Circulation Of Bile Acids Research Articles

Alterations in Circulating Bile Acids in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Systematic Review and Meta-Analysis.

Background: Previous studies have suggested that bile acids (BAs) may participate in the development and/or progression of metabolic dysfunction-associated steatotic liver disease (MASLD). The present study aimed to define whether specific BA molecular species are selectively associated with MASLD development, disease severity, or geographic region. Methods: We comprehensively identified all eligible studies reporting circulating BAs in both MASLD patients and healthy controls through 30 July 2023. The pooled results were expressed as the standard mean difference (SMD) and 95% confidence interval (CI). Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Results: Nineteen studies with 154,807 individuals were included. Meta-analysis results showed that total BA levels in MASLD patients were higher than those in healthy controls (SMD = 1.03, 95% CI: 0.63-1.42). When total BAs were divided into unconjugated and conjugated BAs or primary and secondary BAs, the pooled results were consistent with the overall estimates except for secondary BAs. Furthermore, we examined each individual BA and found that 9 of the 15 BAs were increased in MASLD patients, especially ursodeoxycholic acids (UDCA), taurococholic acid (TCA), chenodeoxycholic acids (CDCA), taurochenodeoxycholic acids (TCDCA), and glycocholic acids (GCA). Subgroup analysis revealed that different geographic regions or disease severities led to diverse BA profiles. Notably, TCA, taurodeoxycholic acid (TDCA), taurolithocholic acids (TLCA), and glycolithocholic acids (GLCA) showed a potential ability to differentiate metabolic dysfunction-associated steatohepatitis (MASH) (all p < 0.05). Conclusions: An altered profile of circulating BAs was shown in MASLD patients, providing potential targets for the diagnosis and treatment of MASLD.

The chronic consumption of dietary fructose promotes the gut Clostridium species imbalance and bile acid alterations in developing nonalcoholic fatty liver disease

Excessive fructose intake is associated with the rising prevalence of nonalcoholic fatty liver disease (NAFLD). The gut microbiome (GM) and bile acids (BAs) are involved in the pathogenesis of NAFLD, but the impact of fructose on their cross-talk is unclear. In this study, adult male C57BL/6J mice were fed a normal diet with tap water (ND) or with 4% fructose in the drinking water (Fru), 60% high-fat diet with tap water (HF) or with 4% fructose solution (HFF) for 12 weeks. Targeted BA analysis was performed in five anatomical sites including the liver, ileum contents, portal serum, cecum contents, and feces. Metagenomic sequencing was performed to explore gut dysbiosis. Within 12 weeks, the 4% fructose diet could initially stimulate gut dysbiosis and BA upregulation in the ileum, portal serum, and cecum when the intestinal and hepatic transport system remained stable without hepatic lipid accumulation. However, the chronic consumption of fructose promoted HF-induced NAFLD, with significantly increased body weight, impaired glucose tolerance, and advanced liver steatosis. BA transporters were inhibited in HFF, causing the block of internal BA circulation and increased BA secretion via cecum contents and feces. Notably, lithocholic acid (LCA) and its taurine conjugates were elevated within the enterohepatic circulation. Meanwhile, the Clostridium species were significantly altered in both Fru and HFF groups and were closely associated with fructose and BA metabolism. In summary, excessive fructose caused gut dysbiosis and BA alterations, promoting HF-induced NAFLD. The crosstalk between Clostridium sp. and LCA species were potential targets in fructose-mediated NAFLD.

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

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

Circulating bile acid profile characteristics in PCOS patients and the role of bile acids in predicting the pathogenesis of PCOS.

The metabolic profile of bile acids and their potential role as biomarkers in the pathogenesis of polycystic ovary syndrome (PCOS) have not been thoroughly characterized. Assessing their predictive value for PCOS is of significant importance. In this study, we enrolled 408 women with PCOS and 204 non-PCOS controls. The serum bile acid profile was measured using high-performance liquid chromatography-tandem mass spectrometry (LC/MS). We analyzed the differences in serum bile acid profiles between PCOS patients using the OPLS-DA model. Additionally, we examined the relationship between bile acid profiles and parameters related to glucose metabolism and hyperandrogenism. ROC analysis was employed to identify potential biomarkers for PCOS pathogenesis. XGboost was utilized for cross-validation. The bile acid profile was found to be altered in PCOS patients. Specifically, the primary and secondary unconjugated bile acid fractions were significantly higher in the PCOS population. We identified five bile acid metabolite candidates that exhibited the most significant differences between PCOS and non-PCOS controls. DCA was associated with deposition index, fasting and postprandial insulin but was influenced by testosterone. CDCA and LCA combined with testosterone showed potential as biomarkers for the pathogenesis of PCOS. The circulating bile acid profile undergoes changes in PCOS. DCA is associated with deposition index, fasting and postprandial insulin and its level is influenced by testosterone. CDCA and LCA combined with testosterone have the potential to serve as biomarkers for the pathogenesis of PCOS.

