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To investigate the hypolipidemic effects and antioxidant levels of total flavonoids from seabuckthorn fruit peel and residue, in vitro and in vivo experiments were conducted to examine the hypolipidemic functionality of the purified total flavonoids from seabuckthorn fruit peel and residue (TFSE). The antioxidant activity of TFSE was determined through in vitro experiments, and its binding capacity to three types of bile acids was investigated by simulating the human gastrointestinal environment. This was conducted to evaluate its antioxidant and hypolipidemic effects in vitro. In the in vivo experiment, a high-fat diet-induced hyperlipidemia model was established in C57BL/6J mice, and TFSE was administered orally to compare its effects on body weight, serum, hepatic lipid levels, liver function indicators, and oxidative indicators. Then, histopathological observations of the liver tissue were completed. The in vitro study showed that TFSE exhibited strong scavenging abilities against DPPH and ABTS+ radicals, with IC50 values of 5.20 and 10.24 µg/mL, respectively, thus indicating effective antioxidant activity. Moreover, TFSE showed strong binding capabilities with sodium cholate, glycocholate, and taurocholate, with IC50 values of 11.11, 2.61, and 3.50 mg/mL, respectively, thus highlighting its binding solid capacity with bile acids. Results of the mice experiments showed that, compared to the model group (HFD), the L-TFSE and H-TFSE groups showed inhibited body weight gain, whilst (P<0.05) total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in serum and liver were significantly decreased. At the same time, significantly increased (P<0.05) high-density lipoprotein cholesterol (HDL-C) levels and significantly decreased (P<0.05) levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and lactate dehydrogenase (LDH) in mice serum. Furthermore, TFSE significantly increased (P<0.05) the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels in mice liver, and significantly decreased (P<0.05) the whilst malondialdehyde (MDA) content. In summary, TFSE would improve the hepatic pathological damage caused by a high-fat diet, showed effective lipid-lowering activity and antioxidant activity. This study would provide a theoretical basis for improving the added value of sea buckthorn peel residue products in Xinjiang. [ABSTRACT FROM AUTHOR]

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects. [Display omitted] • 3-sulfated bile acids accumulate in cholestatic patients, causing itch symptoms • The cryo-EM structure of MRGPRX4 (hX4) with DCA-3P unveils how bile acids activate hX4 • Obeticholic acid (OCA) induces an itch side effect by activating hX4 • An OCA derivative, C7, was developed to treat liver diseases without causing itch Bile acids (BAs) are 3-sulfonated to improve their potency to activate MRGPRX4 (hX4), the G-protein-coupled receptor for cholestatic itch. The cryo-EM structure of hX4 binding with a bile acid-derived agonist highlights the importance of the 3-hydroxyl group in BAs to activate hX4 and helps develop the lead compound, C7, as a promising candidate for treating liver diseases without the unwanted side effect of itch. [ABSTRACT FROM AUTHOR]

Proline‐catalyzed aldol reaction of aromatic aldehydes with cyclohexanone was successfully carried out in water without any cosolvent in presence of catalytic amounts of bile acid salt surfactants. The bile acid salts, acting as surfactants, facilitate the dispersion of nonpolar substrates, enabling efficient reaction conditions "in presence of water" which exploit the role of water beyond its simple characteristic as a solvent. While enantioselectivity is moderate, the high yields achieved reflect the potent synergy between proline and sodium deoxycholate (NaDC), underscoring the feasibility of water‐exclusive processes in synthetic organic chemistry. [ABSTRACT FROM AUTHOR]

Colon cancer (CC) is the second most common cause of cancer deaths and the fourth most prevalent cancer in the United States. Recently cholesterol metabolism has been identified as a potential therapeutic avenue due to its consistent association with tumor treatment effects and overall prognosis. We conducted differential gene analysis and KEGG pathway analysis on paired tumor and adjacent-normal samples from the TCGA Colon Adenocarcinoma project, identifying that bile secretion was the only significantly downregulated pathway. To evaluate the relationship between cholesterol metabolism and CC prognosis, we used the genes from this pathway in several statistical models like Cox proportional Hazard (CPH), Random Forest (RF), Lasso Regression (LR), and the eXtreme Gradient Boosting (XGBoost) to identify the genes which contributed highly to the predictive ability of all models, ADCY5, and SLC2A1. We demonstrate that using cholesterol metabolism genes with XGBoost models improves stratification of CC patients into low and high-risk groups compared with traditional CPH, RF and LR models. Spatial transcriptomics (ST) revealed that SLC2A1 (glucose transporter 1, GLUT1) colocalized with small blood vessels. ADCY5 localized to stromal regions in both the ST and protein immunohistochemistry. Interestingly, both these significant genes are expressed in tissues other than the tumor itself, highlighting the complex interplay between the tumor and microenvironment, and that druggable targets may be found in the ability to modify how "normal" tissue interacts with tumors. [ABSTRACT FROM AUTHOR]

Liver fibrosis (LF) is a common sequela to diverse chronic liver injuries, leading to rising rates of cirrhosis and hepatocellular carcinoma (HCC). As the medicinal and edible homologous material, traditional teas have exhibited promising applications in the clinical management of liver fibrosis. Here, we generated a liver fibrosis mouse model to explore the potent therapeutic ability of Ampelopsis grossedentata (AG) tea on this condition by multi-omics analysis. The biochemistry results pointed towards mitigated increases of ALT, AST, TBIL, and ALP triggered by BDL in the AG-treated group. Examination using H&E and Sirius Red staining revealed severe liver injuries, inflammation infiltration, amplified fibrosed regions, and the creation of bile ducts, all of which were fallout from BDL. Immunohistochemistry findings also implicated a noteworthy upregulation of the HSC activation marker α-smooth muscle actin (α-SMA) and the fibrosis marker collagen I in the BDL group. However, these symptoms demonstrated a significant improvement in the group treated with 100 mg/kg AG. Findings from the Western Blot test corroborated the prominent elevation of TNF-α, col1a1, α-SMA, and TGF-β, instigated by BDL, while AG treatment meaningfully modulated these proteins. Furthermore, our study underscored the potential involvement of several microbiota, such as Ruminococcaceae UCG-014, Eubacterium Ruminantium, Ruminococcus 1, Christensenellaceae R-7, Acetatifactor, Dubosiella, Parasutterella, Faecalibaculum, and Defluviitaleaceae UCG-011, in the progression of liver fibrosis and the therapeutic efficacy of AG. This investigation shows that during the process of AG ameliorating BDL-induced liver fibrosis, bile acid derivatives such as CDCA, TCDCA, 3-DHC, UCA, DCA, among others, play significant roles. In this study, we identified that several non-bile acid metabolites, such as Deltarasin, Thr-Ile-Arg, etc., are entailed in the process of AG improving liver fibrosis. [ABSTRACT FROM AUTHOR]

AbstractPhosphatidylcholine (PC) has garnered considerable attention due to its involvement in a wide array of crucial biological functions. However, there is still much to active explore regarding the precise mechanisms that underlie PC’s actions in the context of high-fat diet. In this study, we found that both PC intervention and treatment significantly mitigated lipid accumulation, liver damage, and body weight gaining triggered by the high-fat diet. Untargeted and targeted metabolomic analyses uncovered substantial effects of PC on bile acid metabolism, especially led to a substantial reduction in elevated levels of free bile acids. 16S rRNA gene sequencing revealed that PC modulated the gut microbiota structures and compositions in high-fat diet mice, particularly exhibiting a positive association with Pseudoflavonifractor abundance, and a negative correlation with Olsenella, Parasutterella, and Allobaculum abundance. Our study suggested that PC held promise as a potential candidate for alleviating lipid metabolism injury, liver disease or obesity. [ABSTRACT FROM AUTHOR]

