Search Results (106)

The genus Turicibacter is a common inhabitant of the small intestine of numerous animal species, including chickens. However, little is known about the phenotypic and genetic diversity of the genus. Within the chicken small intestine, bile and its primary components, bile acids, are involved in nutrient absorption and modulating microbial community structure. Here, we compare T. sanguinis MOL361 (type strain of the genus), with three strains of the recently described species T. bilis, two from chicken and one from swine. Multiple bile salt hydrolase (BSH) genes, responsible for modification of host-derived bile acids, were identified in each strain and were compared to other Turicibacter BSH with known activities. The bile acid deconjugation ability of individual strains were assessed using chicken bile, as well as the primary bile acids taurochenodeoxycholic acid and taurocholic acid. Both chicken isolates, T. bilis MMM721 and T. bilis ISU324, as well as T. sanguinis MOL361, significantly reduced the concentrations of the tauro-conjugated bile acids. Overall, this work identifies the context-dependent nature of Turicibacter BSH activity. Full article

Background/Objectives: High-fat-diet (HFD) consumption drives chronic liver injury via gut dysbiosis and metabolic disturban. Apple cider vinegar, rich in polyphenols and organic acids, shows potential in metabolic regulation. This study aimed to investigate whether apple cider vinegar powder (ACVP) alleviates HFD-induced liver injury by modulating the gut–liver axis. Methods: For 12 weeks, C57BL/6 J mice received daily ACVP gavage while being fed a HFD. A series of biological assessments were conducted, including systemic metabolic evaluations (body weight, serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), and lipid/glucose levels), hepatic steatosis (hematoxylin and eosin (H&E) staining), intestinal microbiome characterization (16S rRNA gene genomic analysis), and comprehensive metabolite profiling of cecal contents (non-targeted metabolomics). Pearson correlation networks integrated multi-omics data. Results: ACVP attenuated HFD-induced weight gain by 26.3%, hepatomegaly and dyslipidemia, as well as reduced hepatic lipid vacuoles and serum ALT (48%)/AST (21.5%). ACVP restored gut microbiota diversity, enriching Muribaculaceae. Cecal metabolomics identified 38 HFD-perturbed metabolites reversed by ACVP, including indolelactate, hyocholate, and taurocholic acid. the Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed ACVP-mediated recovery of linoleic acid metabolism. Correlation networks linked Akkermansia to anti-inflammatory metabolites (e.g., trans-ferulic), while Desulfobacterota correlated with pro-inflammatory oxylipins (e.g., 12,13-dihydroxy-9Z-octadecenoic acid (DHOME)). Conclusions: ACVP mitigates HFD-induced liver injury by remodeling gut microbiota, restoring microbial metabolites, and enhancing gut–liver crosstalk. Full article

Tan sheep outperform Dorper sheep in meat-quality traits, including muscle fiber characteristics and fatty acid composition, while Dorper sheep excel in carcass weight. However, the molecular mechanisms underlying these breed-specific traits, especially gut microbiota–bile acid (BA) interactions, remain poorly understood. As host–microbiota co-metabolites, BAs are converted by colonic microbiota via bile salt hydrolase (BSH) and dehydroxylases into secondary BAs, which activate BA receptors to regulate host lipid and glucose metabolism. This study analyzed colonic BA profiles in 8-month-old Tan and Dorper sheep, integrating microbiome and longissimus dorsi muscle transcriptome data to investigate the gut–muscle axis in meat-quality and carcass trait regulation. Results showed that Tan sheep had 1.6-fold higher secondary BA deoxycholic acid (DHCA) levels than Dorper sheep (p < 0.05), whereas Dorper sheep accumulated conjugated primary BAs glycocholic acid (GCA) and tauro-α-muricholic acid (p < 0.05). Tan sheep exhibited downregulated hepatic BA synthesis genes, including cholesterol 7α-hydroxylase (CYP7A1) and 27-hydroxylase (CYP27A1), alongside upregulated transport genes such as bile salt export pump (BSEP), sodium taurocholate cotransporting polypeptide (NTCP), and ATP-binding cassette subfamily B member 4 (ABCB4), with elevated gut BSH activity (p < 0.05). DHCA was strongly correlated with g_Ruminococcaceae_UCG-014, ENSOARG00000001393, and ENSOARG00000016726, muscle fiber density, diameter, and linoleic acid (C18:2n6t) (|r| > 0.5, p < 0.05). In contrast, GCA was significantly associated with g_Lachnoclostridium_10, g_Rikenellaceae_RC9_gut_group, ENSOARG0000001232, carcass weight, and net meat weight (|r| > 0.5, p < 0.05). In conclusion, breed-specific colonic BA profiles were shaped by host–microbiota interactions, with DHCA potentially promoting meat quality in Tan sheep via regulation of muscle fiber development and fatty acid deposition, and GCA influencing carcass traits in Dorper sheep. This study provides novel insights into the gut microbiota–bile acid axis in modulating ruminant phenotypic traits. Full article

