Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

Secondary bile acids and the biliary epithelia: The good and the bad

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.

Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease

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.

Fibroblast growth factor 15,induced by elevated bile acids,mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy

BACKGROUND Fibroblast growth factor(FGF)15/19,which is expressed in and secreted from the distal ileum,can regulate hepatic glucose metabolism in an endocrine manner.The levels of both bile acids(BAs)and FGF15/19 are elevated after bariatric surgery.However,it is unclear whether the increase in FGF15/19 is induced by BAs.Moreover,it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery.AIM To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy(SG).METHODS By calculating and comparing the changes of body weight after SG with SHAM group,we examined the weight-loss effect of SG.The oral glucose tolerance test(OGTT)test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG.By detecting the glycogen content,expression and activity of glycogen synthase as well as the glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(Pepck),we evaluated the hepatic glycogen content and gluconeogenesis activity.We examined the levels of total BA(TBA)together with the farnesoid X receptor(FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery.Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4(FGFR4)with its corresponding signal pathways involved in glucose metabolism were detected.RESULTS After surgery,food intake and body weight gain of SG group was decreased compare with the SHAM group.The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG,while the expression of the key enzyme for hepatic gluconeogenesis:G6Pase and Pepck,were depressed.TBA levels in serum and portal vein were both elevated after SG,the FXR-agonistic BA subspecies:Chenodeoxycholic acid(CDCA),lithocholic acid(LCA)in serum and CDCA,DCA,LCA in portal vein were all higher in SG group than that in SHAM group.Consequently,the ileal expression of FXR and FGF15 were also advanced in SG group.Moreover,the hepatic expression of FGFR4 was stimulated in SG-operated rats.As a result,the activity of its corresponding pathway for glycogen synthesis:FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated,while the corresponding pathway for hepatic gluconeogenesis:FGFR4-cAMP regulatory element-binding protein-peroxisome proliferator-activated receptorγcoactivator-1αpathway was suppressed.CONCLUSION Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR.Furthermore,the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Evaluation of the diagnostic value of total bile acids/platelets in HBV related liver fibrosis

Objective:Explore the diagnostic value of total bile acids/platelets in HBV related liver fibrosis.Methods:160 patients with chronic HBV infection admitted to the Infection Department of the First Affiliated Hospital of Hainan Medical College from February 2021 to December 2022 were selected.They were divided into two groups based on the degree of liver fibrosis detected by liver biopsy:significant liver fibrosis group and non-significant liver fibrosis group.The total bile acid/blood platelet levels and their correlation with liver fibrosis in the two groups were compared and observed,and the efficacy of other non-invasive liver fibrosis diagnostic models was evaluated.Results:(1)Compared with the non-significant liver fibrosis group,the significant liver fibrosis group showed an increase in total bile acid levels,a decrease in platelet levels,and a significant increase in total bile acid/platelet levels(P<0.05).(2)Platelets decrease with the increase of liver fibrosis degree,total bile acids increase with the increase of liver fibrosis degree,and total bile acids/platelets increase with the increase of liver fibrosis degree.(3)The area under the curve(AUC)of total bile acid/platelet,APRI,FIB-4,and elastography in diagnosing the degree of liver fibrosis were 0.69,0.57,0.56,and 0.68,respectively.Conclusions:The diagnostic efficacy of total bile acids/platelets in diagnosing HBV related liver fibrosis is no less than that of other liver fibrosis diagnostic methods,and it is non-invasive,simple,and convenient,which is worthy of further clinical promotion and validation.

^(1)H and ^(13)C NMR spectral assignments for low-concentration bile acids in biological samples

Bile acids are the main body of enterohepatic circulation in vivo.They have essential functions such as emulsifying fat,bacteriostasis and regulating multiple metabolic pathways as signal molecules.However,the assignments of NMR signals for some lowconcentration bile acids are still needed.This study combined 1D nuclear magnetic resonance(NMR)and 2D NMR techniques including 1He1H correlation spectroscopy(COSY),1He1H total correlation spectroscopy(TOCSY),1H J-resolved spectroscopy(J-Res),1He13C heteronuclear single quantum coherence spectroscopy(HSQC),and 1He13C heteronuclear multiple bond correlation spectroscopy(HMBC)to assign the 1H and 13C signals of six bile acids in aqueous solution at physiological pH(~7.4)and nine bile acids in methanol.These data are of importance to the NMR-based studies on lipid digestion,absorption,and metabolism.

Targeted bile acids metabolomics in cholesterol gallbladder polyps and gallstones: From analytical method development towards application to clinical samples

Bile acids(BAs)are synthesized by the liver from cholesterol through several complementary pathways and aberrant cholesterol metabolism plays pivotal roles in the pathogeneses of cholesterol gallbladder polyps(CGP)and cholesterol gallstones(CGS).To date,there is neither systematic study on BAs profile of CGP or CGS,nor the relationship between them.To explore the metabolomics profile of plasma BAs in healthy volunteers,CGP and CGS patients,an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method was developed and validated for simultaneous determination of 42 free and conjugated BAs in human plasma.The developed method was sensitive and reproducible to be applied for the quantification of BAs in the investigation of plasma samples.The results show that,compared to healthy volunteers,CGP and CGS were both characterized by the significant decrease in plasma BAs pool size,furthermore CGP and CGS shared aberrant BAs metabolic characteristics.Chenodeoxycholic acid,glycochenodeoxycholic acid,l-muricholic acid,deoxycholic acid,and 7-ketolithocholic acid were shared potential markers of these two cholesterol gallbladder diseases.Subsequent analysis showed that clinical characteristics including cysteine,ornithine and body mass index might be closely related to metabolisms of certain BA modules.This work provides metabolomic information for the study of gallbladder diseases and analytical methodologies for clinical target analysis and efficacy evaluation related to BAs in medical institutions.