AbstractThis study integrated analyses of gut microbiota and metabolomics to investigate the impact of ellagic acid (EA) on non-alcoholic fatty liver disease (NAFLD). Compared to the high-fructose diet (HFruD) group, the EA group exhibited reduced body weight and fat mass, alongside improvements in blood glucose and lipid metabolism. Liver metabolomics analysis revealed that EA increased the abundance of metabolites in pathways related to unsaturated fatty acids, amino acids and bile acids. Furthermore, EA induced alterations in the composition and structure of gut microbiota, notably decreasing bacterial genera enriched by HFruD while promoting beneficial bacteria such as Faecalibaculum. Correlation analysis demonstrated significant associations among NAFLD markers, gut microbiota and liver metabolites influenced by EA. This study provides new insights into the anti-NAFLD effects of EA, suggesting EA as a promising nutraceutical for improving NAFLD. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion This study evaluates how changes in intestinal bile acid composition, induced by cholestyramine, a bile acid sequestrant, affect metformin's pharmacodynamics (PD).An open‐label, 2‐period 1‐sequence crossover study was conducted with healthy male adults. Each period consisted of both before and after metformin treatments. Cholestyramine was administered during the second period to change the bile acid pool. For, PD assessment, an oral glucose tolerance test was conducted at each treatment in both periods. Metformin was administered 3 times during each period, and cholestyramine was administered 3 times per day for 7 days during the second period. Maximum serum glucose concentration, area under the glucose concentration curve and homeostatic model assessment of insulin resistance were calculated. Baseline‐corrected PD parameters were derived by subtracting pre‐metformin values from post‐metformin values. Lipid and panels and bile acid profiles in stool were measured. Adverse events were monitored throughout the study.Fourteen subjects completed the study. The mean values of 3 PD parameters were all decreased after metformin administration in both periods. Cholestyramine administration led to a further decrease in baseline‐corrected PD parameters, significantly reducing the area under the glucose concentration curve by 44.7%. Diarrhoea, the most common adverse event, was reported in 10 subjects during the metformin alone treatment and in 1 subject during the cholestyramine combined treatment (P < .01).Cholestyramine affected the glucose‐lowering effect of metformin by the possible change in the bile acid pool in the gut, and metformin‐associated diarrhoea was improved by cholestyramine. [ABSTRACT FROM AUTHOR]

Background: Polygonum multiflorum shows dual hepatoprotective and hepatotoxic effects. The bioactive components responsible for these effects are unknown. This study investigates whether cis -2,3,5,4'-tetrahydroxystilbene-2-O- β -D-glucoside (cis -TSG), a stilbene glycoside, has hepatoprotective and/or hepatotoxic effects in a liver injury model. Methods: C57BL/6J mice were administered α -naphthylisothiocyanate (ANIT) to induce cholestasis, followed by treatment with cis-TSG. Hepatoprotective and hepatotoxic effects were assessed using serum biomarkers, liver histology, and metabolomic and lipidomic profiling. Transcriptomic analysis were conducted to explore gene expression changes associated with lipid and bile acid metabolism, inflammation, and oxidative stress. Results and Discussion: ANIT administration caused significant liver injury, evident from elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and dysregulated lipid metabolism. cis -TSG treatment markedly reduced ALT and AST levels, normalized lipid profiles, and ameliorated liver damage, as seen histologically. Metabolomic and lipidomic analyses revealed that cis -TSG influenced key pathways, notably glycerophospholipid metabolism, sphingolipid metabolism, and bile acid biosynthesis. The treatment with cis -TSG increased monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs), enhancing peroxisome proliferator-activated receptor alpha (PPARα) activity. Transcriptomic data confirmed these findings, showing the downregulation of genes linked to lipid metabolism, inflammation, and oxidative stress in the cis -TSG-treated group. The findings suggest that cis -TSG has a hepatoprotective effect through modulation of lipid metabolism and PPARα activation. [ABSTRACT FROM AUTHOR]

Background and Aims • Type 2 Diabetes mellitus (T2DM) has reached an epidemic status worldwide. Targeting bile acid signaling has therapeutic potential for treating T2DM. However, the effect of bile acid on T2DM and related mechanisms remains unclear. Here, we explored the role of bile acid in T2DM and elucidated the mechanisms involved. Methods • We established an STZ-induced rat model of T2DM and divided it into an bile acid-treated group and saline control group according to the random number table method. We incubated the bile acid-treated group with human bile acid via middle small intestine intubation and the saline control group was incubated with the same amount of normal saline. We compared the fasting body mass, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2h-PG), fasting plasma insulin (FINS), fasting plasma triglyceride (TG), cholesterol, and total bile acid levels between the two groups one week before surgery and one to four weeks after surgery. Mechanically, Western blot, IHC, and ELISA assays were employed to detect the effect of bile acid on the TGR5/ GLP-1 and FXR/FGF15 pathways. Results • Bile acid injection could increase the FINS level and decrease the 2h-PBG level of T2DM rats. In addition, bile acid injection did not affect FBG, fasting body mass, TG, CH, and total bile acid. At the same time, bile acid injection could activate the TGR5/GLP-1 pathway but could not influence the FXR/FGF15 pathway. Conclusion • Bile acids treatment promotes glucose homeostasis in the STZ-induced T2MD rat model via the following mechanism by activating the TGR5/GLP-1 signaling pathway rather than FXR/FGF15 pathway to improve glucose tolerance and thus achieve glucose homeostasis. The bile acid/TGR5/GLP-1 signaling pathway may be a crucial mechanism of controlling the blood glucose of T2DM rats, and TGR5/GLP-1 pathway may constitute novel targets for treating T2DM. [ABSTRACT FROM AUTHOR]

We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes Arntl/Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On day 4, separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of Fgf15 and Nr0b2. In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation. NEW & NOTEWORTHY: This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition. [ABSTRACT FROM AUTHOR]

Cyp2c70 knockout (KO) mice lack the liver enzyme responsible for synthesis of 6-hydroxylated muricholate bile acid species and possess a more hydrophobic human-like bile acid composition. Cyp2c70 KO mice develop cholestatic liver injury that can be prevented by the administration of an ileal bile acid transporter (IBAT) inhibitor. In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal farnesoid X receptor (FXR) agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype. Oral administration of SC-435, cilofexor, or combined treatment for 2 wk markedly reduced serum markers of liver injury and improved histological and gene expression markers of fibrosis, liver inflammation, and ductular reaction in male and female Cyp2c70 KO mice, with the greatest benefit in the combination treatment group. The IBAT inhibitor and FXR agonist significantly reduced intrahepatic bile acid content but not hepatic bile acid pool hydrophobicity, and markers of liver injury were strongly correlated with intrahepatic total bile acid and taurochenodeoxycholic acid accretion. Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease. NEW & NOTEWORTHY: Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury. [ABSTRACT FROM AUTHOR]

