roles for regulation of lipid metabolism. However, its associated mechanisms on hyperlipidemia remain unclear. Aim of the studyThis study aims to identify the anti-hypercholesterolemia effects and mechanisms of PMFs in a hypercholesterolemia model triggered by high-fat compounds in an excessive alcohol diet (HFD). Materials and methodsA hypercholesterolemia rat model was induced by HFD, and PMFs was intragastric administered at 125 and 250 mg/kg daily for 16 weeks. The effects of PMFs on hypercholesterolemia were assessed using serum lipids, inflammatory cytokines, and oxidative stress levels. Hematoxylin & eosin (H&E) and Oil Red O staining were performed to evaluate histopathological changes in the rat liver. The levels of total cholesterol (TC) and total bile acid (TBA) in the liver and feces were determined to evaluate lipid metabolism. RAW264.7 and BRL cells loaded with NBD-cholesterol were used to simulate the reverse cholesterol transport (RCT) process in vitro. The signaling pathway of cholesterol and bile acid metabolic was evaluated by Western Blotting (WB) and qRT-PCR. ResultsLipid metabolism disorders, oxidative stress injury, and low-grade inflammation in model rats were ameliorated by PMFs administration. Numerous vacuoles and lipid droplets in hepatocytes were markedly reduced. In vitro experiments results revealed decreased NBD-cholesterol levels in RAW264.7 cells and increased NBD-cholesterol levels in BRL cells following PMFs intervention. PMFs upregulated the expression of proteins associated with the RCT pathway, such as LXRα, ABCA1, LDLR, and SR-BI, thereby promoting TC entry into the liver. Meanwhile, the expression of proteins associated with cholesterol metabolism and efflux pathways such as CYP7A1, CYP27A1, CYP7B1, ABCG5/8, ABCB1, and BSEP were regulated, thereby promoting cholesterol metabolism. Moreover, PMFs treatment regulated the expression of proteins related to the pathway of enterohepatic circulation of bile acids, such as ASBT, OSTα, NTCP, FXR, FGF15, and FGFR4, thereby maintaining lipid metabolism. ConclusionsPMFs might ameliorate hypercholesterolemia by promoting the entry of cholesterol into the liver through the RCT pathway, followed by excretion via metabolism pathways of cholesterol and bile acid. These findings provide a promising therapeutic potential for PMFs to treat hypercholesterolemia.

Enterohepatic circulation of bile acids and its role in pathologies of the hepatobiliary system

Enterohepatic circulation of bile acids is a highly regulated process of secretion of these compounds, intestinal reabsorption and reverse transport to the liver. Violation of this process has significant consequences for the homeostasis of the gastrointestinal tract, liver and the whole organism. This process is tightly controlled by regulatory enzymatic reactions with negative feedback, which leads to the maintenance of a pool and adequate homeostasis of bile acids. The main purpose of this article is to consider the mechanism of enterohepatic circulation of bile acids and evaluate their role both in the formation of pathologies of the hepatobiliary system of various origins, and as a predictor of such processes. We searched for original studies in the scientific databases PubMed, Elsevier Science (Scopus) and Clarivate Analytics (Web of Science) over the past 20 years to identify the features of the above processes, after which a formalized content analysis of the found publications was carried out. Theoretically, every factor that disrupts the enterohepatic circulation leads to pathologies of the hepatobiliary system. However, there are still many unknown aspects when it comes to the regulation of bile acid homeostasis in the enterohepatic circulation. In the last few decades, it is believed that the most important prerequisites for the occurrence of hepatopathy are hypersecretion of bile cholesterol and supersaturation of bile with it. An equally important problem is the change in the pool of bile acids, since its various representatives differ both in chemical activity and in the mechanism of action (from cytotoxicity to cytoprotection).

