Regulation Of Bile Acid Metabolism Research Articles

Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity.

Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity. Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr-/- mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with β-thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron-regulatory proteins 1 and 2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron-fed mice. The FXR agonist, GW4064, almost completely restored dysregulated bile acid signaling and metabolic syndrome in iron-fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with β-thalassemia. FXR plays a pivotal role in regulating iron homeostasis and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for IO-associated chronic liver diseases.

Myostatin Knockout Regulates Bile Acid Metabolism by Promoting Bile Acid Synthesis in Cattle.

Simple SummaryMyostatin (MSTN) gene knockout can increase lean muscle mass and has been widely used in livestock breeding. MSTN deficiency also regulates various metabolic processes. However, the effect of MSTN knockout on the liver, the largest metabolic organ, has not been reported. In this study, physiological and biochemical parameters of serum, untargeted and targeted metabolomics of MSTN+/− and WT cattle were studied, and we found that the knockout of MSTN could regulate liver metabolism and promote bile acid metabolism. This may be due to the enhanced expression of bile acid synthesis genes in MSTN+/− bovine livers. In conclusion, MSTN knockout regulated bile acid metabolism via enhanced bile acid synthesis.Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.

Frankincense vinegar-processing improves the absorption of boswellic acids by regulating bile acid metabolism

BackgroundBoswellic acids in Olibanum (known as frankincense) are potent anti-inflammatory properties in treating ulcerative colitis (UC), but its low bioavailability limited drug development. Evidence accumulated that vinegar processing of frankincense exerts positive effects on improving absorption of compositions. The underlying mechanism is unknown. In recent decades, spectacular growth and multidisciplinary integration of metabolic application were witnessed. The relationship between drug absorption and curative effect has been more or less established. However, it remains a knowledge gap in the field between drug absorption and endocrine metabolism. PurposeTo investigate the enhancement mechanism of vinegar processing in the absorption of boswellic acids via the aspect of bile acid metabolism. MethodsThe effects of raw frankincense (RF) and processed frankincense (PF) were compared by the UC model of rats. The plasma concentration of boswellic acids and the hepatic and colonic bile acids contents were quantified by UPLC-TQ-MS. The levels of mRNA and protein associated with bile acid metabolism were also compared. ResultsThe results showed that PF exhibited re-markable mitigating effects on UC with the elevated plasma level of boswellic acid and upregulated expression of the absorption-related protein multidrug resistance-associated protein 2 (MRP2) and organic anion transporting polypeptide 1B3 (OATP1B3) in the liver and colon. It improved colonic lithocholic acid (LCA), which promoted the expression of bile acid nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), resulting in the upregulation of MRP2 and OATP1B3. ConclusionThis paper revealed the mechanisms behind the absorption promotion effects of processing. Bile acids metabolism exhibits potential status in pharmaceutical development. The results shed light on the interdisciplinary collaboration between the metabolism and drug absorption fields.

Protective effects of taurocholic acid on excessive hepatic lipid accumulation via regulation of bile acid metabolism in grouper.

Dietary bile acid (BA) supplementation can notably ameliorate fatty liver disease caused by high dietary lipids, but the mechanism behind this is poorly understood. The present study was aimed at gaining insight into how TCA (taurocholic acid sodium) reduced hepatic lipid accumulation via the regulation of bile acid metabolism. We explored BA metabolism in juvenile hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂). Three trials were: (1) fed the control, high lipid (HD) or gradient TCA diet; (2) fed a BA diet with or without antibiotics; and (3) injected with an agonist or antagonist of TGR5 (G protein-coupled bile acid receptor 1) and FXR (farnesoid X receptor). The results showed that the TCA diet (about 900 mg kg-1) significantly reduced lipid accumulation in the liver, thus improving liver health. The HD suppressed the abundance of bile-salt hydrolase (BSH) microbes, thus decreasing the concentration of unconjugated primary BAs. TCA administration altered the gut microbial composition and weakened the effects of the HD, thus increasing the level of unconjugated BAs. TCA treatment increased the transport and reabsorption of BAs by activating the TGR5 and FXR signaling pathways, and increased the BA pool size. Furthermore, the presence of microbiota in the intestine increased BA reabsorption and the BA pool size. Our study revealed that exogenous TCA alters the structure of intestinal microbiota and BA composition, then activated the FXR expression, thus regulating the BA metabolism via enhanced BA reabsorption. This, in turn, reduced lipid accumulation and improved the health of the liver in grouper.