With the global epidemic trend of obesity, non‐alcoholic fatty liver disease (NAFLD) has become a significant cause of chronic liver disease, seriously affecting human health. Medium‐chain triglycerides (MCT) with a fatty acid chain length varying between 6 and 10 carbon atoms (most sources from coconut and palm kernel oils), which exhibited activities to improve lipid metabolism, prevent cardiovascular diseases, and enhance immunity. However, the efficacy differences and potential mechanisms between MCT and traditional long‐chain vegetable oils (palm oil, PA; high oleic peanut oil, OA) in obesity‐induced NAFLD were still unclear. The present study treated obesity‐induced NAFLD mice with different dietary lipids for 16 weeks. The results showed that MCT supplements significantly improved abnormal elevation of weight gain and blood lipids and reduced hepatic lipid accumulation to a greater extent than PA and OA. Furthermore, bile acid profiling results indicated that MCT significantly changed the composition of bile acids in the liver, reduced the concentrations of cholic acid (CA), deoxycholic acid (DCA), β‐muricholic acid (β‐MCA), and ursodeoxycholic acid (UDCA) and increased the concentrations of chenodeoxycholic Acid (CDCA), taurochenodeoxycholic acid （TCDCA), hyodeoxycholic acid (HDCA), and taurohyodeoxycholic acid (THDCA). Mechanistically, MCT supplement upregulated FXR signal and inhibited the expression of key genes for triglyceride synthesis in the liver, thereby reducing hepatic lipid accumulation. In summary, MCT exerted a superior effect on PA and OA in improving obesity‐induced NAFLD. These results provided new evidence for the application of MCT in treating NAFLD. [ABSTRACT FROM AUTHOR]

Simple Summary: Polycystic ovary syndrome (PCOS) is a complex condition influenced by genetic, metabolic, hormonal, and environmental factors. It often leads to high androgen levels, disrupted ovarian function, and metabolic issues. In this study, we investigated the effects of nicotinamide mononucleotide (NMN) on a mouse model of PCOS, which was induced using letrozole, a drug that blocks estrogen production. Letrozole treatment raised androgen levels, reduced bile acid levels, and caused liver dysfunction and ovarian abnormalities. Mice also showed irregular reproductive cycles and hormone imbalances. NMN treatment helped lower androgen levels, improved ovarian health, and partially restored bile acid levels. However, it did not fully normalize the reproductive cycle or lipid metabolism. These findings suggest that effective PCOS treatments should focus not only on improving ovarian health but also on addressing liver and gut metabolism to reduce hormonal imbalances and other health issues. Polycystic ovary syndrome (PCOS) involves complex genetic, metabolic, endocrine, and environmental factors. This study explores the effects of nicotinamide mononucleotide (NMN) in a letrozole-induced PCOS mouse model, focusing on metabolic regulation. Letrozole-induced aromatase inhibition elevated androgen and reduced bile acid levels, linking liver dysfunction and gut imbalance to PCOS. Letrozole-treated mice exhibited disrupted estrous cycles, ovarian congestion, and elevated testosterone. NMN intervention alleviated hyperandrogenism, ovarian abnormalities, and bile acid decline but did not fully restore the estrous cycle or improve lipid profiles. Metabolomic analysis showed that NMN partially reversed bile acid and lipid metabolism disturbances. These findings highlight NMN's protective role in reducing hyperandrogenism and ovarian cyst formation. However, effective PCOS treatment should target liver and gut metabolism, not just ovarian symptoms, to mitigate systemic effects. Bile acid dysregulation may play a key role in PCOS progression and warrants further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the effects of dietary curcumin on gut dysbiosis and impaired gut integrity caused by a high-fat, high-sugar diet (HFHSD) in aged male mice. Our results show that curcumin supplementation increases beneficial gut microbes and decreases harmful bacteria, leading to reduced gut inflammation and improved expression of markers of gut barrier integrity. Additionally, curcumin supports bile homeostasis in the context of aging and HFHSD consumption. These findings suggest that curcumin could be a promising dietary intervention for improving gut health in obesity and aging. The gut microbiome plays a critical role in maintaining gut and metabolic health, and its composition is often altered by aging and obesity. This study aimed to investigate the protective effects of curcumin on gut dysbiosis, gut barrier integrity, and bile acid homeostasis in aged mice fed a high-fat, high-sugar diet (HFHSD). Eighteen- to twenty-one-month-old male C57BL/6 mice were divided into groups fed a normal chow diet or HFHSD, with or without curcumin supplementation (0.4% w/w) for 8 and 15 weeks. We assessed body weight, food intake, insulin sensitivity, gut microbiota composition, and gene expression in the gut and liver and performed histological analysis of gut tissues. Curcumin supplementation prevented HFHSD-induced weight gain and metabolic disturbances. In the gut, curcumin-treated mice showed a higher abundance of beneficial bacterial genera, such as Lachnospiraceae, Akkermansia, Mucispirillum, and Verrucomicrobiota, alongside a lower abundance of harmful bacterial genera like Desulfobacteria, Alistipes, and Muribaculaceae compared to control. This shift in gut microbiota was associated with improved gut integrity, as demonstrated by increased expression of the tight junction protein occludin and reduced levels of the pro-inflammatory marker interleukin-1β in the ileum. Additionally, curcumin modulated hepatic gene expression involved in bile acid homeostasis, suggesting a positive effect on liver health. Curcumin supplementation can alleviate the negative effects of aging and an HFHSD on the gut microbiome, improve gut barrier integrity, and maintain bile acid homeostasis. These findings highlight curcumin's potential as a dietary intervention for managing obesity- and age-associated gut health issues. [ABSTRACT FROM AUTHOR]

Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD). In a case-control pilot study of 81 patients with cACLD, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n = 44) with those showing no improvement ("non-regressors"; n = 37) after a minimum of 24 months of successful treatment of the cause of liver disease. Data were validated using an external validation cohort (n = 30). Regardless of the cause of cACLD, the presence of obesity (odds ratio [OR] 0.267 95% CI 0.072-0.882; p = 0.049), high liver stiffness (OR 0.960, 95% CI 0.925-0.995; p = 0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95% CI 0.030-0.773; p = 0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 patients with ACLD genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated with lipid metabolism – especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to the identification of 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers. We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarkers for detecting regression of fibrosis in cACLD. Regression of cirrhosis/advanced chronic liver disease (ACLD) after removal of the underlying cause of liver injury has been observed in human cirrhosis. However, detailed characterization of ACLD regression remains an unmet need. In this study, we provide a comprehensive phenotyping of individuals likely to experience ACLD regression. While obesity, carriage of GCKR variant rs1260326 and high liver stiffness were associated with lower likelihood of regression of ACLD, a signature of circulating lipid metabolites enabled differentiation of regressors from non-regressors after effective etiologic therapy. The lipid signature we discovered and externally validated could be used as non-invasive biomarker to detect regression of fibrosis in patients with compensated ACLD. [Display omitted] • We demonstrate that fibrosis regression of cACLD is shaped by a multifaceted interplay of clinical, genetic, and metabolic factors. • Obesity, high LSM and carrying the rs1260326 variant of GCKR were associated with a lower probability of fibrosis regression. • Metabolomics revealed lipid perturbations associated with fibrosis regression, with taurocholic and taurochenodeoxycholic acid emerging as key predictors. • We identified a lipid signature associated with regression of ACLD that could be used as a non-invasive biomarker. [ABSTRACT FROM AUTHOR]

Surfactants are very important compounds that are ubiquitous in biological systems and detergents. Among them, ferrocene surfactants are a very valuable class of stimuli-responsive materials since the presence of ferrocene moiety discloses the chance to control and even modify their amphiphilic properties via a redox-induced change in the surfactant charge. In this paper, we report a new ferrocene-based surfactant: a ferrocene C-3 derivative of cholic acid, a non-classical surfactant. The title compound of this work was meant to show the significant self-assembly behaviour typical of bile salts, improved by the presence of the aromatic ferrocene subunit. We intended to demonstrate that the presence of the redox mediator should provide the derivative with sensitivity to an oxidative stimulus and control over the aggregation properties. The title compound was prepared in two steps from easily accessible precursors, and its optical properties were investigated through UV-Vis absorption spectroscopy. The determination of its critical micellar concentration and redox potential confirmed this derivative's amphiphilic nature and its tendency to be reversibly oxidized. [ABSTRACT FROM AUTHOR]