In Ukrainian

Regulation of enterohepatic circulation of bile acids in human body is actual task to overcome cardiovascular diseases. The aim of this work was to create biocompatible sorbents with improved sorption ability in relation to bile acids. Mesoporous organosilicas of MCM‑41 type with chemically grafted 3‑aminopropyl and steroid groups were obtained by sol‑gel condensation of tetraethyl orthosilicate and functional silanes in the presence of template cetyltrimethylammonium bromide. Porous structure of synthesized organosilicas was characterized by low‑temperature nitrogen adsorption–desorption and X‑ray diffraction analysis. Formation of typical for MCM‑41 hexagonal arrangement of cylindrical mesopores was confirmed. Structural parameters of synthesized silica materials were calculated. The influence of surface steroid groups on sorption ability of organosilicas was studied on example of bile salts (sodium cholate and taurocholate) in dependence of duration of contact, acidity of medium, and equilibrium concentration. Analysis of kinetic parameters of sorption estimated by Lagergren and Ho-McKey models confirms the proceeding of pseudo-second order process. The most effective sorption of sodium cholate and taurocholate was observed at pH ~ 5 and pH ~ 2, respectively, where the ovterlapping of pH regions of 3‑aminopropyl groups protonation and bile acids dissociation takes place. Analysis of experimentally obtained isotherms by use of Freundlich, Redlich‑Peterson, and BET models was carried out. It has been found that protonated amino groups are the main sorption centers of bile acids protolytic forms by synthesized aminosilica in pH range from 1 to 8. Introduction of steroid groups in surface layer at sol-gel synthesis leads to the increase of bile salts sorption due to the cooperative interactions with formation of supramolecular structures in the surface layer of organosilica. Obtained results prove prospects of usage of organosilica sorbents with surface steroid groups for regulation of bile acids content in human body.

A physiologically based model of bile acid metabolism in mice

Bile acid (BA) metabolism is a complex system that includes a wide variety of primary and secondary, as well as conjugated and unconjugated BAs that undergo continuous enterohepatic circulation (EHC). Alterations in both composition and dynamics of BAs have been associated with various diseases. However, a mechanistic understanding of the relationship between altered BA metabolism and related diseases is lacking. Computational modeling may support functional analyses of the physiological processes involved in the EHC of BAs along the gut-liver axis. In this study, we developed a physiologically based model of murine BA metabolism describing synthesis, hepatic and microbial transformations, systemic distribution, excretion, and EHC of BAs at the whole-body level. For model development, BA metabolism of specific pathogen-free (SPF) mice was characterized invivo by measuring BA levels and composition in various organs, expression of transporters along the gut, and cecal microbiota composition. We found significantly different BA levels between male and female mice that could only be explained by adjusted expression of the hepatic enzymes and transporters in the model. Of note, this finding was in agreement with experimental observations. The model for SPF mice could also describe equivalent experimental data in germ-free mice by specifically switching off microbial activity in the intestine. The here presented model can therefore facilitate and guide functional analyses of BA metabolism in mice, e.g., the effect of pathophysiological alterations on BA metabolism and translation of results from mouse studies to a clinically relevant context through cross-species extrapolation.

Gardenia extract protects against intrahepatic cholestasis by regulating bile acid enterohepatic circulation

Ethnopharmacological relevanceCholestasis is the main manifestation of cholestatic liver disease, which has a risk of progression to end-stage liver disease. Gardeniae Fructus is the dried fruit of Gardeniae jasminoides Ellis, a plant of the Rubiaceae family. Gardeniae Fructus has shown therapeutic potential in cholestasis-related liver diseases and it is generally believed that Gardeniae Fructus ameliorates cholestasis, which could be related to its influence on bile acids (BAs) metabolism. However, the specific targets of Gardeniae Fructus and its impact on enterohepatic circulation of BAs have not yet been fully elucidated. Aim of the studyTo systematically elucidate the mechanism by which Gardenia extract (GE, total iridoids in Gardeniae Fructus, which contains the predominant and characteristic phytoconstituents of Gardeniae Fructus) ameliorates alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury. Materials and methodsSprague-Dawley rats were orally administered water, obeticholic acid (OCA, 2 mg/kg), or GE (21 and 42 mg/kg) once daily for five days. On the third day, the model was established by administration of a single dose of ANIT (40 mg/kg) by oral gavage. Biochemical and pathological analyses, BA metabolomics, transcriptomics, and qRT-PCR were performed. ResultsThe profile of BAs in serum and liver confirmed that GE attenuated ANIT-induced acute cholestasis by affecting BA metabolism in a dose-dependent manner. Liver transcriptomic analysis indicated that GE mainly influenced the primary bile acid (PBA) biosynthesis and bile secretion pathways. GE mainly affected PBA biosynthesis in liver by upregulating Cyp8b1 gene expression, thereby significantly reducing the level of total bile acids (TBA). GE mainly promoted PBA excretion from liver into duodenum by upregulating Fxr and Oatp1 gene expression, thereby increasing the excretion of PBA in feces, and inhibiting PBA in liver entering the blood by alternative routes to reduce TBA levels in serum and urine and improve the enterohepatic circulation of BAs. ConclusionGE attenuated ANIT-induced hepatotoxicity and cholestasis in rats by upregulating Cyp8b1 expression to inhibit BA synthesis in the liver, while also promoting BA excretion via the intestinal-fecal route, and improving enterohepatic circulation of BAs.

