Background During the transition period,cows are prone to negative energy balance,which can lead to a decline in production performance and health in severe cases.In recent years,it has been discovered that bile acids...Background During the transition period,cows are prone to negative energy balance,which can lead to a decline in production performance and health in severe cases.In recent years,it has been discovered that bile acids(BAs)can act not only as fat emulsifiers but also as signaling molecules to regulate body metabolism.Although BAs have been used to some extent in monogastric and aquatic animals,their role in ruminants,particularly in transition cows,remains unclear.Therefore,this study aimed to determine the effects of BAs on the production performance,milk and plasma fatty acid and BA composition,and fecal microbiota in transition dairy cows.Results Forty-six healthy transition Holstein dairy cows with similar conditions were randomly divided into two groups and supplemented with 0 or 20 g/d of BAs from 21 d before the expected calving to 21 d after calving.The production performance was tracked until 60 d after calving.The results indicated that BA supplementation significantly improved postpartum milk fat content and yields as well as the yields of unsaturated fatty acids,monounsaturated fatty acids,and polyunsaturated fatty acids in milk.There was a significant increase in the concentration of triglyceride and the proportion of C≤16 fatty acids in the plasma of cows supplemented with BAs,while the concentration of β-hydroxybutyrate and the proportion of C>16 fatty acids in the plasma decreased significantly.BA supplementation significantly altered the composition of the fecal bacterial community and increased the relative abundance of bacteria beneficial for BA metabolism and transformation(Romboutsia,Clostridium sensu_stricto_6,and Clostridium sensu_stricto_1).Functional prediction analysis showed that the relative abundance of bile salt hydrolase,7 α-hydroxysteroid dehydrogenase,and BA inducible E as well as the pathways related to BA metabolism also significantly increased in cows supplemented BAs.In addition,BA supplementation significantly altered the composition of plasma and fecal BAs,particularly increasing circulating secondary BA concentration,which might induce the complete oxidation of fatty acids in the liver and further reduce the concentration of β-hydroxybutyrate.Conclusions These findings highlight the potential benefits of BA supplementation in improving milk yields and quality,as well as influencing metabolic pathways in transition dairy cows.Meanwhile,further studies are needed to elucidate the underlying mechanisms and explore the broader implications of these results by using more tissue samples.展开更多
BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the mali...BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.展开更多
The liver is a central metabolic organ that regulates numerous physiological processes,including glucose and lipid metabolism,detoxification,and the synthesis of essential proteins and bile.Bile acids(BAs),synthesized...The liver is a central metabolic organ that regulates numerous physiological processes,including glucose and lipid metabolism,detoxification,and the synthesis of essential proteins and bile.Bile acids(BAs),synthesized from cholesterol in hepatocytes,not only facilitate the emulsification and absorption of dietary fats but also act as potent signaling molecules through receptors such as the farnesoid X receptor(FXR)and Takeda G-protein-coupled receptor 5.Metabolic dysfunction-associated steatotic liver disease(MASLD)is a leading cause of chronic liver disease globally,closely linked with obesity,insulin resis-tance,and other components of metabolic syndrome.In MASLD,the metabolism of BAs is markedly disrupted,resulting in alterations in their synthesis,compo-sition,and signaling activity.These changes contribute to hepatic steatosis,inflammation,and fibrosis,thereby exacerbating metabolic dysfunction and liver damage.The altered profiles and signaling activity of BAs in MASLD patients suggest that BAs act not only as biomarkers of disease severity,but also as active mediators of its pathogenesis.Modulators of BA signaling pathways,especially FXR agonists,are the focus of intense research for their potential to beneficially influence liver steatosis and inflammation in MASLD.Recent research has yielded promising results,indicating potential therapeutic application and the introduction of novel agents aimed at modulating BA homeostasis and function.This minireview outlines the physiological roles of BAs,seeks to advance the elucidation of the mechanisms by which their dysregulation contributes to MASLD progression,and highlights current and emerging therapeutic approa-ches.A deeper understanding of these complex interactions is essential for improving the diagnosis,prognosis and treatment of MASLD.展开更多
BACKGROUND Cholangiocarcinoma(CCA)is a highly aggressive malignancy with limited therapeutic options.Dysregulation of the Hippo-yes-associated protein(YAP)signaling pathway plays a key role in tumor progression,but th...BACKGROUND Cholangiocarcinoma(CCA)is a highly aggressive malignancy with limited therapeutic options.Dysregulation of the Hippo-yes-associated protein(YAP)signaling pathway plays a key role in tumor progression,but the effects of distinct bile acids on this pathway remain unclear.AIM To investigate the roles of glycochenodeoxycholic acid(GDCA)and deoxycholic acid(DCA)in CCA progression through Hippo-YAP signaling and to evaluate the effects of YAP-targeted interventions.METHODS The in vitro experiments were performed using HuCCT1 CCA cells treated with GDCA,DCA,and combinations with a YAP inhibitor(verteporfin)or agonist(GA-017).Key molecular changes in the Hippo-YAP pathway were assessed by western blot,immunofluorescence,and reverse transcription quantitative realtime polymerase chain reaction.Functional