Frequent outbreaks of infectious diseases in aquaculture have led to significant economic losses. The leopard coral grouper (Plectropomus leopardus) often suffers from vibriosis. Improving host immunity presents a superior strategy for disease control, with minimal side effects compared to the use of antibiotics, highlighting the necessity of exploring the mechanisms underlying the fish's response to pathogen infections. Here, we conducted a comparative metabolomic analysis on the livers of the P. leopardus infected with Vibrio harveyi. A total of 1124 differential metabolites (DMs) were identified, with 190, 218, 359, and 353 DMs being identified at 6, 12, 24, and 48 h post‐infection (hpi), respectively. Then, based on the time series analysis, we found that the lipid metabolism pathways were modulated in response to the Vibrio infection, with an increase in the quantity of eicosanoids and gycerophospholipids (GPLs), as well as a decrease in the quantity of bile acids (BAs), vitamin D, and sex hormones. Furthermore, 13 enriched pathways involving 31 DMs were identified through KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses. We identified histamine, 15(S)‐HpETE, and anandamide in the transient receptor potential (TRP) channels pathway, as well as (7S,8S)‐DiHODE, 5S,8R‐DiHODE, and 13(S)‐HpODE in the linoleic acid (LA) metabolism pathway. The DM levels increased, which may be attributed to inflammation. The DMs in the thyroid hormone synthesis pathway were identified, and the contents of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) decreased, which may be crucial in antioxidants. Our findings highlighted the dynamic adjustments in lipid metabolism and the response to inflammation and oxidative stress during the infection of V. harveyi in P. leopardus. This study not only deepens our understanding of the metabolic underpinnings of fish immune responses but also lays the groundwork for research into functional metabolomics and mechanisms of disease resistance. [ABSTRACT FROM AUTHOR]

The presence of bile acids in the cystic fibrosis patient's lungs contributes to an increase in the inflammatory response, in the dominance of pathogens, as well as in the decline in lung function, increasing morbidity. The aim of this study is to determine the effects of exposure of Pseudomonas aeruginosa to primary and secondary bile acids on the production of several virulence factors which are involved in its pathogenic power. The presence of bile acids in the bacterial culture medium had no effect on growth up to a concentration of 1 mM. However, a slight decrease in the adhesion index as well as a reduction in the virulence of the bacteria on the HT29 cell line could be observed. In this model, exposure of P. aeruginosa to bile acids showed a significant decrease in the production of LasB and AprA proteases due to the reduction in the expression of their genes. A decrease in pyocyanin production was also observed in relation to the effects of bile acids on the quorum sensing regulators. In order to have an effect on gene expression, it is necessary for bile acids to enter the bacteria. P. aeruginosa harbors two potential homologs of the eukaryotic genes encoding the bile acid transporters NTCP1 and NTCP2 that are expressed in hepatocytes and enterocytes, respectively. By carrying out a comparative BLAST-P between the amino acid sequences of the PAO1 proteins and those of NTCP1 and NTCP2, we identified the products of the PA1650 and PA3264 genes as the unique homologs of the two eukaryotic genes. Exposure of the mutant in the PA1650 gene to chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) showed a less significant effect on pyocyanin production than with the isogenic PAO1 strain. Also, no effect of CDCA on the PA3264 gene mutant was observed. This result indicated that CDCA should enter the bacteria by the transporter produced by this gene. The entry of LCA into bacteria seemed more complex and rather responded to a multifactorial system involving the product of the PA1650 gene but also the products of other genes encoding potential transporters. [ABSTRACT FROM AUTHOR]

Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice. Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging. Results: Plasma exposure (AUC0–48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0–48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification. Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome. [ABSTRACT FROM AUTHOR]

From a detailed review of 90 experimental and clinical metabolomic investigations of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), we have developed metabolomic hallmarks for both obesity and MASLD. Obesity studies were conducted in mice, rats, and humans, with consensus biomarker groups in plasma/serum being essential and nonessential amino acids, energy metabolites, gut microbiota metabolites, acylcarnitines and lysophosphatidylcholines (LPC), which formed the basis of the six metabolomic hallmarks of obesity. Additionally, mice and rats shared elevated cholesterol, humans and rats shared elevated fatty acids, and humans and mice shared elevated VLDL/LDL, bile acids and phosphatidylcholines (PC). MASLD metabolomic studies had been performed in mice, rats, hamsters, cows, geese, blunt snout breams, zebrafish, and humans, with the biomarker groups in agreement between experimental and clinical investigations being energy metabolites, essential and nonessential amino acids, fatty acids, and bile acids, which lay the foundation of the five metabolomic hallmarks of MASLD. Furthermore, the experimental group had higher LPC/PC and cholesteryl esters, and the clinical group had elevated acylcarnitines, lysophosphatidylethanolamines/phosphatidylethanolamines (LPE/PE), triglycerides/diglycerides, and gut microbiota metabolites. These metabolomic hallmarks aid in the understanding of the metabolic role played by obesity in MASLD development, inform mechanistic studies into underlying disease pathogenesis, and are critical for new metabolite-inspired therapies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the most common cancers. Various options are available for treatment, but prognosis is still poor in the more advanced stages. Current screening methods are not as accurate for distinguishing between benign and malignant growths, resulting in unnecessary invasive procedures. Recently a focus has been placed on identifying metabolites. Of these, taurine has frequently been detected, and this particular compound has a multifactorial role in human physiology. Methods: We conducted a systematic review of studies up till November 2023. Searches were done in three databases‐ MEDLINE, CINAHL‐Ebsco, and PubMed. Three independent reviewers filter titles, abstracts, and full‐texts according to selection criteria. Ten studies (samples = 1714) were identified showing a differential level of taurine in CRC patient samples. Quality assessment accounted for the risk of bias of each study using the 'robvis' tool. Where meaningful comparisons could be made, meta‐analyses were carried out using the 'R' program for precalculated effect sizes with 'metagen' in R. The 'meta' package was utilised for creation of forest plots. Findings: Taurine was shown to significantly increase odds of CRC. It was also significantly associated with being a discriminator for CRC as a diagnostic metabolite. This was maintained at various stages of CRC. Taurine had increased expression in CRC patients, especially when the matrix utilised was blood. Nevertheless, there was significant heterogeneity for some outcomes. Interpretation: In conclusion, these findings highlight the potential of using taurine as well as other bile acid metabolites (lithocholic and ursodeoxycholic acid) to diagnose CRC and illustrate the link with microbiome interactions. Overall increased taurine concentration are associated with significantly increased odds for CRC. There was mostly an increase in relative expression of taurine in CRC samples, excluding results from Wang et al. [ABSTRACT FROM AUTHOR]

Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet. [ABSTRACT FROM AUTHOR]