Plasma Bile Acid Profiling and Modulation of Secreted Mucin 5AC in Cholangiocarcinoma.

Studies investigating the potential role of circulating bile acids (BAs) as diagnostic biomarkers for cholangiocarcinoma (CCA) are sparse and existing data do not adjust for confounding variables. Furthermore, the mechanism by which BAs affect the expression of the oncogenic mucin 5AC (MUC5AC) has never been investigated. We performed a case-control study to characterise the profile of circulating BAs in patients with CCA (n = 68) and benign biliary disease (BBD, n = 48) with a validated liquid chromatography-tandem mass spectrometry technique. Odd ratios (OR) for CCA associations were calculated with multivariable logistic regression models based on a directed acyclic graph structure learning algorithm. The most promising BAs were then tested in an in vitro study to investigate their interplay in modulating MUC5AC expression. The total concentration of BAs was markedly higher in patients with CCA compared with BBD controls and accompanied by a shift in BAs profile toward a higher proportion of primary conjugated BAs (OR = 1.50, CI: 1.14 to 1.96, p = 0.003), especially taurochenodeoxycholic acid (TCDCA, OR = 42.29, CI: 3.54 to 504.63, p = 0.003) after multiple adjustments. Western blot analysis of secreted MUC5AC in human primary cholangiocytes treated with primary conjugated BAs or with TCDCA alone allowed us to identify a novel 230 kDa isoform, possibly representing a post-translationally modified MUC5AC specie.

Effects of glyphosate exposure on gut–liver axis: Metabolomic and mechanistic analysis in grass carp (Ctenopharyngodon idellus)

Glyphosate, one of the most widely used herbicide worldwide, is potentially harmful to non-target aquatic organisms. However, the environmental health risks regarding impacts on metabolism homeostasis and underlying mechanisms remain unclear. Here we investigated bioaccumulation, metabolism disorders and mechanisms in grass carp after exposure to glyphosate. Higher accumulation of glyphosate and its major metabolite, aminomethylphosphonic acid, in the gut was detected. Intestinal inflammation, barrier damage and hepatic steatosis were caused by glyphosate exposure. Lipid metabolism disorder was confirmed by the decreased triglyceride, increased total cholesterol and lipoproteins in serum and decreased visceral fat. Metabolomics analysis found that glyphosate exposure significantly inhibited bile acids biosynthesis in liver with decreased total bile acids content, which was further supported by significant downregulations of cyp27a1, cyp8b1 and fxr. Moreover, the dysbiosis of gut microbiota contributed to the inflammation in liver and gut by increasing lipopolysaccharide, as well as to the declined bile acids circulation by reducing secondary bile acids. These results indicated that exposure to environmental levels of glyphosate generated higher bioaccumulation in gut, where evoked enterohepatic injury, intestinal microbiota dysbiosis and disturbed homeostasis of bile acids metabolism; then the functional dysregulation of the gut-liver axis possibly resulted in ultimate lipid metabolism disorder. These findings highlight the metabolism health risks of glyphosate exposure to fish in aquatic environment.

Gut microbiome and metabolic-associated fatty liver disease: Current status and potential applications.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases worldwide. In recent years, the occurrence rate of MAFLD has been on the rise, mainly due to lifestyle changes, high-calorie diets, and imbalanced dietary structures, thereby posing a threat to human health and creating heavy social and economic burdens. With the development of 16S sequencing and integrated multi-omics analysis, the role of the gut microbiota (GM) and its metabolites in MAFLD has been further recognized. The GM plays a role in digestion, energy metabolism, vitamin synthesis, the prevention of pathogenic bacteria colonisation, and immunoregulation. The gut-liver axis is one of the vital links between the GM and the liver. Toxic substances in the intestine can enter the liver through the portal vascular system when the intestinal barrier is severely damaged. The liver also influences the GM in various ways, such as bile acid circulation. The gut-liver axis is essential in maintaining the body's normal physiological state and plays a role in the onset and prognosis of many diseases, including MAFLD. This article reviews the status of the GM and MAFLD and summarizes the GM characteristics in MAFLD. The relationship between the GM and MAFLD is discussed in terms of bile acid circulation, energy metabolism, micronutrients, and signalling pathways. Current MAFLD treatments targeting the GM are also listed.