Taxonomic identification of bile salt hydrolase‐encoding lactobacilli: Modulation of the enterohepatic bile acid profile

AbstractBile salt hydrolases (BSHs) are enzymes that are essential for the enterohepatic metabolism of bile acids (BAs). BSHs catalyze the production of unconjugated BAs and regulate the homeostasis of BA pool. This study identified Lactobacillus as a crucial BSH‐encoding genus, and 16 main species were obtained using metagenomic data from publicly available human gut microbiome databases. Then, the 16 species of lactobacilli were classified into four typical categories by BSH phylotypes, including five species encoding BSH‐T0, six species encoding BSH‐T2, four species encoding BSH‐T3, and Ligilactobacillus salivarius encoding both BSH‐T0 and BSH‐T3. The lactobacilli with the highest in vitro deconjugation activities against seven conjugated BAs were the BSH‐T3‐encoding strains. Furthermore, in vivo studies in mice administered four representative lactobacilli strains encoding different BSH phylotypes showed that treatment with BSH‐T3‐encoding Limosilactobacillus reuteri altered the structure of the gut microbiome and metabolome and significantly increased the levels of unconjugated BAs and total BA excretion. Our findings facilitated the taxonomic identification of crucial BSH‐encoding lactobacilli in human gut microbiota and shed light on their contributions toward modulation of the enterohepatic circulation of BAs, which will contribute to future therapeutic applications of BSH‐encoding probiotics to improve human health.

Efektivitas Ekstrak Daun Annona Muricata Terhadap Penurunan Kolesterol Total Pada Lansia Dengan Hiperkolesterolemia Di Panti Werdha Mojopahit Mojokerto

The elderly experience a decrease in function, especially in the function of blood circulation. Blood circulation diseases and hormonal metabolism disorders experienced by the elderly include hypercholesterolemia. Hypercholesterolemia is a disorder of fat metabolism that triggers an increase in total blood cholesterol levels, namely&gt; 200 mg/dl. The study aimed to determine the effectiveness of A. muricata leaf extract in decreasing total cholesterol levels in the elderly with hypercholesterolemia. Quantitative research method, using a quasi-experimental type with a group pretest-posttest design, with a sample size of 20 elderly. The sampling technique used purposive sampling, was carried out for a week consuming three times a day. The paired t-test showed a value of 8.73 and a p-value of 0.001. This study's results indicated a significant difference between the average cholesterol levels in the pre-test and post-test administration of Annona Muricata leaf extract. Compounds contained in soursop leaves, namely flavonoids, by reducing the activity of HMG-koa reductase (enzyme β-Hydroxy β-methylglutaryl-CoA) can reduce the activity of ACAT (enzyme acyl-Coa cholesterol acyltransferase), and reduce the absorption activity of cholesterol in the liver. Digestive tract. Saponin compounds in soursop leave lower cholesterol by binding to cholesterol in the intestinal lumen, thereby preventing the reabsorption of cholesterol. Saponins can bind with bile acids, which in turn will reduce the enterohepatic circulation of bile acids and cause an increase in the process of excretion of cholesterol.