Gut microbiome is crucial for lipid metabolism in humans and animals. However, how specific gut microbiota and their associated metabolites impact fat deposition remains unclear. In this study, we demonstrated that the colonic microbiome of lean and obese pigs differentially contributes to fat deposition, as evidenced by colonic microbiota transplantation experiments. Notably, the higher abundance of Bifidobacterium pseudocatenulatum was significantly associated with lower backfat thickness in lean pigs. Microbial‐derived lithocholic acid (LCA) species were also significantly enriched in lean pigs and positively correlated with the abundance of B. pseudocatenulatum. In a high‐fat diet (HFD)‐fed mice model, administration of live B. pseudocatenulatum decreased fat deposition and enhances colonic secondary bile acid biosynthesis. Importantly, pharmacological inhibition of the bile salt hydrolase (BSH), which mediates secondary bile acid biosynthesis, impaired the anti‐fat deposition effect of B. pseudocatenulatum in antibiotic‐pretreated, HFD‐fed mice. Furthermore, dietary LCA also decreased fat deposition in HFD‐fed rats and obese pig models. These findings provide mechanistic insights into the anti‐fat deposition role of B. pseudocatenulatum and identify BSH as a potential target for preventing excessive fat deposition in humans and animals. Highlights: The gut microbiota composition and function differ significantly between lean and obese pigs, and breed‐specific microbiomes regulate fat deposition.Gut Bifidobacterium pseudocatenulatum protects against fat deposition by enhancing secondary bile acid biosynthesis.Dietary supplementation with lithocholic acid also helps prevent fat deposition. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes (GD) is associated with a variety of numerous metabolic changes. Discovering related biomarkers by the metabolomic studies can provide a better understanding of the pathological processes involved in the development and progression of GD. Methods: Blood samples were taken from 400 naturally conceived healthy women aged 25–40 years old in the first trimester of pregnancy. Participants were followed up again at 28 weeks of gestation and reevaluated for GD based on American Diabetes Association (ADA) criteria. After identifying 32 women with GD as the case group, 32 healthy matched women selected as the control group. Plasma samples in the first and third trimester, were sent for nuclear magnetic resonance (NMR) testing. Altered biochemical pathways were identified in MetaboAnalyst 4.0 using Human Metabolism Database (HMDB). The comparison of altered metabolomes in two groups was assessed using multivariate logistic regression analysis in SPSS 23 software. Results: In the first trimester, the amount of increase in steroid hormones level was greater in women who progressed to GD (Impact = 0.344). In the third trimester, although we had lower levels of steroid hormones, prostaglandins and bile acids in the diabetic group vs healthy subjects, however the level of glycine conjugated bile acid was higher in affected women by GD (P = 0.016). Conclusions: For the first time, we reported new disrupted pathways such as steroid hormone pathways and their related altered metabolites in a group of Iranian population with GD. This may provide a better and faster way to predict, diagnose and prevent GDM in the future. Surely, further studies are required for the validation of the results. [ABSTRACT FROM AUTHOR]

Cholesterol is a key sterol whose homeostasis is primarily maintained through bile acid metabolism. Proper bile acid formation is vital for nutrient and fat-soluble vitamin absorption and emulsification of lipids. Synthesis of bile acids occurs through two main pathways, both of which rely on 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) to begin epimerization of the 3β hydroxyl of cholesterol into its active 3α conformation. In this sequence, HSD3B7 catalyzes the dehydrogenation of the 3β-hydroxy group followed by isomerization of the Δ5-cholestene-3-one. These reactions are some of the many steps that transform cholesterol for either storage or secretion. HSD3B7 has distinct activity from other 3β-HSD family members leaving significant gaps in our understanding of its mode of catalysis and substrate specificity. In addition, the role of HSD3B7 in health and disease positions it as a metabolic vulnerability that could be harnessed as a therapeutic target. To this end, we evaluated the mechanism of HSD3B7 catalysis and reveal that HSD3B7 displays activity toward diverse 7α-hydroxylated oxysterols. HSD3B7 retains its catalytic efficiency toward these substrates, suggesting that its substrate binding pocket can withstand changes in polarity upon alterations to this hydrocarbon tail. Experiments aimed at determining substrate order are consistent with HSD3B7 catalyzing a sequential ordered bi–bi reaction mechanism with the binding of NAD+ followed by 7α-hydroxycholesterol to form a central complex. HSD3B7 bifunctional activity is dependent on membrane localization through a putative membrane–associated helix giving insight into potential regulation of enzyme activity. We found strong binding of the NADH product thought to activate the isomerization reaction. Homology models of HSD3B7 reveal a potential substrate pocket that allows for oxysterol binding, and mutagenesis was utilized to support this model. Together, these studies offer an understanding of substrate specificity and kinetic mechanism of HSD3B7, which can be exploited for future drug development. [ABSTRACT FROM AUTHOR]

Background Primary sclerosing cholangitis associated with inflammatory bowel disease [IBD-PSC] carries significant morbidity compared to IBD without PSC. Alterations in microbial composition and bile acid [BA] profiles have been shown to modulate chronic inflammation in IBD, but data in IBD-PSC are scarce. We aimed to assess the differences in gut microbiome composition as well as in the BAs profile and BA-related microbial functions between IBD-PSC and IBD-only. Methods In total, 54 IBD-PSC and 62 IBD-only subjects were enrolled from 2012 to 2021. Baseline samples were collected for faecal DNA shotgun metagenomic sequencing, faecal and serum BA quantification using mass spectrometry, and faecal calprotectin. Liver fibrosis measured by transient elastography was assessed in the IBD-PSC group. Data were analysed using general linear regression models and Spearman rank correlation tests. Results Patients with IBD-PSC had reduced microbial gene richness [ p  = 0.004] and significant compositional shifts [PERMANOVA: R 2 = 0.01, p  = 0.03] compared to IBD-only. IBD-PSC was associated with altered microbial composition and function, including decreased abundance of Blautia obeum , increased abundance of Veillonella atypica , Veillonella dispar , and Clostridium scindens [ q  < 0.05 for all], and increased abundance of microbial genes involved in secondary BA metabolism. Decreased serum sulphated and increased serum conjugated secondary BAs were associated with IBD-PSC and increased liver fibrosis. Conclusion We identified differences in microbial species, functional capacity, and serum BA profiles in IBD-PSC compared with IBD-only. Our findings provide insight into the pathophysiology of IBD associated with PSC and suggest possible targets for modulating the risk and course of IBD in subjects with PSC. [ABSTRACT FROM AUTHOR]

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Cirrhotic cardiomyopathy is defined as systolic and diastolic dysfunction in patients with cirrhosis, in the absence of any primary heart disease. These changes are mainly due to the malfunction or abnormalities of cardiomyocytes. Similar to non-cirrhotic heart failure, cardiomyocytes in cirrhotic cardiomyopathy demonstrate a variety of abnormalities: from the cell membrane to the cytosol and nucleus. At the cell membrane level, biophysical plasma membrane fluidity, and membrane-bound receptors such as the beta-adrenergic, muscarinic and cannabinoid receptors are abnormal either functionally or structurally. Other changes include ion channels such as L-type calcium channels, potassium channels, and sodium transporters. In the cytosol, calcium release and uptake processes are dysfunctional and the myofilaments such as myosin heavy chain and titin, are either functionally abnormal or have structural alterations. Like the fibrotic liver, the heart in cirrhosis also shows fibrotic changes such as a collagen isoform switch from more compliant collagen III to stiffer collagen I which also impacts diastolic function. Other abnormalities include the secondary messenger cyclic adenosine monophosphate, cyclic guanosine monophosphate, and their downstream effectors such as protein kinase A and G-proteins. Finally, other changes such as excessive apoptosis of cardiomyocytes also play a critical role in the pathogenesis of cirrhotic cardiomyopathy. The present review aims to summarize these changes and review their critical role in the pathogenesis of cirrhotic cardiomyopathy. [ABSTRACT FROM AUTHOR]