Antihypertensive effect and underlying mechanism of tripeptide NCW on spontaneously hypertensive rats using metabolomics analysis.

Tripeptide NCW identified in our previous study displayed a strong ACE inhibitory activity, but whether it has any antihypertensive effect in vivo remains unknown. Thus, in this study, we aimed to investigate the protective effects of tripeptide NCW in spontaneously hypertensive rats (SHRs) and to further figure out the serum metabolic profiling variations due to its oral administration via UPLC-Q-TOF-MS/MS-based metabolomics analysis to clarify the underlying hypotensive mechanism. After three weeks of oral administration, the tripeptide NCW-treated group (NCW/SHR group, 80 mg per kg BW per d) showed significantly reduced systolic and diastolic blood pressure by 48.08 ± 3.84 mmHg and 48.92 ± 5.77 mmHg, respectively. Additionally, a total of 25 blood pressure-related metabolites were identified as being significantly changed in SHRs given tripeptide NCW after three weeks. These 25 metabolites might be biomarkers that indicated that the tripeptide NCW exhibits antihypertensive activity via regulating bile acid metabolism, lipid metabolism, amino acid metabolism, purinergic signaling, pantothenate and CoA biosynthesis, and the citrate cycle. Collectively, tripeptide NCW has a protective effect on SHRs associated with serum metabolite abnormalities.

Bacillus amyloliquefaciens SC06 alleviates the obesity of ob/ob mice and improves their intestinal microbiota and bile acid metabolism.

Dietary interventions with probiotics have been widely reported to be effective in regulating obesity, and the intestinal microbiota is considered to be an important environmental factor. However, few reports focus on the interactions of microbiota-metabolites-phenotypic variables in ob/ob mice, and they have not been characterized in great detail. In this study, we investigated the effects of Bacillus amyloliquefaciens SC06 on obesity, the intestinal microbiota and the bile acid metabolism of ob/ob mice using biochemical testing, histochemical staining, high-throughput sequencing of the 16S rRNA gene, LC-MS/MS analysis and qRT-PCR. The results showed that SC06 ameliorated the fat mass percentage, hepatic steatosis and liver lipid metabolism disorders and reshaped the gut microbiota and metabolites in male ob/ob mice, specifically deceasing f_S24-7, p_TM7, s_Alistipes massiliensis, f_Rikenellaceae, f_Prevotellaceae, f_Lactobacillaceae, g_Alistipes, g_Flexispira, g_Lactobacillus, g_Odoribacter, g_AF12 and g_Prevotella and increasing f_Bacteroidaceae, g_Bacteroides and f_Desulfovibrionaceae. Meanwhile, SC06 treatment groups had lower ibuprofen and higher glycodeoxycholic acid and 7-dehydrocholesterol. Correlation analysis further clarified the relationships between compositional changes in the microbiota and alterations in the metabolites and phenotypes of ob/ob mice. Moreover, SC06 downregulated bile acid synthesis, export and re-absorption in the liver and increased ileum re-absorption into the blood in ob/ob mice, which may be mediated by the FXR-SHP/FGF15 signaling pathway. These results suggest that Bacillus amyloliquefaciens SC06 can ameliorate obesity in male ob/ob mice by reshaping the intestinal microbial composition, changing metabolites and regulating bile acid metabolism via the FXR signaling pathway.

Highland barley β-glucan alleviated western diet-induced non-alcoholic fatty liver disease via increasing energy expenditure and regulating bile acid metabolism in mice.