: Negative energy balance (NEB) in dairy cows induces excessive lipolysis, leading to elevated levels of β-hydroxybutyric acid (BHBA), which, when accumulated, can cause liver damage. Rutin (RT), a natural flavonoid with antioxidant and anti-inflammatory properties, has demonstrated potential hepatoprotective effects; however, its ability to mitigate BHBA-induced hepatocellular injury in calves remains unclear. This study first assessed the impact of various BHBA concentrations on oxidative stress in calf hepatocytes, then explored the protective effects and underlying mechanisms of RT, and finally employed untargeted metabolomics to further elucidate RT’s mode of action. The results showed that exposure to 1.2 mM BHBA significantly increased malondialdehyde (MDA), nitric oxide (NO) contents, and reactive oxygen species (ROS) levels, while markedly decreasing glutathione (GSH) content and catalase (CAT) activity compared with the blank control. Notably, pretreatment with 100 μg/mL RT resulted in the greatest increase in GSH contents (180%) compared to BHBA treatment alone, while 150 μg/mL RT led to the most pronounced reduction in MDA contents (220%). Furthermore, BHBA treatment significantly upregulated the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1) at both the mRNA and protein levels. These alterations were effectively reversed by pretreatment with 100 μg/mL RT. Non-targeted metabolomics identified 1525 metabolites in total. Based on OPLS-DA, metabolites with a variable importance in projection (VIP) > 1 and p < 0.05 were considered significantly altered. Compared with the blank control, BHBA treatment upregulated 47 metabolites—including 8-hydroxy-2′-deoxyguanosine, 3-hydroxyisovaleric acid, and N-palmitoyl-sphingosine—and downregulated 58 metabolites, such as betaine, linolenic acid, and arachidonic acid. In contrast, RT pretreatment upregulated 207 metabolites relative to the BHBA treatment, including linolenic acid, taurocholic acid, and 4-hydroxybenzoic acid, and downregulated 126 metabolites, including 3-hydroxyisovaleric acid, 8-hydroxy-2′-deoxyguanosine, and pyruvaldehyde. Pathway enrichment analysis indicated that RT alleviated BHBA-induced hepatocyte injury primarily by modulating the fatty acid degradation pathway. In summary, RT mitigated BHBA-induced oxidative stress in calf hepatocytes by regulating the Keap1/Nrf2 signaling pathway and further exerted protective effects through metabolic reprogramming. Full article

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11^R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11^R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the ³H-taurocholate transport of the Abcb11^R1128C protein in Madin–Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11^R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11^R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter’s traffic. Full article

Systemic molecular responses to pathogen-associated molecular patterns and their modulation by antioxidants are poorly understood in humans. Here, we present a two-stage clinical interventional study in healthy humans challenged with lipopolysaccharide. In the first step, the kinetics of inflammatory modulators within 8 h were investigated by plasma proteomics and lipidomics. In a second step, the effects of a placebo-controlled antioxidant intervention on the individual responses prior to another lipopolysaccharide challenge were determined. Plasma proteomics revealed an early involvement of the endothelium and platelets, followed by the induction of liver-derived acute phase proteins and an innate immune cell response. Untargeted lipidomics revealed an early release of fatty acids and taurocholic acid, followed by complex regulatory events exerted by oxylipins. The consistent lipopolysaccharide-induced downregulation of lysophospholipids suggested the involvement of the Lands cycle, and the downregulation of deoxycholic acid reinforced emerging links between the inflammasome and bile acids. Groups of molecules with similar kinetics to lipopolysaccharide challenge were observed to share precursors, synthesizing enzymes or cellular origin. Dietary antioxidant supplementation prior to lipopolysaccharide challenge had no detectable effect on protein kinetics but significantly downregulated pro-inflammatory sphingosine-1-phosphate and increased levels of oxylipins, 20-HEPE, and 22-HDoHE, which have been described to facilitate the resolution of inflammation. The present study identified a complex network of lipid mediators deregulated in plasma upon lipopolysaccharide challenge and highlighted the role of platelets, endothelial cells, and erythrocytes as potential inflammatory modulators. While dietary antioxidant supplementation hardly affected the initiation of inflammation, it may exert its effects supporting the resolution of inflammation. Full article