In this study, we investigated whether three microbial strains, Lactiplantibacillus plantarum J-135, Saccharomyces cerevisiae DAE-4, and Bacillus velezensis PBS-17, could be used to reduce mold growth and spoilage during the production of fermented feed. These microorganisms were isolated and characterized via an evaluation of their antibacterial activity, enzymatic activity, bile acid resistance, and acid tolerance. L. plantarum J-135 and S. cerevisiae DAE-4 demonstrated excellent acid tolerance and bile acid resistance, and L. plantarum J-135 exhibited antibacterial activity against Salmonella species. B. velezensis PBS-17 showed the greatest protease, cellulase, α-amylase, and phytase enzymatic activities, and displayed antibacterial activity against Fusarium solani, Aspergillus flavus, Penicillium sp., and Fusarium oxysporum. The three isolated strains were diluted to the same concentration (1:1:1) to create a culture solution, which was added to a standard feed (experimental group) to prepare fermented feed. This was compared with feed treated with a commercially available single probiotic preparation (control group 1) or a mixed microbial preparation that was composed of multiple strains, including B. subtilis. The feed treated with the single probiotic preparation spoiled after 21 days due to insufficient lactic acid bacteria growth, whereas the feed treated with the mixed microbial preparation exhibited mold growth after 14 days. The bacteria and fungi that cause spoilage during fermented feed production were effectively controlled in feed treated with L. plantarum J-135, S. cerevisiae DAE-4, and B. velezensis PBS-17. Therefore, the mixture of these three microbial strains may reduce the risk of spoilage during fermented silage and feed processing, thereby improving storage properties and stability. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic condition that affects about 7 million people worldwide, and new therapies are needed. Understanding the complex roles that bile acids (BAs) play in IBD may lead to the development of novel IBD treatments independent of direct immunosuppression. This review discusses the latest discoveries in the roles BAs play in IBD pathogenesis and explores how these discoveries offer promising new therapeutic targets to treat IBD and improve patient outcomes. Several therapies discussed include specific BA receptor (BAR) agonists, dietary therapies, supplements, probiotics, and mesenchymal stem cell therapies that have all been shown to decrease IBD disease activity. [ABSTRACT FROM AUTHOR]

Recent progress on the underlying biological mechanisms of healthy longevity has propelled the field from elucidating genetic modification of healthy longevity hallmarks to defining mechanisms of gut microbiota influencing it. Importantly, the role of gut microbiota in the healthy longevity of the host may provide unprecedented opportunities to decipher the plasticity of lifespan on a natural evolutionary scale and shed light on using microbiota-targeted strategies to promote healthy aging and combat age-related diseases. This review investigates how gut microbiota affects healthy longevity, focusing on the mechanisms through which gut microbiota modulates it. Specifically, we focused on the ability of gut microbiota to enhance the intestinal barrier integrity, provide protection from inflammaging, ameliorate nutrientsensing pathways, optimize mitochondrial function, and improve defense against age-related diseases, thus participating in enhancing longevity and healthspan. [ABSTRACT FROM AUTHOR]

Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD. [ABSTRACT FROM AUTHOR]

Background: Cholelithiasis is a rare disease in infants, and there is limited data on its risk factors and management. Objectives: To evaluate the risk factors, management, and response to medical treatment of cholelithiasis in infants. Methods: Infants diagnosed with cholelithiasis by ultrasound between 2018 and 2023 were retrospectively analyzed. Details of patient history, imaging findings, current symptoms, and treatments were reviewed. Results: Over 5 years, 98 infants were diagnosed with cholelithiasis. Thirty-three (33.7%) were girls, and the most common risk factors were the use of cephalosporin antibiotic therapy in 46.9%, sepsis in 30.6%, total parenteral nutrition in 29.6%, prematurity in 27.6%, congenital heart disease in 18.4%, and genetic disease (Down syndrome diagnosis in seven patients) in 16.3%. Only fifteen patients (15.3%) were symptomatic. Ursodeoxycholic acid (UDCA) treatment was given to 90.8% of patients, but nine of them used it for a short period or irregularly, and regular users were 81.6%. Gallstones disappeared in 46 patients (46.9%), including 14 (30.4%) without using UDCA regularly. The response rate to UDCA treatment was lower in preterm infants (p = 0.004). Gallstone resolution was higher in the nonusers, 14/18 (77.8%) versus 32/79 (40.5%) (p = 0.03). Acute cholecystitis was observed in only four patients; no other complications were noted. No infant required surgical or endoscopic treatment. Conclusions: UDCA should not be used routinely in children, especially infants, except in symptomatic children with a contraindication to surgery or to reduce clinical symptoms. In the absence of symptoms, patients may be monitored clinically. [ABSTRACT FROM AUTHOR]

Alterations to lipid storage, and the consequent effects on liver structure, need to be considered when replacing wild‐derived fish meal (wd‐FM) with alternative ingredients in formulated diets for commercially aquacultured species. The replacement of wd‐FM is likely to alter the available level of precursors for bile acid production, potentially impacting the absorption of dietary lipids and fat‐soluble vitamins. In this 252‐day study, Yellowtail Kingfish, Seriola lalandi (2.52 ± 0.25 kg; 546 ± 20 mm [fork length; mean ± standard deviation]) were fed five different diets. A 30% wd‐FM diet served as a control. Dietary wd‐FM inclusions were reduced to 20% and 10%, replaced with FM by‐product meal. In addition, dietary wd‐FM levels were reduced to 20% and replaced with poultry meal (PM) or soy protein concentrate (SPC) in two other separate diets. Fat deposition in the liver was similar amongst all treatment groups with bile duct proliferation and periductular fibrosis observed in the livers of fish fed diets with wd‐FM replacement with 10% PM or 10% SPC. Fish fed FM by‐product meal at 10% and 20% replacement displayed similar liver structures to control fish. Yellowtail Kingfish fed a 30% wd‐FM diet may have the FM replaced by up to 66.67% FM by‐product, 33.3% PM or 33.3% SPC without any significant impact on total bile acid synthesis, storage and excretion and liver lipid storage. This research expands our ability to deliver cost‐effective nutritional solutions in support of Yellowtail Kingfish culture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: This systematic review evaluates the effectiveness of fecal microbiota transplantation (FMT) in treating Clostridioides difficile infection (CDI) in mouse models using a metabolomics-based approach. Methods: A comprehensive search was conducted in three databases (PubMed, Scopus, Google Scholar) from 10 April 2024 to 17 June 2024. Out of the 460 research studies reviewed and subjected to exclusion criteria, only 5 studies met all the inclusion criteria and were analyzed. Results: These studies consistently showed that FMT effectively restored gut microbiota and altered metabolic profiles, particularly increasing short-chain fatty acids (SCFAs) and secondary bile acids, which inhibited C. difficile growth. FMT proved superior to antibiotic and probiotic treatments in re-establishing a healthy gut microbiome, as evidenced by significant changes in the amino acid and carbohydrate levels. Despite its promise, variability in the outcomes—due to factors such as immune status, treatment protocols, and donor microbiome differences—underscores the need for standardization. Rather than pursuing immediate standardization, the documentation of factors such as donor and recipient microbiome profiles, preparation methods, and administration details could help identify optimal configurations for specific contexts and patient needs. In all the studies, FMT was successful in restoring the metabolic profile in mice. Conclusions: These findings align with the clinical data from CDI patients, suggesting that FMT holds potential as a therapeutic strategy for gut health restoration and CDI management. Further studies could pave the way for adoption in clinical practice. [ABSTRACT FROM AUTHOR]

Taurine is a non-essential sulfur-containing amino acid that is widely distributed in the human body, primarily supplemented through the diet. Taurine can combine with bile acids to form taurine-conjugated bile acids (Tau-Bas), which can be dissociated to release taurine by the gut microbiota. The interaction between taurine/Tau-Bas and the gut microbiota significantly influences both physiological and pathological processes. This article provides an overview of the gut microbiota and the sources and transformation of taurine in the body, and focuses on the interaction between taurine and the gut microbiota and the effect of taurine supplementation on reshaping gut microbiota homeostasis. The aim is to provide a scientific basis for the development of preventive and therapeutic measures for diseases related to gut microbiota imbalance.