Non-alcoholic fatty liver disease (NAFLD) has become a public health burden. Controlling bile acids (BAs) metabolism andenergy expenditure are potential therapies for NAFLD. Because one of the main health effects of cereal β-glucan (BG) is its ability to lower cholesterol by interacting with BAs, BG may regulate imbalances of the metabolism of BAs during NAFLD. Therefore, by using metabolic tests coupled with the profiling of hepatic BAs, we have assessed the effect of BG from highland barley on western diet (WD) induced NAFLD mice. BG treatment prevented fat accumulation and increased adipose lipolysis. These moderating effects were associated with an increased energy expenditure. Moreover, BG-treated mice enhanced the production of hepatic BAs, which may be connected with the activation of farnesoid X receptor (FXR) signaling in the liver and inhibition of FXR signaling in the ileum. Our results suggest that BG prevents fat accumulation by increasing energy expenditure, a mechanism associated with major changes in the composition of hepatic BAs.

Dihydromyricetin prevents obesity via regulating bile acid metabolism associated with the farnesoid X receptor in ob/ob mice.

With the high incidence of obesity around the globe, the potential role of bile acid metabolism and gut microbiota in modulating obesity aroused great enthusiasm. Here we studied the anti-obesity effect of dihydromyricetin (DHM), the main biologically active component in Ampelopsis grossedentata, which was applied for thousands of years in the form of tea beverages. A 12-week treatment of DHM significantly reduced body weight gain of the ob/ob mice. Meanwhile, serum parameters that are closely associated with obesity, including levels of total cholesterol, triglyceride, low density lipoprotein, nonestesterified fatty acid, and activity of alanine amino transferase and aspartate aminotransferase were all lower than the non-treated ob/ob mice. Using LC-MS/MS technology, we determined that DHM could enhance the bile acid (BA) conjugation, BA transport in the liver and inhibit the reabsorption of BAs in the ileum mediated by farnesoid X receptor (FXR)-related signalling pathways. Key genes in regulating enterohepatic circulation of BAs were verified by qPCR, and regulators related to FXR pathway were verified by western-blot. We also found that DHM could effectively inhibit the de novo lipogenesis through FXR-SREBP-1C pathway in the liver. In addition, metagenome analysis of the microbiota showed that DHM may affect the activity of bile salt hydrolase by inhibiting the level of Lactobacillus. In summary, the anti-obesity effect of DHM may be attributed to its positive effects on BA metabolism associated with FXR activation.

LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production.

Background & AimsLiver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis.MethodsWe generated mice with IEC-specific deletion of LKB1 (LKB1ΔIEC) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, metagenomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis.ResultsLKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1ΔIEC mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA synthesis, was found in the small intestine (SI) ileum of LKB1ΔIEC mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-βMCA) were observed in the SI of LKB1ΔIEC mice. Moreover, LKB1ΔIEC mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1ΔIEC mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure.ConclusionsLKB1 in IECs manages BA homeostasis by controlling FGF15/19 production.

Association of Maternal Thyroid Function with Gestational Hypercholanemia.

Background: High bile acid concentration is associated with adverse perinatal outcomes (i.e., stillbirth and preterm birth) and experimental studies indicate that thyroid hormone regulates bile acid metabolism, but this has not yet been translated to clinical data in pregnant women. We aim to explore the association of thyroid function with bile acid concentrations and the risk of gestational hypercholanemia. Methods: This study comprised 68,016 singleton pregnancies without known thyroid or hepatobiliary diseases before pregnancy and thyroid medication based on a prospective cohort. Thyroid function and serum total bile acid (TBA) were routinely screened in both early (9-13 weeks) and late pregnancy (32-36 weeks). Hypercholanemia was defined as serum TBA concentration ≥10 μmol/L. Multiple linear regression models and multiple logistic regression models were performed. Results: A higher free thyroxine (fT4) during both early or late pregnancy was associated with a higher TBA concentration and a higher risk of hypercholanemia (all p < 0.01). A higher thyrotropin (TSH) in early pregnancy was associated with a higher TBA concentration in early pregnancy (p = 0.0155), but with a lower TBA concentration during later pregnancy (p < 0.0001), and there was no association of TSH with hypercholanemia. Overt hyperthyroidism in late pregnancy was associated with a 2.12-fold higher risk of hypercholanemia ([confidence interval; CI 1.12-4.03], p = 0.021) and subclinical hyperthyroidism during later pregnancy was associated with a 1.5-fold higher risk of hypercholanemia ([CI 1.14-1.97], p = 0.0034). Sensitivity analyses indicated that a high fT4 throughout pregnancy was associated with a higher risk of hypercholanemia rather than only in early or late pregnancy. Conclusions: A higher fT4 concentration during either early or late pregnancy, but not the TSH concentration, is associated with higher TBA and a higher risk of gestational hypercholanemia. Furthermore, hyperthyroidism during pregnancy could be a novel risk factor for hypercholanemia.