assays,including Cell Counting Kit-8,5-ethynyl-2’-deoxyuridine,Transwell,and terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate-nick end labelling,were conducted to evaluate cell proliferation,migration,invasion,and apoptosis.In vivo,nude mice bearing subcutaneous HuCCT1 tumors were treated with GDCA,DCA,or combined YAP modulators.Tumor growth was monitored,and molecular analyses of tumor tissues were performed using western blot.RESULTS The GDCA significantly activated YAP by reducing mammalian STE20-like protein kinase 1 and large tumor suppressor 1 phosphorylation,promoting YAP nuclear translocation,and enhancing tumor cell proliferation,migration,and invasion.In contrast,DCA inhibited YAP activation,suppressed tumor cell functions,and increased apoptosis.GDCA combined with YAP inhibitors attenuated its tumor-promoting effects,while DCA combined with YAP agonists reversed its inhibitory effects.In vivo,GDCA accelerated tumor growth,while DCA reduced tumor size and weight,with molecular changes consistent with in vitro findings.CONCLUSION The GDCA and DCA exert opposing effects on CCA progression through Hippo-YAP signaling.GDCA promotes tumor growth via YAP activation,while DCA inhibits these processes.YAP-targeted interventions demonstrate therapeutic potential,providing insights into new treatment strategies for CCA.展开更多
Gallic acid(GA),a plant phenol ubiquitously present in fruits and vegetables,has demonstrated efficacy in ameliorating ulcerative colitis(UC).Despite previous reports,the precise mechanism of GA's therapeutic acti...Gallic acid(GA),a plant phenol ubiquitously present in fruits and vegetables,has demonstrated efficacy in ameliorating ulcerative colitis(UC).Despite previous reports,the precise mechanism of GA's therapeutic action remains elusive.Herein,the present study aims to delineate the mechanism underlying the anti-UC effects of GA by focusing on the interplay of gut microbiota,microbial and host cometabolites,and gut immune regulation.The findings revealed that GA treatment improved the colitis symptoms and systematic inflammatory response,reliant on gut microbiota,as evidenced by microbiota depletion and fecal microbiota transplantation.According to the 16S r DNA sequencing results,GA altered the gut microbiota community structure and upregulated the biosynthesis of secondary bile acids(SBAs).Metabolomics and flow cytometry(FCS)analysis revealed a substantial increase in SBAs production,including ursodeoxycholic acid(UDCA),lithocholic acid(LCA),3-oxo-lithocholic acid(3-oxo-LCA)and iso-allolithocholic acid(Isoallo LCA),which further upregulated the proportion of regulatory T(Treg)cells and downregulated the proportion of T helper type 17(Th17)cells in the colon,ultimately resulting in an improved Treg/Th17 balance.Further FCS and real-time quantitative PCR assays provided mechanistic insights,demonstrating that UDCA and Isoallo LCA facilitate Treg cell differentiation through the upregulation of nuclear hormone receptor 4A1(NR4A1).This research elucidated that GA effectively mitigates colitis by modulating the Treg/Th17 balance,facilitated by the enhanced synthesis of microbiota-derived SBAs.These insights unveil innovative pathways through which GA exerts its anti-UC effects,emphasizing the potential therapeutic benefits of incorporating a GAenriched diet into UC management.展开更多
Background Salmonella Typhimurium(S.Typhimurium)is a common pathogenic microorganism and poses a threat to the efficiency of poultry farms.As signaling molecules regulating the interaction between the host and gut mic...Background Salmonella Typhimurium(S.Typhimurium)is a common pathogenic microorganism and poses a threat to the efficiency of poultry farms.As signaling molecules regulating the interaction between the host and gut microbiota,bile acids(BAs)play a protective role in maintaining gut homeostasis.However,the antibacterial effect of BAs on Salmonella infection in broilers has remained unexplored.Therefore,the aim of this study was to investigate the potential role of feeding BAs in protecting against S.Typhimurium infection in broilers.Methods A total of 1441-day-old Arbor Acres male broilers were randomly assigned to 4 groups,including non-challenged birds fed a basal diet(CON),S.Typhimurium-challenged birds(ST),S.Typhimurium-challenged birds treated with 0.15 g/kg antibiotic after infection(ST-ANT),and S.Typhimurium-challenged birds fed a basal diet supplemented with 350 mg/kg of BAs(ST-BA).Results BAs supplementation ameliorated weight loss induced by S.Typhimurium infection and reduced the colonization of Salmonella in the liver and small intestine in broilers(P<0.05).Compared to the ST group,broilers in ST-BA group had a higher ileal mucosal thickness and villus height,and BAs also ameliorated the increase of diamine oxidase(DAO)level in serum(P<0.05).It was observed that the mucus layer thickness and the number of villous and cryptic goblet cells(GCs)were increased in the ST-BA group,consistent with the upregulation of MUC2 gene expression in the ileal mucosa(P<0.05).Moreover,the m RNA expressions of Toll-like receptor 5(TLR5),Toll-like receptor 4(TLR4),and interleukin 1 beta(IL1b)were downregulated in the ileum by BAs treatment(P<0.05).16S rDNA sequencing analysis revealed that,compared to ST group,BAs ameliorated the decreases in Bacteroidota,Bacteroidaceae and Bacteroides abundances,which were negatively correlated with serum DAO activity,and the increases in Campylobacterota,Campylobacteraceae and Campylobacter abundances,which were negatively correlated with body weight but positively correlated with serum D-lactic acid(D-LA)levels(P<0.05).Conclusions Dietary BAs supplementation strengthens the intestinal mucosal barrier and reverses dysbiosis of gut microbiota,which eventually relieves the damage to the intestinal barrier and weight loss induced by S.Typhimurium infection in broilers.展开更多