Bile acid (BA), as an important amphoteric sterol in bile, can regulate glucose and lipid metabolism and homeostasis, intestinal microecology, the intestinal barrier, inflammation, the immune system and the nervous system and other physiological functions through interaction with receptors and the intestinal flora, and consequently affect metabolism and nutritional health in the body. In this article, the synthesis pathways of the major new functional BAs are reviewed, and recent progress in research on their functional activity, chemical synthesis and biotransformation is systematically summarized. In addition, this article summarizes the functional studies of selected novel BAs (isodeoxycholic acid, isolithocholic acid (isoLCA), isoallodeoxycholic acid, and isoallolithocholic acid), as well as the microbial sources and catalytic properties of bioconvertases associated with the novel BAs and their potential for application in BA synthesis. Moreover, this article provides an outlook on the application potential of functional BAs in the fields of food and medicine, which provide a reference for the synthesis and transformation of new functional BAs and their comprehensive applications.

Aim: demonstration of basic molecular biological, metabolic and immunological effects of fecal microbiota transplantation (FMT), on the example of a rare case of acute graft-versus-host disease (GVHD) with intestinal damage in a patient after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Materials and methods. To monitor the basic effects of FMT, we performed targeted DNA sequencing of 16S rRNA gene (V3–V4) using MiSeq platform as well as multiplex real-time PCR, MS/gas chromatography technique, immunophenotyping of blood lymphocytes, histological and immunohistochemical techniques.Clinical case. A 40-year-old female patient diagnosed with myelodysplastic syndrome, with a history of two unsuccessful allo-HSCTs due to graft failure, underwent the third haploidentical HSCT (haplo-HSCT) from her father as ‘salvage’ therapy. Due to early viral/bacterial colitis post-transplant associated with a multidrug-resistant strain of K. pneumoniae and herpes virus type 6, FMT was performed on days 46 and 47 after allo-HSCT. Complete resolution of the enteropathy symptoms was noted following FMT. However, immunosuppressive therapy was canceled on D+106 after haplo-HSCT due to the detection of minimal residual disease causing development of the ‘overlap’-type GVHD with damage skin lesions grade 4, and intestinal mucous membranes grade 3. This complication required resumption and subsequent intensification of immunosuppressive therapy with complete resolution of GVHD symptoms. Following FMT treatment, the patient showed complete resolution of clinical colitis symptoms. According to results of 16S rRNA sequencing, the species-specific diversity of fecal microbiota increased significantly, along with decreased relative contents of opportunistic bacteria (Klebsiella, Enterococcus, Streptococcus genera). A significant growth was revealed for commensal Bacteroidota, and re-emergence of Faecalibacterium, Blautia, Roseburia. Acute gastrointestinal GVHD promoted by tacrolimus withdrawal was associated with repeated depletion of intestinal microbiota. Upon resolution of GVHD and resumed immunosuppression, increased microbiota diversity (Shannon index) was again recorded, and the parameters of patient’s fecal microbiota reached the donor values. The microbiota shifts at all clinical stages (before and after FMT, at the peak of acute intestinal GVHD and intensive immunosuppressive therapy) showed some relations with metabolism of bile and fatty acids in blood plasma and immune parameters.Conclusions. FMT may be a component of complex therapy aimed at early reconstitution of immune system and organic acid metabolism in patients after allo-HSCT. The composition of fecal microbiota, metabolic profile and spectrum of lymphocyte subpopulations may be markers for monitoring complex rehabilitation after allo-HSCT.

Intestinal metabolites produced by gut microbes play a significant role in host health. Due to their different chemical structures, they are often analyzed using multiple analyzers and methods, such as gas chromatography/mass spectrometry (GC/MS) for SCFAs and liquid chromatography/mass spectrometry (LC/MS) for bile acids (BAs), amino acids (AAs), and sugars. In this study, we aimed to develop a specialized method for the simultaneous determination of important intestinal metabolites, specifically addressing the main issue of SCFA volatilization during the dry solidification process. We discovered that these compounds can all be measured in fecal samples by GC/MS after trimethylsilyl (TMS) derivatization despite the expected volatility of SCFAs. Validating the results using SCFA standards suggested that the fecal matrix exerts a stabilizing effect. This method enabled the simultaneous quantification of 65 metabolites. For further validation in a biological context, a mouse study showed that high-MAC and high-fat diets increased SCFAs and BAs in feces, respectively, and showed a negative correlation between Alistipes and sugars, all consistent with previous studies. As a result, we successfully developed a specialized simultaneous quantification method for SCFAs, BAs, AAs, AA derivatives, and sugars in fecal samples using GC/MS-based metabolomics in conjunction with a TMS derivatization pretreatment process.

Changes in the composition of gut-associated microbial communities are associated with many human illnesses, but the factors driving dysbiosis remain incompletely understood. One factor governing the microbiota composition in the gut is bile. Bile acids shape the microbiota composition through their antimicrobial activity and by activating host signaling pathways that maintain gut homeostasis. Although bile acids are host-derived, their functions are integrally linked to bacterial metabolism, which shapes the composition of the intestinal bile acid pool. Conditions that change the size or composition of the bile acid pool can trigger alterations in the microbiota composition that exacerbate inflammation or favor infection with opportunistic pathogens. Therefore, manipulating the composition or size of the bile acid pool might be a promising strategy to remediate dysbiosis.

Background: Primary bile acid synthesis is impaired in peroxisomal disorders, leading to the accumulation of long-chain bile acids, specifically dihydroxycholestanoic and trihydroxycholestanoic acids. Quantification of the diastereoisomers of these C27 bile acids is essential for the differential diagnosis of these disorders. Methods: High-performance liquid chromatography electrospray ionization-tandem mass spectrometry with stable-isotope dilution was used to quantify all eight diastereoisomers of cholestanoic acids in serum. Clinical ranges were established for patients with and without cholestatic liver disease, as well as for those with peroxisomal disorders. Results: The assay was linear over the range of 20–2,500 ng/mL, and intra- and inter-assay imprecision was 10-fold higher (14.06 ± 2.59 μmol/L). Patients with heterozygous mutations in PEX genes had low concentrations of serum C27 bile acids. In all groups, the (25S)- and (25R)-diastereomers were present in a ratio of 0.3. In cases of 2-methylacyl-CoA racemase deficiency, serum total C27 bile acids were markedly elevated (10.61 ± 0.92 μmol/L) and comprised exclusively the (25R)-diastereoisomer. Conclusions: This tandem mass spectrometric assay quantifies all diastereoisomers of the C27 cholestanoic acids in serum and was used to establish typical clinical concentration ranges. The method is applicable to the diagnosis of peroxisomal disorders and differentiates 2-methylacyl-CoA racemase deficiency from other peroxisomal biogenesis disorders.

Abstract Colorectal polyps are precursors of colorectal cancer. Metabolic dysfunction associated steatohepatitis (MASH) is one of metabolic dysfunction associated fatty liver disease (MAFLD) phenotypic manifestations. Much evidence has suggested an association between MASH and polyps. This study investigated the biomarkers of MASH and colorectal polyps, and the prediction of targeted drugs using an integrated bioinformatics analysis method. Differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) were performed on GSE89632 and GSE41258 datasets, 49 shared genes revealed after intersection. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses depicted they were mainly enriched in apoptosis, proliferation and infection pathways. Machine learning algorithms identified S100P, FOXO1, and LPAR1 were biomarkers for colorectal polyps and MASH, ROC curve and violin plot showed ideal AUC and stable expression patterns in both the discovery and validation sets. GSEA analysis showed significant enrichment of bile acid and fatty acid pathways when grouped by the expression levels of the three candidate biomarkers. Immune infiltration analysis showed a significant infiltration of M0 macrophages and Treg cells in the colorectal polyps group. A total of 9 small molecule compounds were considered as potential chemoprevention agents in MASH and colorectal polyps by using the CMap website. Using integrated bioinformatics analysis, the molecular mechanism between MASH and colorectal polyps has been further explored.