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is insidious, with only 15–20% of those diagnosed suitable for surgical resection as it is either too advanced and has invaded local structures or has already spread to distant sites. The associated tumor microenvironment provides a protective shield which limits the efficacy of chemotherapeutic agents, but also impairs the delivery of nutrients required for the PDAC cells. To compensate for this, metabolic adaptions occur to provide alternative sources of fuel. The aim of this study is to explore metabolomic differences between participants with resectable PDAC compared to healthy volunteers (HV). The objectives were to use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to determine if resectable PDAC induces sufficient metabolic adaptations and variations which could be used to discriminate between the two groups. Methods: Plasma samples were collected from fasted individuals with resectable PDAC (n = 23, median age 68 [IQR 56–75], 69.6% male) and HV (n = 24, median age 63 [IQR 58–71], 54.2% male). Samples were analyzed using NMR and the Biocrates MxP Quant 500 kit at University Hospital Southampton. Results: NMR spectroscopy identified six independent metabolites that significantly discriminated between the PDAC and HV groups, including elevated plasma concentrations of 3-hydroxybutyrate and citrate, with decreased amounts of glutamine and histidine. MS analysis identified 84 metabolites with a significant difference between the PDAC and HV cohorts. The metabolites with a fold change (FC) > 1.5 in the PDAC population were conjugated bile acids (taurocholic acid, glycocholic acid, and glycochenodexoycholic acid). Discussion: In conclusion, using metabolomics, biochemical differences between resectable PDAC and HV were detected. These differences indicate metabolic plasticity and utilization of alternative fuel sources. Full article

Prediabetes (pre-DM) is the buffer period before developing overt type 2 diabetes (T2DM), and the search for novel food agents to protect against pre-DM is in high demand. Our team previously reported that the Grifola frondosa (maitake mushroom) polysaccharide F2 reduced insulin resistance in T2DM rats induced by streptozocin (STZ) combined with a high-fat diet (HFD). This study aimed to evaluate the effects of G. frondosa polysaccharide F2 on disordered lipid and glucose metabolism and to investigate its mechanisms in pre-DM mice. F2 (30 and 60 mg/kg/d) was administered (i.g.) for 5 weeks to pre-DM mice. The results showed that F2 decreased the fasting blood glucose and lipid profile index of pre-DM mice (p < 0.05 or 0.0001). An untargeted metabolomics analysis of feces from pre-DM mice showed that F2 reduced the content of conjugated bile acids, including taurochenodeoxycholic acid and taurocholic acid, and increased the free bile acids of lithocholic acid. The results of 16S rDNA sequencing of feces from pre-DM mice showed that bile salt hydrolase (BSH)-producing bacteria, including Bacillus, Bifidobacterium, and Lactococcus, may be the therapy targets of F2 in pre-DM mice. Through the integrated analysis of untargeted metabolomics and 16S rDNA sequencing, it was found that F2 may ameliorate glucose and lipid metabolism disorders by promoting bile acid metabolism while regulating the abundance of BSH-producing bacteria (Lactococcus spp.), suggesting its potential as a functional food ingredient for the prevention of T2DM. Full article

Background/Objectives: The purpose of this study was to create bile acid-containing liposomes to improve methotrexate blood-brain barrier penetration and to assess the liposome transportation mechanism across the blood–brain barrier. Methods: The improvement of liposome penetration was investigated utilizing human brain microvascular endothelial cells in an in vitro blood-brain barrier model. Using confocal laser scanning microscopy (CLSM) and flow cytometry, liposomes were labeled with fluorescent phospholipids to facilitate their passage across the blood–brain barrier. Results: The produced liposomes with bile acid exhibited a negative surface charge and an average particle size of between 30 and 148 nm. According to an in vitro blood-brain barrier penetration study, the methotrexate penetration was increased by liposomes containing 1% glycocholic acid but not by liposomes containing taurocholic acid. For transport pathway evaluation across the blood-brain barrier of these liposomes, CLSM revealed that fluorescent liposomes were present inside cells treated with specific endocytosis inhibitors, indicating that the cellular internalization of the particles was not involved in endocytosis. Conclusions: Liposomes supplemented with 1% glycocholic acid could enhance the penetration of methotrexate across the blood-brain barrier, while taurocholic acid could not. The transport of liposomes with 1% glycocholic acid across the blood-brain barrier occurs via the transcellular pathway through which it penetrates cells. In contrast, the paracellular pathway was a minor pathway. Full article