Methionine,an essential amino acid,is abundant in animal protein.High dietary methionine intake is associated with the promotion of colorectal cancer(CRC);however,the mechanisms remain unclear.This study aimed to inve...Methionine,an essential amino acid,is abundant in animal protein.High dietary methionine intake is associated with the promotion of colorectal cancer(CRC);however,the mechanisms remain unclear.This study aimed to investigate the underlying mechanisms of high dietary methionine promoting CRC and evaluate the effect of high dietary methionine on healthy intestine.Our results demonstrated that high dietary methionine intake exhibited a higher incidence and invasion of tumors in azoxymethane/dextran sulfate sodium-induced mice.Meanwhile,the gut microbiota were disturbed,consequently fostering the metabolism of secondary bile acids.The contents of lithocholic acid and deoxycholic acid significantly increased(P<0.01),which further activated the bile acid membrane receptors TGR5,and then the activated TGR5 promoted tumor proliferation through STAT3 and YAP pathways.Pseudo-germ-free mice validated the role of gut microbiota and secondary bile acids in promoting CRC by high dietary methionine.Notably,similar disturbances in gut microbiota and bile acid metabolism were observed in the intestine of healthy mice with high dietary methionine intake.In conclusion,dysregulation of bile acid metabolism and activation of the corresponding receptor TGR5 were mechanisms promoting CRC associated with high dietary methionine intake.展开更多
The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocy...The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.展开更多
Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious eff...Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.展开更多
AIM： To investigate whether high-fat-feeding is associ- ated with increased intestinal permeability via altera- tions in bile acid metabolism.METHODS： Male C57BI/6J mice were fed on a high-fat （n = 26） or low-fat ...AIM： To investigate whether high-fat-feeding is associ- ated with increased intestinal permeability via altera- tions in bile acid metabolism.METHODS： Male C57BI/6J mice were fed on a high-fat （n = 26） or low-fat diet （n = 24） for 15 wk. Intestinal permeability was measured from duodenum, jejunum, ileum and colon in an Ussing chamber system using 4 kDa FITC-labeled dextran as an indicator. Fecal bile ac- ids were analyzed with gas chromatography. Segments of jejunum and colon were analyzed for the expression of farnesoid X receptor （FXR） and tumor necrosis factor展开更多
BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profil...BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.展开更多
BACKGROUND Bile acids(BAs)have attracted attention in the research of irritable bowel syndrome with predominant diarrhea(IBS-D)due to their ability to modulate bowel function and their tight connection with the gut mi...BACKGROUND Bile acids(BAs)have attracted attention in the research of irritable bowel syndrome with predominant diarrhea(IBS-D)due to their ability to modulate bowel function and their tight connection with the gut microbiota.The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations.We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome.AIM To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.METHODS Fifty-five IBS-D patients diagnosed according to the Rome Ⅳ criteria and twentyeight age-,sex-,and body mass index-matched healthy controls(HCs)were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital.First,clinical manifestations were assessed with standardized questionnaires,and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system.Fecal primary BAs including cholic acid(CA)and chenodeoxycholic acid(CDCA),secondary BAs including deoxycholic acid(DCA),lithocholic acid(LCA),and ursodeoxycholic acid(UDCA)as well as the corresponding tauro-and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry.The gut microbiota was analyzed using 16S rRNA gene sequencing.Correlations between fecal BAs with clinical features and gut microbiota were explored.RESULTS Fecal CA(IBS-D:3037.66[282.82,6917.47]nmol/g,HC:20.19[5.03,1304.28]nmol/g;P<0.001)and CDCA(IBS-D:1721.86[352.80,2613.83]nmol/g,HC:57.16[13.76,1639.92]nmol/g;P<0.001)were significantly increased,while LCA(IBSD:1621.65[58.99,2396.49]nmol/g,HC:2339.24[1737.09,2782.40];P=0.002)and UDCA(IBS-D:8.92[2.33,23.93]nmol/g,HC:17.21[8.76,33.48]nmol/g;P=0.025)were significantly decreased in IBS-D patients compared to HCs.Defecation frequency was positively associated with CA(r=0.294,P=0.030)and CDCA(r=0.290,P=0.032)and negatively associated with DCA(r=−0.332,P=0.013)and LCA(r=−0.326,P=0.015)in IBS-D patients.In total,23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test.The first sensation threshold was negatively correlated with CDCA(r=−0.459,P=0.028)in IBS-D patients.Furthermore,the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients(P<0.001),and 12 genera were significantly lower in IBS-D patients than in HCs(P<0.05),with 6 belonging to Ruminococcaceae.Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects.CONCLUSION The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis,especially the reduction of genera in Ruminococcaceae.展开更多
The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and...The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites.The interaction between the gut microbiome and bile acids is bidirectional.The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes.Similarly,bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system.The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases,especially liver diseases.As essential mediators of the gut-liver crosstalk,bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1.Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases.We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.展开更多
AIM: To examine the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in rat esophageal lesions induced by reflux of duodenal contents.
Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glu...Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glucose metabolism and modulate temperature and energy homeostasis. Furthermore, bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death. Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors, of intracefular kinases and of the plasma membranebound, G-protein coupled bile acid receptor TGRS/Gpbar-1.展开更多
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease.As a result of the interaction b...Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease.As a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption.With the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors.Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal immunology.Inflammatory bowel disease can be treated in new ways by using these potential molecules.This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications.In addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.展开更多
In the present study, we aimed to investigate the underlying mechanism of acetaminophen（APAP）-induced hepatotoxicity by measuring the expression levels of liver transporters and concentrations of bile acids（BAs） i...In the present study, we aimed to investigate the underlying mechanism of acetaminophen（APAP）-induced hepatotoxicity by measuring the expression levels of liver transporters and concentrations of bile acids（BAs） in rat plasma and liver. SD rats（42） were randomly assigned into six groups, including 6-h control group, APAP 6-h group, 12-h control group, APAP 12-h group, 24-h control group and APAP 24-h group. The estimation study of BAs in plasma and liver was performed on LC-MS/MS. The levels of bile salt export pump（Bsep）, multidrug resistant protein 2（Mrp2）, multidrug resistant protein 4（Mrp4）, Na＋/taurocholate cotransporting polypeptide（Ntcp） and organic anion transporting polypeptide 2（Oatp2） in the liver were analyzed by Western blotting analysis. Compared with the corresponding control groups, no difference was found in the BA levels and the expressions of BA transporters in the plasma and liver after 6 h of APAP administration. While BA levels were significantly decreased in the plasma and increased in the liver after 12 h of APAP administration（P0.05）; and the expressions of Bsep and Mrp2 were significantly reduced（P0.05）. After 24 h of APAP administration, BA levels were both greatly increased in the plasma and liver（P0.05）; and the expressions of Mrp4 and Oatp2 were significantly decreased（P0.05）. In response to over-dose APAP, Bsep, Mrp2, Mrp4 and Oatp2 levels were reduced at different time points, causing the accumulation of BAs, and such accumulation may ultimately lead to the severe liver injury, which could be an underlying mechanism of the APAP-induced hepatotoxicity.展开更多
Intestinal flora plays a key role in nutrient absorption,metabolism and immune defense,and is considered to be the cornerstone of maintaining the health of human hosts.Bile acids synthesized in the liver can not only ...Intestinal flora plays a key role in nutrient absorption,metabolism and immune defense,and is considered to be the cornerstone of maintaining the health of human hosts.Bile acids synthesized in the liver can not only promote the absorption of fat-soluble substances in the intestine,but also directly or indirectly affect the structure and function of intestinal flora.Under the action of intestinal flora,bile acids can be converted into secondary bile acids,which can be reabsorbed back to the liver through the enterohepatic circulation.The complex dialogue mechanism between intestinal flora and bile acids is involved in the development of intestinal inflammation such as inflammatory bowel disease(IBD).In this review,the effects of intestinal flora,bile acids and their interactions on IBD and the progress of treatment were reviewed.展开更多
Tanreqing(TRQ), a traditional Chinese medicine(TCM) formula, can alleviate liver injury and improve liver function. Its pharmacological mechanisms of actions are still unclear due to its complex components and multi-t...Tanreqing(TRQ), a traditional Chinese medicine(TCM) formula, can alleviate liver injury and improve liver function. Its pharmacological mechanisms of actions are still unclear due to its complex components and multi-target natures. Metabolomic study is an effective approach to investigating drug pharmacological actions, new diagnostic markers, and potential mechanisms of actions. In the present study, a new strategy was used to evaluate the protective effect of TRQ capsule against carbon tetrachloride(CCl_4)-induced hepatotoxicity in rats, by analyzing metabolic profiling of endogenous bile acids(BAs) along with biochemical and histological analyses. BAs concentrations were determined by ultra-performance liquid chromatography coupled with quadrupole mass spectrometry(UPLC-MS). Principal component analysis and partial least squares discriminant analysis were then employed to analyze the UPLC-MS results and compare the hepatoprotective effect of TRQ capsule in different groups at the doses of 0.36, 1.44, and 2.88 g·kg^(-1) body weight, respectively. Moreover, our results suggested that taurocholic acid(TCA) and taurohyodesoxycholic acid(THDCA) were the most important biochemical markers, which were indicative of CCl_4-induced acute hepatic damage and hepatoprotective effect of TRQ capsule. Therefore, this new strategy would be an excellent alternative method for evaluating hepatoprotective effect and proposing potential mechanisms of action for other drugs as well.展开更多
BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune diseases.The golden standard for diagnosis of these diseases requires a liver biopsy.Liver biopsy is not widely accept...BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune diseases.The golden standard for diagnosis of these diseases requires a liver biopsy.Liver biopsy is not widely accepted by patients because of its invasive nature,and atypical liver histology can confuse diagnosis.In view of the lack of effective diagnostic markers for PBC and AIH,combined with the increasingly mature metabolomics technologies,including full-contour metabolomics and target.AIM To determine non-invasive,reliable,and sensitive biochemical markers for the differential diagnosis of PBC and AIH.METHODS Serum samples from 54 patients with PBC,26 patients with AIH and 30 healthy controls were analyzed by Ultra-high performance liquid chromatographytandem mass spectrometry serum metabolomics.The metabolites and metabolic pathways were identified,and the metabolic changes,metabolic pathways and inter-group differences between PBC and AIH were analyzed.Fifteen kinds of target metabolites of bile acids(BAs)were quantitatively analyzed by SRM,and the differential metabolites related to the diagnosis of PBC were screened by receiver operating characteristic curve analysis.RESULTS We found the changes in the levels of amino acids,BAs,organic acids,phospholipids,choline,sugar,and sugar alcohols in patients with PBC and AIH.Furthermore,the SRM assay of BAs revealed the increased levels of chenodeoxycholic acid,lithocholic acid(LCA),taurolithocholic acid(TLCA),and LCA+TLCA in the PBC group compared with those in the AIH group.The levels of BAs may be used as biomarkers to differentiate PBC from AIH diseases.The levels of glycochenodeoxycholic acid,glycochenodeoxycholic sulfate,and taurodeoxycholic acid were gradually elevated with the increase of Child-Pugh class,which was correlated with the severity of disease.CONCLUSION The results demonstrated that the levels of BAs could serve as potential biomarkers for the early diagnosis and assessment of the severity of PBC and AIH.展开更多
基金supported by the National Center of Technology Innovation for Dairy(No.2024-JSGG-021)the National Natural Science Foundation of China(No.32102570)the Key Research and Development Project of Ningxia(No.2024BBF01006).