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

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

Absence of gut microbiota reduces neonatal survival and exacerbates liver disease in Cyp2c70-deficient mice with a human-like bile acid composition.

Mice with deletion of Cyp2c70 have a human-like bile acid composition, display age- and sex-dependent signs of hepatobiliary disease and can be used as a model to study interactions between bile acids and the gut microbiota in cholestatic liver disease. In the present study, we rederived Cyp2c70-/- mice as germ-free (GF) and colonized them with a human or a mouse microbiota to investigate whether the presence of a microbiota can be protective in cholangiopathic liver disease associated with Cyp2c70-deficiency. GF Cyp2c70-/- mice showed reduced neonatal survival, liver fibrosis, and distinct cholangiocyte proliferation. Colonization of germ-free breeding pairs with a human or a mouse microbiota normalized neonatal survival of the offspring, and particularly colonization with mouse microbiota from a conventionally raised mouse improved the liver phenotype at 6-10 weeks of age. The improved liver phenotype in conventionalized (CD) Cyp2c70-/- mice was associated with increased levels of tauro-ursodeoxycholic acid (TUDCA) and UDCA, resulting in a more hydrophilic bile acid profile compared with GF and humanized Cyp2c70-/- mice. The hydrophobicity index of biliary bile acids of CD Cyp2c70-/- mice was associated with changes in gut microbiota, liver weight, liver transaminases, and liver fibrosis. Hence, our results indicate that neonatal survival of Cyp2c70-/- mice seems to depend on the establishment of a gut microbiota at birth, and the improved liver phenotype in CD Cyp2c70-/- mice may be mediated by a larger proportion of TUDCA/UDCA in the circulating bile acid pool and/or by the presence of specific bacteria.

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

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

A bout of endurance and resistance exercise transiently decreases plasma levels of bile acids in young, sedentary adults.

Circulating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here, we evaluate the effects of a bout of maximal endurance exercise (EE) and resistance exercise (RE) on plasma levels of BA in young, sedentary adults. Concentration of eight plasma BA was measured by liquid chromatography-tandem mass spectrometry before and 3, 30, 60, and 120 min after each exercise bout. Cardiorespiratory fitness (CRF) was assessed in 14 young adults (21.8 ± 2.5 yo, 12 women); muscle strength was assessed in 17 young adults (22.4 ± 2.5 yo, 11 women). EE transiently decreased plasma levels of total, primary, and secondary BA at 3 and 30 min after exercise. RE exerted a prolonged reduction in plasma levels of secondary BA (p < 0.001) that lasted until 120 min. Primary BA levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) were different across individuals with low/high CRF levels after EE (p ≤ 0.044); CA levels were different across individuals with low/high handgrip strength levels. High CRF individuals presented higher levels of CA and CDCA 120 min after exercise vs baseline (+77% and +65%) vs the low CRF group (-5% and -39%). High handgrip strength levels individuals presented higher levels of CA 120 min after exercise versus baseline (+63%) versus the low handgrip strength group (+6%). The study findings indicate that an individual's level of physical fitness can influence how circulating BA respond to both endurance and resistance exercise. Additionally, the study suggests that changes in plasma BA levels after exercising could be related to the control of glucose homeostasis in humans.

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

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

Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study.

Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. This open-label study evaluated the safety and tolerability of maralixibat ≤10mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

Bile acid metabolites in early pregnancy and risk of gestational diabetes mellitus: Results from a prospective cohort study.

To evaluate the associations of plasma bile acid metabolites, especially in early pregnancy, with gestational diabetes mellitus (GDM) risk among pregnant women. Plasma concentrations of 15 bile acid metabolites were measured in 645 women at early pregnancy from the Jiashan Birth Cohort using a liquid chromatography-tandem mass spectrometry metabolomics platform. Using logistic and cubic spline models, we examined associations between baseline plasma bile acid metabolites and GDM risk during mid-late pregnancy. A meta-analysis of prospective studies of bile acid and GDM risk was performed. The linear and nonlinear univariate models identified eight metabolites associated with GDM, including cholic acid, taurocholic acid (TCA), glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid (LCA), ursodeoxycholic acid and taurolithocholic acid (all P <0.05). Multivariable analysis indicated that TCA and LCA levels were positively (odds ratio [OR] 2.07, 95% confidential interval [CI] 1.05, 3.96; P = 0.030) and negatively (OR 0.83, 95% CI 0.68, 1.01; P = 0.065) associated with GDM, respectively, after adjusting for confounders. The TCA-GDM association showed a positive linear shaped relationship (OR 2.07, 95% CI 1.05, 3.96; P = 0.030); while LCA was negatively related with GDM risk in linearity (OR 0.83, 95% CI 0.68, 1.01; P = 0.065). The meta-analysis of five studies showed a consistent bile acid and GDM association, with a risk ratio (RR) of 2.43 (1.95, 3.03). This study indicated that, the levels of circulating bile acids in early pregnancy were associated with risk of GDM, independent of GDM risk factors. Most GDM-associated bile acids were primary conjugated and secondary unconjugated bile acids.