Background: Even though many metabolic liver diseases can now be diagnosed using blood tests and diagnostic imaging, early diagnosis remains difficult. Understanding mechanisms contributing to the progression from Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Alcoholic Hepatitis (AH) to cirrhosis is critical to reduce the burden of end-stage liver disease. Monitoring individual bile acids has been proposed as a way to distinguish various liver disorders. Methods: This study explored bile acid profiles in patients with MASH and AH. Plasma samples from patients with MASH, AH, and a control group were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify bile acid concentrations. Targeted metabolomic analysis was performed to compare bile acid levels between the hepatitis and control groups. Results: Concentrations of ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA), taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), glycoursodeoxycholic acid (GUDCA), glycochenodeoxycholic acid (GCDCA), and glycocholic acid (GCA) were significantly elevated in the hepatitis group. Correlation analysis revealed strong positive relationships between the total and direct bilirubin levels and TUDCA and GCDCA. Aspartate aminotransferase (AST) showed strong positive correlations with TCDCA and GCDCA. Child–Pugh score, Fibrosis-4 index, and non-alcoholic fatty liver disease fibrosis score were positively correlated with GCA, whereas the aspartate aminotransferase-to-platelet ratio correlated with TCA, TCDCA, and GCA. The model for end-stage liver disease (MELD) score showed a strong positive correlation with GCDCA. Implications: GCDCA may serve as a predictive biomarker for liver damage, potentially enabling early diagnosis and targeted intervention in patients with MASH and AH. Full article

The aqueous extract of Lycium ruthenicum Murray (LRE) could attenuate neuroinflammation in mice induced by a high-fat and high-fructose diet (HFFD). Moreover, LRE could adjust bile acid (BA) metabolism and the gut microbiota. Behavioral tests revealed that LRE prevented HFFD-induced cognitive deficits. The treatment of LRE resulted in a decreased expression of inflammation-related mRNA of TNF-α, IL-6, and IL-1β in the cerebral cortex and hippocampus. Furthermore, LRE ameliorated gut microbiota disorder caused by HFFD by markedly elevating the relative abundances of Streptococcus and probiotics such as Lactococcus. Concurrently, it reduced the relative abundances of Helicobacter and Clostridium_XIVa. The levels of tauroursodeoxycholic acid, known for its neuroprotective property, and taurocholic acid, recognized as an anti-inflammatory agent, were significantly enhanced in the hippocampus and cerebral cortex due to the treatment with LRE. In a word, LRE might have the potential to alleviate HFFD-induced cognitive dysfunction by modulating intestinal microbiota and promoting the synthesis of neuroprotective BAs. Full article

Background: Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Silybin meglumine (SLB-M) is widely used in treating various liver diseases including liver fibrosis. However, research on its effects on bile acid (BA) metabolism is limited. This study investigated the therapeutic effects of SLB-M on liver fibrosis and BA metabolism in a CCl₄-induced murine model. Methods: A murine liver fibrosis model was induced by CCl4. Fibrosis was evaluated using HE, picrosirius red, and Masson’s trichrome staining. Liver function was assessed by serum and hepatic biochemical markers. Bile acid (BA) metabolism was analyzed using LC-MS/MS. Bioinformatics analyses, including PPI network, GO, and KEGG pathway analyses, were employed to explore molecular mechanisms. Gene expression alterations in liver tissue were examined via qRT-PCR. Results: SLB-M treatment resulted in significant histological improvements in liver tissue, reducing collagen deposition and restoring liver architecture. Biochemically, SLB-M not only normalized serum liver enzyme levels (ALT, AST, TBA, and GGT) but also mitigated disruptions in both systemic and hepatic BA metabolism by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl₄-induced murine model. Notably, SLB-M efficiently improved the imbalance of BA homeostasis in liver caused by CCl₄ via activating Farnesoid X receptor. Conclusions: These findings underscore SLB-M decreased inflammatory response, reconstructed BA homeostasis possibly by regulating key pathways, and gene expressions in BA metabolism. Full article