文摘Background During the transition period,cows are prone to negative energy balance,which can lead to a decline in production performance and health in severe cases.In recent years,it has been discovered that bile acids(BAs)can act not only as fat emulsifiers but also as signaling molecules to regulate body metabolism.Although BAs have been used to some extent in monogastric and aquatic animals,their role in ruminants,particularly in transition cows,remains unclear.Therefore,this study aimed to determine the effects of BAs on the production performance,milk and plasma fatty acid and BA composition,and fecal microbiota in transition dairy cows.Results Forty-six healthy transition Holstein dairy cows with similar conditions were randomly divided into two groups and supplemented with 0 or 20 g/d of BAs from 21 d before the expected calving to 21 d after calving.The production performance was tracked until 60 d after calving.The results indicated that BA supplementation significantly improved postpartum milk fat content and yields as well as the yields of unsaturated fatty acids,monounsaturated fatty acids,and polyunsaturated fatty acids in milk.There was a significant increase in the concentration of triglyceride and the proportion of C≤16 fatty acids in the plasma of cows supplemented with BAs,while the concentration of β-hydroxybutyrate and the proportion of C>16 fatty acids in the plasma decreased significantly.BA supplementation significantly altered the composition of the fecal bacterial community and increased the relative abundance of bacteria beneficial for BA metabolism and transformation(Romboutsia,Clostridium sensu_stricto_6,and Clostridium sensu_stricto_1).Functional prediction analysis showed that the relative abundance of bile salt hydrolase,7 α-hydroxysteroid dehydrogenase,and BA inducible E as well as the pathways related to BA metabolism also significantly increased in cows supplemented BAs.In addition,BA supplementation significantly altered the composition of plasma and fecal BAs,particularly increasing circulating secondary BA concentration,which might induce the complete oxidation of fatty acids in the liver and further reduce the concentration of β-hydroxybutyrate.Conclusions These findings highlight the potential benefits of BA supplementation in improving milk yields and quality,as well as influencing metabolic pathways in transition dairy cows.Meanwhile,further studies are needed to elucidate the underlying mechanisms and explore the broader implications of these results by using more tissue samples.
文摘BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.
文摘The liver is a central metabolic organ that regulates numerous physiological processes,including glucose and lipid metabolism,detoxification,and the synthesis of essential proteins and bile.Bile acids(BAs),synthesized from cholesterol in hepatocytes,not only facilitate the emulsification and absorption of dietary fats but also act as potent signaling molecules through receptors such as the farnesoid X receptor(FXR)and Takeda G-protein-coupled receptor 5.Metabolic dysfunction-associated steatotic liver disease(MASLD)is a leading cause of chronic liver disease globally,closely linked with obesity,insulin resis-tance,and other components of metabolic syndrome.In MASLD,the metabolism of BAs is markedly disrupted,resulting in alterations in their synthesis,compo-sition,and signaling activity.These changes contribute to hepatic steatosis,inflammation,and fibrosis,thereby exacerbating metabolic dysfunction and liver damage.The altered profiles and signaling activity of BAs in MASLD patients suggest that BAs act not only as biomarkers of disease severity,but also as active mediators of its pathogenesis.Modulators of BA signaling pathways,especially FXR agonists,are the focus of intense research for their potential to beneficially influence liver steatosis and inflammation in MASLD.Recent research has yielded promising results,indicating potential therapeutic application and the introduction of novel agents aimed at modulating BA homeostasis and function.This minireview outlines the physiological roles of BAs,seeks to advance the elucidation of the mechanisms by which their dysregulation contributes to MASLD progression,and highlights current and emerging therapeutic approa-ches.A deeper understanding of these complex interactions is essential for improving the diagnosis,prognosis and treatment of MASLD.
文摘BACKGROUND Cholangiocarcinoma(CCA)is a highly aggressive malignancy with limited therapeutic options.Dysregulation of the Hippo-yes-associated protein(YAP)signaling pathway plays a key role in tumor progression,but the effects of distinct bile acids on this pathway remain unclear.AIM To investigate the roles of glycochenodeoxycholic acid(GDCA)and deoxycholic acid(DCA)in CCA progression through Hippo-YAP signaling and to evaluate the effects of YAP-targeted interventions.METHODS The in vitro experiments were performed using HuCCT1 CCA cells treated with GDCA,DCA,and combinations with a YAP inhibitor(verteporfin)or agonist(GA-017).Key molecular changes in the Hippo-YAP pathway were assessed by western blot,immunofluorescence,and reverse transcription quantitative realtime polymerase chain reaction.Functional assays,including Cell Counting Kit-8,5-ethynyl-2’-deoxyuridine,Transwell,and terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate-nick end labelling,were conducted to evaluate cell proliferation,migration,invasion,and apoptosis.In vivo,nude mice bearing subcutaneous HuCCT1 tumors were treated with GDCA,DCA,or combined YAP modulators.Tumor growth was monitored,and molecular analyses of tumor tissues were performed using western blot.RESULTS The GDCA significantly activated YAP by reducing mammalian STE20-like protein kinase 1 and large tumor suppressor 1 phosphorylation,promoting YAP nuclear translocation,and enhancing tumor cell proliferation,migration,and invasion.In contrast,DCA inhibited YAP activation,suppressed tumor cell functions,and increased apoptosis.GDCA combined with YAP inhibitors attenuated its tumor-promoting effects,while DCA combined with YAP agonists reversed its inhibitory effects.In vivo,GDCA accelerated tumor growth,while DCA reduced tumor size and weight,with molecular changes consistent with in vitro findings.CONCLUSION The GDCA and DCA exert opposing effects on CCA progression through Hippo-YAP signaling.GDCA promotes tumor growth via YAP activation,while DCA inhibits these processes.YAP-targeted interventions demonstrate therapeutic potential,providing insights into new treatment strategies for CCA.