Protective mechanism of homologous lactic acid bacteria against cholestatic liver injury in snakehead fish

Cholestatic liver injury, a typical symptom of hepatobiliary syndrome, is usually accompanied by bile acid (BA) metabolism disorders and intestinal microbiota imbalance. Lactic acid bacteria (LAB) play an active role in regulating liver and gallbladder diseases and the balance of intestinal microbiota. In the study, the protective mechanism of homologous LAB (Lactococcus lactis L19, Genbank: MT102745.1) isolated from the intestine of snakehead fish (Channa argus, C. argus) against lithocholic acid (LCA)-induced cholestatic liver injury in C. argus was explored. Biochemical results illustrated that LCA feeding markedly increased the serum AST, ALT, ALP, TBA, TBIL and DBIL activities and treatment with L19 diet reversed the increase of these BA biomarkers. Liver histology results identified the amelioration of LCA-induced cholestasis after L19 treatment. Gene analysis indicated that L19 activated fxr and regulated BA metabolism, including promoted BA transport from the liver into the intestine by inducing the expressions of fxr-target genes bsep, mrp2, mrp3, mrp4, and Ostβ, and reduced BA reabsorption by inhibiting the expression of ntcp. In addition, L19 reduced BA synthesis by inhibiting the expressions of fxr-target genes cyp7a1, cyp8b1, cyp27a1, and hmgcr via the Fxr-Shp signaling pathway, and promoted BA metabolism by inducing the expression of sult2a1. Protein analysis indicated that L19 promoted BA metabolism and transport through activating the Fxr-target proteins Bsep, Shp and Cyp7a1. Intestinal microbiota analysis demonstrated that the LCA group was dominated by Proteobacteria and Chlamydiae, while L19 treatment can reduce the abundance of Proteobacteria, increase the abundance of Firmicutes, and regulate the composition of intestinal microbiota. For the first time, we found that L. lactis L19 can activate Fxr, regulate BA metabolism and intestinal microbiota to exert protective effects against cholestatic liver injury. Therefore, L. lactis L19 might be a potent measure for the prevention against LCA-induced cholestatic liver injury of fish, possibly via Fxr-Bsep and Fxr-Shp signal pathway and intestinal microbiota alteration.

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice.

Bile acid (BA) metabolism is an attractive therapeutic target in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the effect of ilexsaponin A1 (IsA), a major bioactive ingredient of Ilex, on high-fat diet (HFD)-induced NAFLD in mice with a focus on BA homeostasis. Male C57BL/6J mice were fed an HFD to induce NAFLD and were treated with IsA (120 mg/kg) for 8 weeks. The results showed that administration of IsA significantly decreased serum total cholesterol (TC), attenuated liver steatosis, and decreased total hepatic BA levels in HFD-induced NAFLD mice. IsA-treated mice showed increased BA synthesis in the alternative pathway by upregulating the gene expression levels of sterol 27-hydroxylase (CYP27A1) and cholesterol 7b-hydroxylase (CYP7B1). IsA treatment accelerated efflux and decreased uptake of BA in liver by increasing hepatic farnesoid X receptor (FXR) and bile salt export pump (BSEP) expression, and reducing Na+-taurocholic acid cotransporting polypeptide (NTCP) expression. Alterations in the gut microbiota and increased bile salt hydrolase (BSH) activity might be related to enhanced fecal BA excretion in IsA-treated mice. This study demonstrates that consumption of IsA may prevent HFD-induced NAFLD and exert cholesterol-lowering effects, possibly by regulating the gut microbiota and BA metabolism.