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

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

Bifidobacterium supplementation attenuates hypercholesterolemia induced gut-brain-testis dysfunction in a rat model

Hypercholesterolemia is the state of high LDL blood cholesterol levels. This may lead to cholesterol accumulation in organs and cause diseases such as male infertility and NAFLD. Recent studies have shown strong correlations between Bifidobacterium strains and plasma cholesterol reduction. Bifidobacterium species are gram positive bacteria known to colonize the human gastrointestinal tract. Studies suggest that Bifidobacterium may reduce serum cholesterol levels by increasing bile salt hydrolase (BSH) activity. BSH increases fecal excretion of bile salt, and to compensate the loss of circulating bile acids, productions of bile acids using cholesterol are promoted. Currently, medications such as statins are commonly used. However, long term consumption could cause adverse effects on male reproductive organs. Bifidobacterium strains are known to regulate the hypothalamus-pituitary-gonadal (HPG) axis by modulating gut microbiota . Gut microbial bacteria such as Bifidobacterium contribute to the host metabolism by enhancing gut barrier integrity, reducing inflammation cytokine expressions, and increasing metabolite productions such as short chain fatty acids (SCFAs). Particularly, SCFAs like butyrate can cross the blood-brain barrier, and consequently affect the HPG axis. This suggests that Bifidobacterium strains may lower serum cholesterol while protecting reproductive organs. Therefore, this study aimed to evaluate and compare the serum cholesterol lowering and HPG axis protecting effects of Bifidobacterium strains with statin in the gut-brain-testis axis of a high cholesterol diet (HCD) induced hypercholesterolemia rat model. 6-week oral gavage of Bifidobacterium strains known to have BSH activity effectively reduced serum total cholesterol and LDL cholesterol levels in rats given HCD for the same period. Moreover, serum inflammatory cytokine IL-1β was reduced by Bifidobacterium treatment. Bifidobacterium also exerted protective effects against intestinal, testicular, and cerebral damage by attenuating disruption of histology and modulating transcript levels of inflammation markers. Notably, Bifidobacterium alleviated the HCD-induced reduction of male sex hormone synthesis markers in the testis, which statin had no effect. Fecal analysis revealed that Bifidobacterium treatment modulates gut microbiota compositions and metabolite levels such as SCFAs. Particularly, 16s rRNA genomic annotation showed that Bifidobacterium strains may have specific functions related to cholesterol reduction. Altogether, Bifidobacterium supplementation may reduce serum cholesterol levels by altering gut microbiota compositions, which affect gut metabolite compositions, inflammatory markers, and sex hormone synthesis markers. In conclusion, Bifidobacterium supplementation is a potential therapeutic approach for hypercholesterolemia-induced intestine, brain, and testis dysfunction. This work was supported by Cellbiotech Co., Ltd. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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

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

Association between diet and circulating bile acids in an italian general population

Association between diet and circulating bile acids in an italian general population

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

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

Investigation of therapeutic effects of rhubarb decoction retention enema on minimal hepatic encephalopathy in rats based on 16S rDNA gene sequencing and bile acid metabolomics

Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE), with high incidence and a high rate of clinically missed diagnosis. Early diagnosis of MHE and effective clinical intervention are of great importance. Rhubarb decoction (RD)-induced retention enema can effectively improve the cognitive function of patients with MHE, whereas disturbances in the enterohepatic circulation of bile acid (BAs) can induce MHE. However, the molecular mechanisms underlying the therapeutic effects of RD have not been examined from the perspective of intestinal microbiota and bile metabolomics. In this study, we investigated the effects of RD-induced retention enema on intestinal microbiota and bile metabolites in rats with CCl4- and TAA-induced MHE. RD-induced retention enema significantly improved liver function, reduced blood ammonia levels, alleviated cerebral oedema and restored cognitive function in rats with MHE. In addition, it increased the abundance of intestinal microbes; partially reversed the disorder in the composition of intestinal microbiota, including the Bifidobacterium and Bacteroides genera; and regulated BA metabolism, such as taurine combined with increased BA synthesis. In conclusion, this study highlights the potential importance of BA enterohepatic circulation for RD to improve cognitive function in MHE rats, providing a new perspective on the mechanism of this herb. The findings of this study will facilitate experimental research on RD and help to develop RD-based strategies for clinical application.