Hongqu rice wine is a traditional Chinese yellow wine produced from a single ingredient. To enhance the competitiveness of the product and better adapt to market development trends, the development of a complexed Hongqu rice wine using a variety of ingredients is necessary to enhance the nutritional value of the product and diversify its flavor. This study explored production technology for the development of a complexed Hongqu rice wine using kiwiberry as the raw material. The mixed fermentation process was optimized using single-factor experiments and response surface methodology (RSM). The optimal conditions were a juice addition time of 93 h, a fermentation temperature of 31 °C, and a juice addition amount of 75 g/100 g. Under these conditions, the complexed Hongqu rice wine had an alcohol content of 8.7% vol, a total phenolic content of 0.42 mg GAE/mL, and a total flavonoid content of 0.32 mg CE/mL. In total, 27 metabolites were identified. The relative levels of 15 metabolites, including quercetin-3-glucoside and rutin, increased significantly after the adding of the kiwiberry (VIP > 1.0, p < 0.05, FC > 2). Antioxidant activity experiments showed that the Hongqu rice wine had notable antioxidant capacity and that adding the kiwiberry significantly enhanced this capacity. Additionally, the complexed Hongqu rice wine exhibited hypoglycemic and bile acid-binding properties. It achieved 78.68 ± 0.44% inhibition of α-amylase and 58.02 ± 0.50% inhibition of α-glucosidase. The binding activities with sodium glycocholate, sodium cholate, and sodium taurocholate were 40.25 ± 0.64%, 49.08 ± 1.05%, and 60.58 ± 0.80%, respectively. Consequently, a complexed Hongqu rice wine rich in quercetin-3-glucoside and rutin, with notable antioxidant activities, was developed. This wine has potential applications in functional food development. Full article

Bile acids (BAs) are the main endogenous modulators of the composition and metabolic activity of the intestinal microbiota. In the present work, the effect of conjugated (glycodeoxycholic, glycocholic, taurodeoxycholic, taurocholic acids) and free BAs [cholic acid (CA) and deoxycholic acid (DCA)] on the survival, biological molecules, and structural and surface properties of two potential probiotic lactic acid bacteria (LAB) was evaluated. For this, viability assays, Raman spectroscopy, scanning electron microscopy (SEM), and zeta potential (ZP) measurements were employed. Our results evidenced that free BAs were more toxic than conjugates, with CA being significantly more harmful than deoxycholic acid (DCA). RAMAN studies show that BAs modify the bands corresponding to proteins, lipids, carbohydrates, and DNA. SEM showed that BAs cause surface distortions with depressions and fold formation, as well as incomplete cell division. DCA was the one that least altered the ZP of bacteria when compared to CA and taurodeoxycholic acid, with gradual changes towards more positive values. In general, the magnitude of these effects was different according to the BA and its concentration, being more evident in the presence of CA, even at low concentrations, which would explain its greater inhibitory effect. This work provides solid evidence on the effects of BAs on LAB that will allow for the development of strategies by which to modulate the composition of the microbiota positively. Full article

Chronic infections often involve notorious pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, demanding innovative antimicrobial strategies due to escalating resistance. This investigation scrutinized the antibacterial prowess of bile salts, notably taurocholic acid (TCA), ursodeoxycholic acid (UDCA), and ox bile salt (OBS), against these pathogens. Evaluations encompassed minimum inhibitory concentration (MIC) determination, scrutiny of their impact on biofilm formation, and anti-virulence mechanisms. UDCA exhibited the highest efficacy, suppressing S. aureus and P. aeruginosa biofilms by 83.5% and 78%, respectively, at peak concentration. TCA also significantly reduced biofilm development by 81% for S. aureus and 75% for P. aeruginosa. Microscopic analysis revealed substantial disruption of biofilm architecture by UDCA and TCA. Conversely, OBS demonstrated ineffectiveness against both pathogens. Mechanistic assays elucidated UDCA and TCA’s detrimental impact on the cell membrane, prompting the release of macromolecular compounds. Additionally, UDCA and TCA inhibited protease and elastase synthesis in P. aeruginosa and staphyloxanthin and lipase production in S. aureus. These results underscore the potential of UDCA and TCA in impeding biofilm formation and mitigating the pathogenicity of S. aureus and P. aeruginosa. Full article