Identifying Biomarkers to Predict the Prognosis of Biliary Atresia by Weighted Gene Co-Expression Network Analysis.

The prognosis of children with biliary atresia (BA) after Kasai operation remains difficult to predict, and liver fibrosis is closely related to the prognosis of children with BA. We aimed to find biomarkers for native liver survival (NLS) prediction by weighted gene co-expression network analysis (WGCNA). The biological processes and signal pathways that biomarkers involved in were further analyzed by bioinformatics. Quantitative Real-time PCR, Western blot and immunohistochemistry was performed to detect biomarkers expression. The relationship of biomarkers with clinicopathological characteristics of BA was also investigated. LECT2 was overexpressed or knockdown in LX-2 cells, and the expression of fibrogenic genes such as a-SMA and COL1A1 was quantified. We found that LECT2 mRNA expression was higher in BA liver tissues compared with normal liver tissues. Bioinformatics showed that LECT2 mainly played a fibrosis-promoting role in the development in BA by regulating bile acid metabolism and promoting inflammatory response. LECT2 immunohistochemistry scores of BA children were higher than control group (p = 0.001). Survival analysis revealed that LECT2 high expression is an unfavorable prognostic factor for native liver survival in BA patients. Additionally, the high LECT2 expression was an independent prognostic factor affecting native liver survival (HR 3.702, 95%CI:2.085–6.575, p = 0.001). LECT2 modulates TGF-β mediated a-SMA and COL1A1 expression in LX-2 cells. siRNA-LECT2 inhibits the expression of a-SMA and COL1A1 in LX-2 cells. Overexpression of LECT2 resulted in an increase in a-SMA and COL1A1 expression. Knockdown of LECT2 inhibits the proliferation and increase apoptosis in activated LX-2 cells. LECT2 may act as a new prognostic biomarker for native liver survival in BA patients.

Policosanol alleviates hepatic lipid accumulation by regulating bile acids metabolism in C57BL6/mice through AMPK-FXR-TGR5 cross-talk.

Policosanol exhibits a lipid accumulation alleviating effect, but the underlying mechanisms remains unclear. Bile acids are a significant factor in regulating cholesterol and lipid metabolism homeostasis in mammals. This study was aimed to elucidate the alleviating effect and underlying mechanisms of policosanol on hepatic lipid accumulation through bile acid (BA) metabolism. Policosanol supplementation significantly reduced hepatic triglycerides (19.29%), cholesterol (30.38%) in high fat diet (HFD) induced obese mice (P<0.05). Furthermore, compared with the control group, HFD decreased the levels of total BAs (TBAs, 37.67%) and cholic acid (CA, 62.74%) in the serum of mice (P<0.05). Meanwhile, compared to HFD group, policosanol also increased the level of secondary BAs (SBAs) and muricholic acids (MCAs, P<0.05). qRT-PCR combined with protein level analysis revealed that policosanol significantly decreased sterol regulatory element-binding protein (SREBP-1c) and CD36, and increased the expression level of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1, P<0.05). Additionally, in the liver, policosanol was found downregulated the expression of farnesoid X receptor (FXR)-small heterodimer partner (SHP), and activate the Takeda G-coupled protein receptor 5 (TGR5)-adenosine-monophosphate-activated protein kinase (APMK) signaling pathway (P<0.05). Peroxisome proliferator activated receptor (PPAR)-α, hormone sensitive lipase (HSL), and carnitine palmitoyltransferase (CPT)-1α also significantly increased in HP group (P<0.05). The aforementioned results reveal that the potential mechanism of policosanol in alleviating liver lipid accumulation is to promote BA synthesis and lipolysis through regulating the cross-talk of the AMPK-FXR-TGR5. New insight for the application of policosanol as an anti-fatty liver functional food ingredient or supplement is also provided. PRACTICAL APPLICATION: Policosanol is an important active component of cereals and insect waxes (15-80%). However, almost no policosanol in refined foods such as clear corn germ oil and wheat flour. This study showed that oral administration of policosanol can significantly reduce triglyceride and cholesterol levels in the liver through affecting AMPK-TGR5-FXR cross-talk, whereas no significant toxicological effect is reported in human and mouse models. This study may provide theoretical support for the theory of dietary structure and the development of dietary supplements to improve lipid metabolism targeting the "bile acid-AMPK-TGR5" pathway.