基金funded by the National Natural Science Foundation of China(82174104 and 22104158)Guangzhou Science and Technology Program(2023B03J1382)+2 种基金Nansha Science and Technology Program(2022ZD004)Science and Technology Innovation Strategy of Guangdong Province(2020A1111350001)Natural Science Foundation of Hunan Province(2021JJ40041)。
文摘Gallic acid(GA),a plant phenol ubiquitously present in fruits and vegetables,has demonstrated efficacy in ameliorating ulcerative colitis(UC).Despite previous reports,the precise mechanism of GA's therapeutic action remains elusive.Herein,the present study aims to delineate the mechanism underlying the anti-UC effects of GA by focusing on the interplay of gut microbiota,microbial and host cometabolites,and gut immune regulation.The findings revealed that GA treatment improved the colitis symptoms and systematic inflammatory response,reliant on gut microbiota,as evidenced by microbiota depletion and fecal microbiota transplantation.According to the 16S r DNA sequencing results,GA altered the gut microbiota community structure and upregulated the biosynthesis of secondary bile acids(SBAs).Metabolomics and flow cytometry(FCS)analysis revealed a substantial increase in SBAs production,including ursodeoxycholic acid(UDCA),lithocholic acid(LCA),3-oxo-lithocholic acid(3-oxo-LCA)and iso-allolithocholic acid(Isoallo LCA),which further upregulated the proportion of regulatory T(Treg)cells and downregulated the proportion of T helper type 17(Th17)cells in the colon,ultimately resulting in an improved Treg/Th17 balance.Further FCS and real-time quantitative PCR assays provided mechanistic insights,demonstrating that UDCA and Isoallo LCA facilitate Treg cell differentiation through the upregulation of nuclear hormone receptor 4A1(NR4A1).This research elucidated that GA effectively mitigates colitis by modulating the Treg/Th17 balance,facilitated by the enhanced synthesis of microbiota-derived SBAs.These insights unveil innovative pathways through which GA exerts its anti-UC effects,emphasizing the potential therapeutic benefits of incorporating a GAenriched diet into UC management.
基金The National Key R&D Program of China(2023YFD2000802)provided financial contributions。
文摘Background Salmonella Typhimurium(S.Typhimurium)is a common pathogenic microorganism and poses a threat to the efficiency of poultry farms.As signaling molecules regulating the interaction between the host and gut microbiota,bile acids(BAs)play a protective role in maintaining gut homeostasis.However,the antibacterial effect of BAs on Salmonella infection in broilers has remained unexplored.Therefore,the aim of this study was to investigate the potential role of feeding BAs in protecting against S.Typhimurium infection in broilers.Methods A total of 1441-day-old Arbor Acres male broilers were randomly assigned to 4 groups,including non-challenged birds fed a basal diet(CON),S.Typhimurium-challenged birds(ST),S.Typhimurium-challenged birds treated with 0.15 g/kg antibiotic after infection(ST-ANT),and S.Typhimurium-challenged birds fed a basal diet supplemented with 350 mg/kg of BAs(ST-BA).Results BAs supplementation ameliorated weight loss induced by S.Typhimurium infection and reduced the colonization of Salmonella in the liver and small intestine in broilers(P<0.05).Compared to the ST group,broilers in ST-BA group had a higher ileal mucosal thickness and villus height,and BAs also ameliorated the increase of diamine oxidase(DAO)level in serum(P<0.05).It was observed that the mucus layer thickness and the number of villous and cryptic goblet cells(GCs)were increased in the ST-BA group,consistent with the upregulation of MUC2 gene expression in the ileal mucosa(P<0.05).Moreover,the m RNA expressions of Toll-like receptor 5(TLR5),Toll-like receptor 4(TLR4),and interleukin 1 beta(IL1b)were downregulated in the ileum by BAs treatment(P<0.05).16S rDNA sequencing analysis revealed that,compared to ST group,BAs ameliorated the decreases in Bacteroidota,Bacteroidaceae and Bacteroides abundances,which were negatively correlated with serum DAO activity,and the increases in Campylobacterota,Campylobacteraceae and Campylobacter abundances,which were negatively correlated with body weight but positively correlated with serum D-lactic acid(D-LA)levels(P<0.05).Conclusions Dietary BAs supplementation strengthens the intestinal mucosal barrier and reverses dysbiosis of gut microbiota,which eventually relieves the damage to the intestinal barrier and weight loss induced by S.Typhimurium infection in broilers.
基金financially supported by the National Natural Science Foundation of China(32001795)。
文摘Methionine,an essential amino acid,is abundant in animal protein.High dietary methionine intake is associated with the promotion of colorectal cancer(CRC);however,the mechanisms remain unclear.This study aimed to investigate the underlying mechanisms of high dietary methionine promoting CRC and evaluate the effect of high dietary methionine on healthy intestine.Our results demonstrated that high dietary methionine intake exhibited a higher incidence and invasion of tumors in azoxymethane/dextran sulfate sodium-induced mice.Meanwhile,the gut microbiota were disturbed,consequently fostering the metabolism of secondary bile acids.The contents of lithocholic acid and deoxycholic acid significantly increased(P<0.01),which further activated the bile acid membrane receptors TGR5,and then the activated TGR5 promoted tumor proliferation through STAT3 and YAP pathways.Pseudo-germ-free mice validated the role of gut microbiota and secondary bile acids in promoting CRC by high dietary methionine.Notably,similar disturbances in gut microbiota and bile acid metabolism were observed in the intestine of healthy mice with high dietary methionine intake.In conclusion,dysregulation of bile acid metabolism and activation of the corresponding receptor TGR5 were mechanisms promoting CRC associated with high dietary methionine intake.
文摘The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.e.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.
基金Supported by Grants from the NIH (R21CA111513-01A1, 5 RO1 CA119087, and SPORE Grant 1 P50CA95060)grants from the Arizona Biomedical Research Commission (#0012 & #0803)by Biomedical Diagnostics & Research In., Tucson Arizona, and by a VA Merit Review Grant
文摘Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.