Abstract Background Given the high prevalence of gestational diabetes mellitus and its significant impact on maternal and neonatal health, identifying reliable biomarkers for prediction and diagnosis is essential. The increased incidence of gestational diabetes mellitus among patients with intrahepatic cholestasis of pregnancy suggests a possible association between serum total bile acid levels and gestational diabetes mellitus. This study evaluated the relationship between total bile acid levels and gestational diabetes mellitus incidence. Methods A systematic search was performed on February 19, 2024, for studies examining the association between total bile acid levels and gestational diabetes mellitus incidence in both the general pregnant population and patients diagnosed with intrahepatic cholestasis of pregnancy. Meta-analyses were conducted to compare pooled total bile acid levels between patients with and without gestational diabetes mellitus, as well as to assess gestational diabetes mellitus prevalence in patients with mild (10 ≤ total bile acid

ABSTRACT: Bile acids (BA) play a crucial role not only in lipid digestion but also in the regulation of overall energy homeostasis, including glucose and lipid metabolism. The aim of this study was to investigate BA profiles and mRNA expression of BA-related genes in the liver of high versus normal body condition in dairy cows. We hypothesized that body condition and the transition from gestation to lactation affect hepatic BA concentrations as well as the mRNA abundance of BA-related receptors, regulatory enzymes, and transporters. Therefore, we analyzed BA in the liver as well as the mRNA abundance of BA-related synthesizing enzymes, transporters, and receptors in the liver during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into groups with high body condition score (HBCS; n = 19) or normal body condition score (NBCS; n = 19) based on BCS and backfat thickness (BFT). Cows were fed diets aimed at achieving the targeted differences in BCS and BFT (NBCS: BCS 3.75, BFT >1.4 cm) until they were dried off at wk 7 before parturition. Both groups were fed identical diets during the dry period and subsequent lactation. Liver biopsies were taken at wk −7, 1, 3, and 12 relative to parturition. For BA measurement, a targeted metabolomics approach with liquid chromatography electrospray ionization MS/MS was used to analyze BA in the liver. The mRNA abundance of targeted genes related to BA synthesizing enzymes, transporters, and receptors in the liver was analyzed using microfluidic quantitative PCR. In total, we could detect 14 BA in the liver: 6 primary and 8 secondary BA, with glycocholic acid (GCA) being the most abundant one. The increase of glycine-conjugated BA after parturition, in parallel to increasing serum glycine concentrations may originate from an enhanced mobilization of muscle protein to meet the high nutritional requirements in early lactating cows. Higher DMI in NBCS cows compared with HBCS cows was associated with higher liver BA concentrations such as GCA, deoxycholic acid, and cholic acid. The mRNA abundance of BA-related enzymes measured herein suggests the dominance of the alternative signaling pathway in the liver of HBCS cows. Overall, BA profiles and BA metabolism in the liver depend on both, the body condition and lactation-induced effects in periparturient dairy cows.

Abstract Background Bile acids are vital regulators of liver metabolism, and their dysregulation is closely linked with the progression of nonalcoholic fatty liver disease (NAFLD). Profiling these bile acids may provide valuable diagnostic and prognostic markers for these conditions. This study aimed to evaluate bile acid profiles in NAFLD patients and assess their potential as biomarkers for diagnosing and predicting disease progression. Serum levels of 14 bile acids were measured in 25 normal healthy controls (NHC), 35patients with metabolic dysfunction–associated steatotic liver disease (MASLD), and 40 patients with NASH, categorized by the NAFLD Activity Score (NAS). Quantification was performed using high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS). Results Primary unconjugated bile acids, CA and CDCA, along with conjugated acids GCA, GCDCA, TCA, and TCDCA, were significantly elevated in both MASLD and NASH compared to NHC (all p

Abstract Background Metabolomics is an emerging field that quantifies numerous metabolites systematically aiming to determine the metabolites corresponding to each biological phenotype and then provide an analysis of the mechanisms involved. Bile acids (as an organic metabolites) are synthesized in the liver from cholesterol and could be used as indicator of hepatobiliary impairment. However, the role of these bile acids in the pathogenesis of cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) is still unclear. Therefore, the current study aimed to use serum bile acid profiles potential diagnostic biomarkers for early detection of cholangiocarcinoma and differentiating it from hepatocellular carcinoma. Subjects and methods Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/ MS) analytical method was used for the measurement of bile acids in the serum of patients with hepatocellular carcinoma (n = 35), cholangiocarcinoma (n = 35), and control group (n = 35) to determine role as markers for differentiation between hepatocellular carcinoma and cholangiocarcinoma. Results This study revealed that there was a significant increase in all 14 bile acids in both HCC and CCA compared to control. Also, there was significant increase in LCA, TCA, GDCA, and GCA in cholangiocarcinoma (CCA) compared to HCC with AUC 0.775, 0.825, 0.797, and 0.831 respectively with highest sensitivity and specificity for GCA (82% and 74%, respectively) for differentiation between the two types of cancers. Conclusion Determination of the serum bile acids pattern using UPLC/MS/MS may help to differentiate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) especially GCA which may be a good biomarker for differentiation between two types of liver cancers.

Abstract Background Metabolic disorders have become one of the global medical problems. Due to the complexity of its pathogenesis, there is still no effective treatment. Bile acids (BAs) and gut microbiota (GM) have been proved to be closely related to host metabolism, which could be important targets for metabolic disorders. Zhi-Kang-Yin (ZKY) is a traditional Chinese medicine (TCM) formula developed by the research team according to theory of TCM and has been shown to improve metabolism in clinic. However, the underlying mechanisms are unclear. Aim of the study This study aimed to investigate the potential mechanisms of the beneficial effect of ZKY on metabolism. Methods High-fat diet (HFD)-fed mice were treated with and without ZKY. The glucose and lipid metabolism-related indexes were measured. BA profile, GM composition and hepatic transcriptome were then investigated to analyze the changes of BAs, GM, and hepatic gene expression. Moreover, the relationship between GM and BAs was identified with functional gene quantification and ex vivo fermentation experiment. Results ZKY reduced weight gain and lipid levels in both liver and serum, attenuated hepatic steatosis and improved glucose tolerance in HFD-fed mice. BA profile detection showed that ZKY changed the composition of BAs and increased the proportion of unconjugated BAs and non-12-OH BAs. Hepatic transcriptomic analysis revealed fatty acid metabolism and BA biosynthesis related pathways were regulated. In addition, ZKY significantly changed the structure of GM and upregulated the gene copy number of bacterial bile salt hydrolase. Meanwhile, ZKY directly promoted the growth of Bifidobacterium, which is a well-known bile salt hydrolase-producing genus. The ex vivo co-culture experiment with gut microbiota and BAs demonstrated that the changes of BAs profile in ZKY group were mediated by ZKY-shifted GM, which led to increased expression of genes associated with fatty acid degradation in the liver. Conclusion Our study indicated that the effect of ZKY on improving metabolism is associated with the modulation of GM-BAs axis, especially, by upregulating the abundance of bile salt hydrolase-expression bacteria and increasing the levels of unconjugated BAs. This study indicates that GM-BAs axis might be an important pathway for improving metabolic disorders by ZKY.