Role of bile acids in liver diseases mediated by the gut microbiome

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.

Altered profiles of fecal bile acids correlate with gut microbiota and inflammatory responses in patients with ulcerative colitis

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.

Altered metabolism of bile acids correlates with clinical parameters and the gut microbiota in patients with diarrhea-predominant irritable bowel syndrome

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.

New insights into the interplay between intestinal flora and bile acids in inflammatory bowel disease

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.

Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis

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.

Roles of bile acids in enteric virus replication

Bile acids(BAs)are evolutionally conserved molecules synthesized in the liver from cholesterol to facilitating the absorption of fat-soluble nutrients.In the intestines,where enteric viruses replicate,BAs also act as signaling molecules that modulate various biological functions via activation of specific receptors and cell signaling pathways.To date,BAs present either pro-viral or anti-viral effects for the replication of enteric viruses in vivo and in vitro.In this review,we summarized current information on biosynthesis,transportation and metabolism of BAs and the role of BAs in replication of enteric caliciviruses,rotaviruses,and coronaviruses.We also discussed the application of BAs for cell culture adaptation of fastidious enteric caliciviruses and control of virus infection,which may provide novel insights into the development of antivirals and/or disinfectants for enteric viruses.

Bile acids and microbes in metabolic disease

Bile acids(BAs)serve as physiological detergents that enable the intestinal absorption and transportation of nutrients,lipids and vitamins.BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism,microbiota habitat regulation and cell signaling.BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy,lipid,glucose,and drug metabolism.The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism.Therefore,altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes,such as diabetes mellitus,obesity/hypercholesterolemia,and cardiovascular diseases.BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases.This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases.Moreover,we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders.Finally,we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

BACKGROUND The mechanisms underlying diabetes remission after duodenal-jejunal bypass(DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids(BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.AIM To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.METHODS Twenty diabetic rats were randomly allocated to the sham(n = 10) and DJB(n = 10) groups. Body weight, food intake, fasting blood glucose(FBG), serum and intraduodenal total BA(TBA) levels were measured accordingly. Oral glucose tolerance test(OGTT) and intraperitoneal pyruvate tolerance test(ip PTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor(FXR), small heterodimer partner(SHP), and Takeda G-protein-coupled receptor 5(TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK(p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.RESULTS The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ip PTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated m RNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the m RNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.CONCLUSION DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.

Bile acids in serum and bile of patients with cholesterol gallstone

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Advances in the mechanism of bile acids in liver regeneration

Hepatocytes can divide rapidly and proliferate in the absence of inflammation and fibroplasia in the damaged or partial hepatectomy(PHx)of the liver,which is essential for the recovery of related patients.Recent studies have found that bile acids(BA)play an important role in the process of liver regeneration.In the early stages of PHx,bile acid overload occurs,and liver injury is aggravated by loading.Later bile acids can induce protective and proliferative responses in the liver and promote liver regeneration.In this paper,we summarize the negative effects after bile acid overload and its positive role as a signaling molecule involved in related signaling pathways on liver regeneration,including protection of the liver and promotion of liver regeneration,and its double-edswordged"in Liver regeneration.This provides a theoretical basis for subsequent in-depth study of the mechanism and benefit avoidance in clinical treatment.

METABOLISM PATTERN OF FECAL BILE ACIDS IN PATIENTS WITH LARGE BOWEL CANCER

The feca! bite acids were extracted from 21 patients with large bowel (colonic and rectal) cancer and 21 controls, and the bile acid composition and concentration were measured by gas chromatography. The total bile acid concentration and concentration of individual bile acids were not statistically different between colonic and rectal cancer. Bat the concentration and the percentage composition of secondary bile acids (deoxycholic and lithocholic acids) were significantly higher than that in controls. However the percentage composition of primary bile acids (cholic and chenocholic acids) were significantly lower than that in controls. The results suggest that incidence of large bowel cancer is closely related to the metabolism of fecal bile acids, and the etiology of colonic and rectal cancers may be the same.

Red Yeast Rice Increases Excretion of Bile Acids in Hamsters

Objective To investigate the hypocholesterolemic activity of red yeast rice （RYR） and its underlying mechanism. Methods Three groups of hamsters were fed either the control diet or one of the two experimental diets containing by weight 0.1% RYR （0.1RYR） or 0.3% RYR （0.3RYR）. Blood （0.5 mL） was collected from the retro-orbital sinus into a heparinized capillary tube at the end of week 0, 3, and 6. Plasma lipoproteins were measured using enzymatic kits, while fecal neutral and acidic sterols were quantified using a gas-liquid chromatography. Results Plasma total cholesterol was reduced by 12% in 0.1RYR group and by 18% in 0.3RYR group compared with the control value. Similarly, plasma triacylglycerol was decreased by 11% in 0.1RYR group and by 24% in 0.3RYR group. Western blotting analysis demonstrated that RYR had no effect on sterol regulatory element binding protein 2, fiver X receptor, 3-hydroxy-3-methylglutary-CoA reductase, LDL receptor, and cholesterol-7α-hydroxylase. HPLC analysis confirmed that RYR contained 0.88% monacolin K. It was recently found that RYR supplementation increased excretion of fecal acidic sterols by 34 folds compared with the conlrol value. Conclusion Hypocholesterolemic activity of RYR is mediated at least partially by enhancement of acidic sterol excretion.