基金Supported by The Foundation for Nutrition Research and the Finnish Funding Agency of Technology and Innovation
文摘AIM： To investigate whether high-fat-feeding is associ- ated with increased intestinal permeability via altera- tions in bile acid metabolism.METHODS： Male C57BI/6J mice were fed on a high-fat （n = 26） or low-fat diet （n = 24） for 15 wk. Intestinal permeability was measured from duodenum, jejunum, ileum and colon in an Ussing chamber system using 4 kDa FITC-labeled dextran as an indicator. Fecal bile ac- ids were analyzed with gas chromatography. Segments of jejunum and colon were analyzed for the expression of farnesoid X receptor （FXR） and tumor necrosis factor
基金Supported by National Key Technology Support Program during“12th Five-Year Plan”Period of China,No.2014BAI08B00National Key Research and Development Plan for Precision Medicine Research,No.2017YFC0910002and Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008.
文摘BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.
基金Supported by the National Key Technology Support Program during“12th Five-Year Plan”Period of China,No.2014BAI08B00the Leap-forward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008and the Project“The role of the gut microbiota and metabolites in the pathogenesis of diarrheapredominant irritable bowel syndrome”of China-Japan Friendship Hospital,No.2019-64-K44.
文摘BACKGROUND Bile acids(BAs)have attracted attention in the research of irritable bowel syndrome with predominant diarrhea(IBS-D)due to their ability to modulate bowel function and their tight connection with the gut microbiota.The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations.We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome.AIM To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.METHODS Fifty-five IBS-D patients diagnosed according to the Rome Ⅳ criteria and twentyeight age-,sex-,and body mass index-matched healthy controls(HCs)were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital.First,clinical manifestations were assessed with standardized questionnaires,and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system.Fecal primary BAs including cholic acid(CA)and chenodeoxycholic acid(CDCA),secondary BAs including deoxycholic acid(DCA),lithocholic acid(LCA),and ursodeoxycholic acid(UDCA)as well as the corresponding tauro-and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry.The gut microbiota was analyzed using 16S rRNA gene sequencing.Correlations between fecal BAs with clinical features and gut microbiota were explored.RESULTS Fecal CA(IBS-D:3037.66[282.82,6917.47]nmol/g,HC:20.19[5.03,1304.28]nmol/g;P<0.001)and CDCA(IBS-D:1721.86[352.80,2613.83]nmol/g,HC:57.16[13.76,1639.92]nmol/g;P<0.001)were significantly increased,while LCA(IBSD:1621.65[58.99,2396.49]nmol/g,HC:2339.24[1737.09,2782.40];P=0.002)and UDCA(IBS-D:8.92[2.33,23.93]nmol/g,HC:17.21[8.76,33.48]nmol/g;P=0.025)were significantly decreased in IBS-D patients compared to HCs.Defecation frequency was positively associated with CA(r=0.294,P=0.030)and CDCA(r=0.290,P=0.032)and negatively associated with DCA(r=−0.332,P=0.013)and LCA(r=−0.326,P=0.015)in IBS-D patients.In total,23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test.The first sensation threshold was negatively correlated with CDCA(r=−0.459,P=0.028)in IBS-D patients.Furthermore,the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients(P<0.001),and 12 genera were significantly lower in IBS-D patients than in HCs(P<0.05),with 6 belonging to Ruminococcaceae.Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects.CONCLUSION The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis,especially the reduction of genera in Ruminococcaceae.
基金Supported by National Science and Technology Major Project of China,No.2018ZX10302206.
文摘The intensive crosstalk between the liver and the intestine performs many essential functions.This crosstalk is important for natural immune surveillance,adaptive immune response regulation and nutrient metabolism and elimination of toxic bacterial metabolites.The interaction between the gut microbiome and bile acids is bidirectional.The gut microbiome regulates the synthesis of bile acids and their biological signaling activity and circulation via enzymes.Similarly,bile acids also shape the composition of the gut microbiome by modulating the host’s natural antibacterial defense and the intestinal immune system.The interaction between bile acids and the gut microbiome has been implicated in the pathophysiology of many intestinal and extra intestinal diseases,especially liver diseases.As essential mediators of the gut-liver crosstalk,bile acids regulate specific host metabolic pathways and modulate the inflammatory responses through farnesoid X-activated receptor and G protein-coupled bile acid receptor 1.Several clinical trials have demonstrated the signaling effects of bile acids in the context of liver diseases.We hypothesize the existence of a gut microbiome-bile acids-liver triangle and explore the potential therapeutic strategies for liver diseases targeting the triangle.
文摘AIM: To examine the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in rat esophageal lesions induced by reflux of duodenal contents.
文摘Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile acid, lipid and glucose metabolism and modulate temperature and energy homeostasis. Furthermore, bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death. Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors, of intracefular kinases and of the plasma membranebound, G-protein coupled bile acid receptor TGRS/Gpbar-1.
基金National Natural Science Foundation of China,No.81900466and Hunan Provincial Natural Science Foundation of China,No.2020JJ5307.