New Insights of Anti-Hyperglycemic Agents and Traditional Chinese Medicine on Gut Microbiota in Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic disease characterized by chronic hyperglycemia. Human microbiota, which is regarded as a “hidden organ”, plays an important role in the initiation and development of T2DM. In addition, anti-hyperglycemic agents and traditional Chinese medicine may affect the composition of gut microbiota and consequently improve glucose metabolism. However, the relationship between gut microbiota, T2DM and anti-hyperglycemic agents or traditional Chinese medicine is poorly understood. In this review, we summarized pre-clinical and clinical studies to elucidate the possible underlying mechanism. Some anti-hyperglycemic agents and traditional Chinese medicine may partly exert hypoglycemic effects by altering the gut microbiota composition in ways that reduce metabolic endotoxemia, maintain the integrity of intestinal mucosal barrier, promote the production of short-chain fatty acids (SCFAs), decrease trimethylamine-N-oxide (TMAO) and regulate bile acid metabolism. In conclusion, gut microbiota may provide some new therapeutic targets for treatment of patients with diabetes mellitus.

Mechanism of Paeoniflorin on ANIT-Induced Cholestatic Liver Injury Using Integrated Metabolomics and Network Pharmacology.

Background: Paeoniflorin (PF), the major active compound isolated from the roots of Paeonia lactiflora Pall., has been used in the treatment of severe hepatic diseases for several decades and displays bright prospects in liver protective effect. However, its biological mechanism that regulates bile acid metabolism and cholestatic liver injury has not been fully elucidated. Our study aims to investigate the mechanism by which PF in the treatment of cholestatic liver injury using a comprehensive approach combining metabolomics and network pharmacological analysis.Methods: The hepatoprotective effect of PF against cholestasis liver injury, induced by α-naphthylisothiocyanate (ANIT), was evaluated in rats. The serum biochemical indices including ALT, AST, TBA, TBIL, ALP, ALB, and the pathological characteristics of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to explore the feces of rats with ANIT-induced cholestatic liver injury treated with PF and the potential biomarkers were screened by metabolomics. The targets for the regulation of potential biomarkers by PF were screened by network pharmacology, and then the relevant key targets were verified by immunohistochemical and western blotting methods.Results: PF significantly improved serum indexes and alleviated liver histological damage. Metabolomics analyses showed that the therapeutic effect of PF is mainly associated with the regulation of 13 metabolites involved in 16 metabolic pathways. The “PF-targets-metabolites” interaction network was constructed, and then five key targets including CDC25B, CYP2C9, MAOB, mTOR, and ABCB1 that regulated the potential biomarkers were obtained. The above five targets were further verified by immunohistochemistry and western blotting, and the results showed that PF significantly improved the expression of key proteins regulating these biomarkers.Conclusion: Our study provides direct evidence for the modulatory properties of PF treatment on ANIT-induced cholestatic liver injury using metabolomics and network pharmacology analyses. PF exhibits favorable pharmacological effect by regulating related signal pathways and key targets for biomarkers. Therefore, these findings may help better understand the complex mechanisms and provide a new and effective approach to the treatment of cholestatic liver injury.

Novel Metabolic Regulation of Bile Acid Responses to Low Cholesterol in Whole-Grain-Diet-Fed Mice.