Dietary bile acids promote sterol metabolism, bile acids enterohepatic circulation, and apoptosis in juvenile Pacific white shrimp (Litopenaeus vannamei)

Bile acids have an important role in the growth and sterol metabolism of shrimp. The aim of this study was to elucidate the effects of bile acids supplementation in the low fishmeal diets on sterol metabolism, bile acids enterohepatic circulation, bile acid profile, and apoptosis in Pacific white shrimp Litopenaeus vannamei. Six diets were formulated in this experiment, HFM diet (25% fishmeal), LFM diet (10 % fishmeal), and LFM supplemented with four levels (0.15, 0.3, 0.6, 0.9 g kg−1) of bile acids, which were LBA1, LBA2, LBA3, LBA4, respectively. Soy protein concentrate and cottonseed protein concentrate blend was used to replace fishmeal of 60 %. After 50 days of feeding trial, the shrimp fed the LBA4 diet showed significantly increased final body weight than that fed the LFM diet (P < 0.05). In the sterol metabolism, the shrimp fed the LBA1 diet was significantly increased the HMG-CoA reductase membrane form (hmgcr) and Niemann-Pick type C-2-like protein (npc2) expression compare with that fed the LFM diet, shrimp in LBA2 group was significantly increased the related genes expression [hmgcr and NPC intracellular cholesterol transporter 1-like (npc1)] than those in the LFM group of hepatopancreas (P < 0.05). In the lipid metabolism, the shrimp in LBA2 group was significantly increased the carnitine palmitoyltransferase-1 (cpt-1) and AMP-activated protein kinase (ampk) expression than that in the LFM group, shrimp in the LBA3 group was significantly increased the fatty acid binding protein fatty acid (fabp) expression than that in the LFM group (P < 0.05). In the bile acids metabolism, the multidrug resistance-associated protein 1-like (mrp2), multidrug resistance-associated protein 2-like (mrp3) and solute carrier family 22 member 7-like (oatp) expressions were significantly increased in LBA1 and LBA2 groups than those in the LFM group of hepatopancreas, organic solute transporter subunit alpha-like (ostα), mrp2, and acyl-coenzyme A thioesterase 1-like (baat) expressions were significantly up-regulated in LBA4 group than those in the LFM group of intestine (P < 0.05). Supplementary bile acids in the diet could decrease the apoptosis-related protein expression (BCL-2 and CASPASE3) compare with the shrimp fed low fishmeal diet (P < 0.05). The concentration of beta MCA in hemolymph bile acids profile increases with bile acids supplementation. The results showed that bile acids enhanced growth performance, promoted sterol metabolism, enhanced enterohepatic circulation, and reduced apoptosis in shrimp on low fishmeal diets. Data availability statementThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical.

THU-240 - Altered levels of secondary bile acids in enterohepatic circulation impairs liver regeneration in a rat model of partial hepatectomy

THU-240 - Altered levels of secondary bile acids in enterohepatic circulation impairs liver regeneration in a rat model of partial hepatectomy

Lactobacillus fermentum MCC2760 abrogate high-fat induced perturbations in the enterohepatic circulation of bile acids in rats

This study in hyperlipidemic rats elucidated the effect of Lactobacillus fermentum MCC2760 on intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic BA transporters. Diets rich in saturated fatty acids [coconut oil (CO)] and omega-6 fatty acids [sunflower oil (SFO)] at 25g fat/100g diet were fed to rats with or without MCC2760 (109 cells/kg body weight). After 60days of feeding, intestinal BA uptake and expression of Asbt, Osta/b mRNA and protein, and hepatic expression of Ntcp, Bsep, Cyp7a1, Fxr, Shp, Lrh-1, and Hnf4a mRNA were measured. Hepatic expression of HMG-CoA reductase protein and its activity and total BAs in serum, liver, and feces were assessed. Hyperlipidaemic groups (HF-CO and HF-SFO) had: 1) increased intestinal BA uptake, Asbt and Osta/b mRNA expression, and ASBT staining 2) increased BA in serum, 3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, and NTCP staining 4) increased activity of HMG-CoA reductase, 5) increased hepatic expression of Fxr and Shp mRNA, 6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and 7) decreased BA in Feces when compared to their respective controls (N-CO and N-SFO) and experimental groups (HF-CO+LF and HF-SFO+LF). Immunostaining revealed increased intestinal Asbt and hepatic Ntcp protein expression in the HF-CO and HF-SFO groups compared to control and experimental groups. Incorporating probiotics like MCC2760 abrogated hyperlipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in rats. Probiotic MCC2760 can be used to modulate lipid metabolism in high-fat-induced hyperlipidemic conditions.