文摘Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease.As a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption.With the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors.Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal immunology.Inflammatory bowel disease can be treated in new ways by using these potential molecules.This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications.In addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
基金The National Natural Science Foundation of China(Grant No.81373494 and 81041086)Tianqing Liver Disease Rearch Fund(Grant No.TQGB20180088)
文摘In the present study, we aimed to investigate the underlying mechanism of acetaminophen（APAP）-induced hepatotoxicity by measuring the expression levels of liver transporters and concentrations of bile acids（BAs） in rat plasma and liver. SD rats（42） were randomly assigned into six groups, including 6-h control group, APAP 6-h group, 12-h control group, APAP 12-h group, 24-h control group and APAP 24-h group. The estimation study of BAs in plasma and liver was performed on LC-MS/MS. The levels of bile salt export pump（Bsep）, multidrug resistant protein 2（Mrp2）, multidrug resistant protein 4（Mrp4）, Na＋/taurocholate cotransporting polypeptide（Ntcp） and organic anion transporting polypeptide 2（Oatp2） in the liver were analyzed by Western blotting analysis. Compared with the corresponding control groups, no difference was found in the BA levels and the expressions of BA transporters in the plasma and liver after 6 h of APAP administration. While BA levels were significantly decreased in the plasma and increased in the liver after 12 h of APAP administration（P0.05）; and the expressions of Bsep and Mrp2 were significantly reduced（P0.05）. After 24 h of APAP administration, BA levels were both greatly increased in the plasma and liver（P0.05）; and the expressions of Mrp4 and Oatp2 were significantly decreased（P0.05）. In response to over-dose APAP, Bsep, Mrp2, Mrp4 and Oatp2 levels were reduced at different time points, causing the accumulation of BAs, and such accumulation may ultimately lead to the severe liver injury, which could be an underlying mechanism of the APAP-induced hepatotoxicity.
基金Supported by General Research of Xi’an Science and Technology Planning Project,No.2022JH-YBYJ-0265Shaanxi Province Natural Science Basic Research Program-General Project,No.2019JM-580+1 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.2019-ZZ-JC010Shaanxi Provincial Hospital of Traditional Chinese Medicine,No.2021-07 and No.2018-04。
文摘Intestinal flora plays a key role in nutrient absorption,metabolism and immune defense,and is considered to be the cornerstone of maintaining the health of human hosts.Bile acids synthesized in the liver can not only promote the absorption of fat-soluble substances in the intestine,but also directly or indirectly affect the structure and function of intestinal flora.Under the action of intestinal flora,bile acids can be converted into secondary bile acids,which can be reabsorbed back to the liver through the enterohepatic circulation.The complex dialogue mechanism between intestinal flora and bile acids is involved in the development of intestinal inflammation such as inflammatory bowel disease(IBD).In this review,the effects of intestinal flora,bile acids and their interactions on IBD and the progress of treatment were reviewed.
基金supported by the National Natural Science Foundation of China(No.81403089)the China Postdoctoral Science Foundation(No.2012M520920)
文摘Tanreqing(TRQ), a traditional Chinese medicine(TCM) formula, can alleviate liver injury and improve liver function. Its pharmacological mechanisms of actions are still unclear due to its complex components and multi-target natures. Metabolomic study is an effective approach to investigating drug pharmacological actions, new diagnostic markers, and potential mechanisms of actions. In the present study, a new strategy was used to evaluate the protective effect of TRQ capsule against carbon tetrachloride(CCl_4)-induced hepatotoxicity in rats, by analyzing metabolic profiling of endogenous bile acids(BAs) along with biochemical and histological analyses. BAs concentrations were determined by ultra-performance liquid chromatography coupled with quadrupole mass spectrometry(UPLC-MS). Principal component analysis and partial least squares discriminant analysis were then employed to analyze the UPLC-MS results and compare the hepatoprotective effect of TRQ capsule in different groups at the doses of 0.36, 1.44, and 2.88 g·kg^(-1) body weight, respectively. Moreover, our results suggested that taurocholic acid(TCA) and taurohyodesoxycholic acid(THDCA) were the most important biochemical markers, which were indicative of CCl_4-induced acute hepatic damage and hepatoprotective effect of TRQ capsule. Therefore, this new strategy would be an excellent alternative method for evaluating hepatoprotective effect and proposing potential mechanisms of action for other drugs as well.
基金Supported by Health and Family Planning Commission Project of Jilin Province,No.2016Q043Health and Hygiene Committee Project of Jilin Province,No.2021LC082。
文摘BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune diseases.The golden standard for diagnosis of these diseases requires a liver biopsy.Liver biopsy is not widely accepted by patients because of its invasive nature,and atypical liver histology can confuse diagnosis.In view of the lack of effective diagnostic markers for PBC and AIH,combined with the increasingly mature metabolomics technologies,including full-contour metabolomics and target.AIM To determine non-invasive,reliable,and sensitive biochemical markers for the differential diagnosis of PBC and AIH.METHODS Serum samples from 54 patients with PBC,26 patients with AIH and 30 healthy controls were analyzed by Ultra-high performance liquid chromatographytandem mass spectrometry serum metabolomics.The metabolites and metabolic pathways were identified,and the metabolic changes,metabolic pathways and inter-group differences between PBC and AIH were analyzed.Fifteen kinds of target metabolites of bile acids(BAs)were quantitatively analyzed by SRM,and the differential metabolites related to the diagnosis of PBC were screened by receiver operating characteristic curve analysis.RESULTS We found the changes in the levels of amino acids,BAs,organic acids,phospholipids,choline,sugar,and sugar alcohols in patients with PBC and AIH.Furthermore,the SRM assay of BAs revealed the increased levels of chenodeoxycholic acid,lithocholic acid(LCA),taurolithocholic acid(TLCA),and LCA+TLCA in the PBC group compared with those in the AIH group.The levels of BAs may be used as biomarkers to differentiate PBC from AIH diseases.The levels of glycochenodeoxycholic acid,glycochenodeoxycholic sulfate,and taurodeoxycholic acid were gradually elevated with the increase of Child-Pugh class,which was correlated with the severity of disease.CONCLUSION The results demonstrated that the levels of BAs could serve as potential biomarkers for the early diagnosis and assessment of the severity of PBC and AIH.