Hypercholesterolemia is a major risk factor for chronic metabolic diseases. Nevertheless, a whole-grain diet could ameliorate this issue in a number of ways, including by regulating bile acid metabolism. However, the potential mechanism is unclear. The aim of the current study is to explore the effects of whole-grain diets (brown rice diet and whole wheat diet) on bile acid homeostasis. After intervention for 8 weeks in mouse model, whole-grain diets showed reduced feed conversion ratio, and the lipid levels (total cholesterol (TC) and triglycerides (TG)) were also meliorated in the serum and liver of mice. Moreover, whole-grain diets reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (cholesterol synthesis) in the liver of mice. Interestingly, whole-grain diets not only promoted the mRNA expressions of low-density lipoprotein receptor (LDLR), ATP binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) (reverse cholesterol transport) but also facilitated the expressions of cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7a1) and cytochrome P450, family 27, subfamily a, polypeptide 1 (CYP27a1) (bile acid synthesis). Further study found that whole-grain diets promoted intestinal bile acid reabsorption and reduced bile acid excretion. Our study provided a novel metabolic regulation of bile acids in response to reduced cholesterol levels induced by whole-grain diets.

Sodium butyrate alleviates cholesterol gallstones by regulating bile acid metabolism

Cholesterol overloading and bile acid metabolic disorders play an important role in the onset of cholesterol gallstone (CGS). Short-chain fatty acids (SCFAs) can regulate bile acid metabolism by modulating the gut microbiota. However, the role and mechanism by which sodium butyrate (NaB) targets bile acids to attenuate CGS are still unknown. In this study, continuous administration of 12 mg/day for 8 weeks was decreased the incidence of gallstones induced by lithogenic diet (LD) from 100% to 25%. NaB modulated SCFAs and improved the gut microbiota. The remodeling of the gut microbiota changed the bile acid compositions and decreased cecal tauro-α-muricholic acid (T-α-MCA) and tauro-β-muricholic acid (T-β-MCA) which are effective farnesoid X receptor (FXR) antagonists. The quantitative real-time PCR examination showed that NaB significantly increased levels of ileal Fxr, fibroblast growth factor-15 (Fgf-15) and small heterodimer partner (Shp) mRNA and subsequently inhibited bile acid synthesis. In addition, NaB enhanced bile acid excretion by increasing the levels of hepatic multidrug resistance protein 2 (Mdr2) and bile salt export pump (Bsep) mRNA, and it enhanced bile acid reabsorption in the intestine by increasing the levels of ileal bile acid transporter (Ibat) mRNA. In addition, NaB reduced the absorption of cholesterol in the intestine and inhibited the excretion of cholesterol in the liver, which reduced the cholesterol concentration in serum and bile. Furthermore, the protective effects of NaB administration were abolished by FXR antagonists.Taken together, our results suggest that NaB mitigates CGS by modulating the gut microbiota to regulate the FXR-FGF-15/SHP signaling pathway.

Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin

BackgroundLeptin-deficient ob/ob mice and leptin receptor-deficient db/db mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although ob/ob and db/db mice are similarly gaining weight and developing massive obesity, db/db mice are more diabetic than ob/ob mice. It remains still unclear why targeting the same pathway—leptin signaling—leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in ob/ob and db/db mice.ResultsSix-week-old ob/ob and db/db mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between ob/ob and db/db mice. Strikingly, the fat distribution was different, with db/db mice having more subcutaneous and ob/ob mice having more epididymal fat. In addition, liver steatosis was more pronounced in the ob/ob mice than in db/db mice. We also found very distinct inflammatory profiles between ob/ob and db/db mice, with a more pronounced inflammatory tone in the liver for ob/ob mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for db/db mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes.ConclusionTaken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition.DUGQcxDcUnuc9Bgg7Th-A2Video abstract.

Advances in research on the relationship between bile acid, gut microbiota and the occurrence and development of cholangiocarcinoma

Cholangiocarcinoma is a kind of malignant tumor that originates from the bile duct epithelium. Due to its insidious nature, there is no effective early diagnosis and treatment method. Therefore, once it is detected, it is at an advanced stage and has a poor prognosis. Bile acid is the main component of bile, which acts on cholangiocytes through bile acid receptors and plays a key role in the development of cholangiocarcinoma. Gut microbiota can participate in the occurrence of cholangiocarcinoma by regulating bile acid metabolism. This review mainly focuses on the role of bile acid and bile acid receptors in the occurrence and development of cholangiocarcinoma and the impact of gut microbiota in it.