Polysaccharide from Angelica sinensis with medicinal and edible purposes ameliorated NAFLD by the bile acids mediated activation of FXR

Liver and gut communicates with each other through metabolites and the gut-liver axis plays a crucial role in lipid metabolism. Enterohepatic bile acid circulation is an important constitution of gut-liver axis. Farnesoid X receptor (FXR)，a bile acid mediated nuclear receptor, is promising therapeutic targets for the non-alcoholic fatty liver disease (NAFLD). More and more studies have confirmed the effects of Angelica sinensis polysaccharide (ASP) on liver protection and lipid regulation. However, little attention has been paid to the role of ASP on the gut-liver axis, which is crucial to clarify how ASP play a role in liver protection after oral administration. In vivo and in vitro models of NAFLD were established to examine the effect of ASP on hepatic fat accumulation. Our results showed that ASP could alleviate liver fat accumulation. However, the expression of FXR was not changed when ASP directly acting on hepatocytes, while ASP could change the expression of FXR in liver and intestine of mice after oral administration. In addition, our results showed that ASP could promote the excretion of bile acids, thereby increasing cholesterol metabolism. Our research provided a new concept for the mechanism of ASP regulating liver lipid metabolism and exerting liver protection.

Prevention of High-Fat-Diet-Induced Dyslipidemia byLactobacillus plantarumLP104 through Mediating Bile Acid Enterohepatic Axis Circulation and Intestinal Flora

This work aimed to investigate the alleviative mechanism of Lactobacillus plantarum LP104 (LP104) isolated from kimchi on high-fat-diet-induced dyslipidemia by targeting the intestinal flora and bile acid (BA) metabolism. Oral administration of LP104 over 8 weeks reduced body weight gain and body fat, as well as ameliorating serum and hepatic dyslipidemia in HFD-fed C57BL/6N mice significantly. LP104 intervention also increased the ileal tauro-α/β-muricholic acid sodium salt (T-α-MCA or T-β-MCA) and tauroursodeoxycholic acid (TUDCA) concentrations to suppress the enterohepatic farnesoid X receptor/fibroblast growth factor 15-fibroblast growth factor receptor 4 (FXR/FGF15-FGFR4) signaling pathway, which stimulated the hepatic cholic acid (CA) and chenodeoxycholic acid (CDCA) de novo synthesis through using cholesterol. Then, LP104 treatment accelerated BA excretion with the feces and cholesterol efflux to improve HFD-caused hyperlipidemia effectively. The 16S rRNA gene high-throughput sequencing revealed that LP104 promoted intestinal flora rebalance by increasing the abundances of Bacteroides, Akkermansia, Lactobacillus, and Clostridium and decreasing the abundance of Oscillospira and Coprococcus. Meanwhile, Spearman correlation analysis demonstrated that the differential flora were closely related to BA signaling molecules including CA, CDCA, T-α-MCA, T-β-MCA, and TUDCA after LP104 intervention. These findings provided new evidence that LP104 had the potential to be used as a naturally functional food for the prevention of dyslipidemia.

Bile Acid Alterations Characterize the Early Onset and Progression of Nonalcoholic Fatty Liver Disease in Young Mice Fed with High Fat and Fructose Diet.

Bile acids (BAs) are closely associated with obesity and non-alcoholic fatty liver disease (NAFLD). How BAs change within the enterohepatic circulation during the onset and progression of NAFLD as biomarkers deserves to be explored. Four-week-old young mice were fed with high-fat diet plus 4% v/w fructose drinking water (HFF) or normal diet with tap water (ND) for 4 and 12 weeks. In comparison, eight-week-old adult mice were fed with HFF or ND for 12 weeks. BAs were measured in six different anatomical sites to evaluate the systematic changes of BAs within the enterohepatic circulation. The dysregulated BA metabolism had occurred in HFF after 4-week intervention, represented by increased primary BAs and decreased hyocholic acid (HCA) species. After 12 weeks, the impact was more significant with increased secondary BA synthesis and excretion, particularly for lithocholic acid (LCA) species. More interestingly, the BA changes were more significant in younger mice in response to 12-week diet intervention. The enterohepatic circulation of BAs changed with the development of NAFLD, and the younger mice were more susceptible to the unhealthy diet. HCA and LCA species may be potential biomarkers for predicting the development of NAFLD.