Bile Acid Levels Research Articles

The role of the Systemic Inflammatory Response Index (SIRI) and other maternal biochemical markers in determining the severity of intrahepatic cholestasis of pregnancy.

To investigate the roles of the systemic inflammatory response index (SIRI) and other biochemical markers obtained from maternal blood in determining the diagnosis and severity of pregnancy cholestasis. In this retrospective case-control study, a total of 815 pregnant women including 546 healthy pregnant women [serum total bile acid (TBA) level < 10 μmol/L, control group], 185 patients with mild cholestasis [serum TBA level < 40 μmol/L, mild intrahepatic cholestasis of pregnancy (ICP) group] and 84 patients with severe cholestasis (serum TBA level ≥ 40 μmol/L, severe ICP group) were evaluated. The groups were compared regarding demographic data, clinical characteristics, SIRI (neutrophilcount*monocytecount/lymphocyte count), and other laboratory data. Cut-off values that could predict ICP were calculated. The average neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI) were found to be statistically significantly higher in the severe ICP group compared with the control group and mild ICP group (p < 0.01 and p < 0.05). The best SIRI cut-off value was 2.3302 (60.3% sensitivity and 52.2% specificity) [area under the curve: 0.590 ± 0.023, 95% confidence interval (CI): 0.546-0.634; p < 0.001]. SIRI may be a useful marker in determining the diagnosis and severity of ICP. However, were commend that studies be conducted in larger groups and indifferent trimesters.

Comparative Analysis of γ-Cyclodextrin, Perilla Oil, and Their Inclusion Complexes on Liver Injury and Dyslipidemia Associated with Elevated Gastrointestinal 12-Hydroxylated Bile Acid Levels

Our previous study demonstrated that γ-cyclodextrin (γ-CD)–perilla oil inclusion complexes increase plasma α-linolenic acid and eicosapentaenoic acid levels in healthy rats without adverse effects. The present study examined the effects of perilla oil, γ-CD, and their inclusion complexes on rats fed cholic acid (CA) to mimic the elevated gastrointestinal 12-hydroxylated (12OH) bile acid levels in high-fat diet-fed rats. Rats fed CA (CA group) tended to have higher AST, ALT, plasma total cholesterol (T-CHO), and triglyceride (TG) levels compared to controls fed a standard diet without CA. Rats fed CA and perilla oil (CA+LP group) showed a tendency for lower AST and plasma TG levels than those in the CA group. Rats fed CA and γ-CD (CA+CD group) had significantly higher AST, ALT, plasma T-CHO, and TG levels than the controls, indicating severe liver injury and dyslipidemia. Rats fed CA and the γ-CD–perilla oil inclusion complex (CA+IC group) had significantly lower AST and ALT levels than the CA+CD rats, with a trend towards lower plasma T-CHO and TG levels. Plasma α-linolenic acid and eicosapentaenoic acid levels were significantly higher in the CA+LP and CA+IC groups than in the controls and CA+CD groups. However, the CA+IC group tended to have lower α-linolenic acid levels and significantly lower eicosapentaenoic acid levels than the CA+LP group. This suggests an accelerated conversion of α-linolenic acid to eicosapentaenoic acid in the CA+IC group, which may contribute to the attenuation of liver injury and dyslipidemia. These findings suggest that γ-CD may exacerbate liver injury and dyslipidemia caused by elevated gastrointestinal 12OH bile acid levels, whereas γ-CD–perilla oil inclusion complexes may ameliorate these effects by altering fatty acid metabolism. Furthermore, we recommend evaluating γ-CD safety in both healthy and pathological models and carefully selecting compounds co-ingested with γ-CD.

Sequential Versus Continuous Feeding and Its Effect on the Gut Microbiota in Critically Ill Patients: A Randomized Controlled Trial.

Gut microbiota disturbance may worsen critical illnesses and is responsible for the progression of multiple organ dysfunction syndrome. In our previous study, there was a trend towards a higher α-diversity of the gut microbiota in sequential feeding (SF) than in continuous feeding (CF) for critically ill patients. We designed this non-blinded, randomized controlled study to confirm these results. All the enrolled patients received continuous feeding in the beginning. After achieving ≥80% of the nutrition target calories (25-30 kcal/kg/d), the patients were randomized into the SF group or the CF group. In the SF group, continuous feeding was changed into intermittent feeding. The total daily dosage of enteral nutrition was equally distributed during three periods at 7-9:00, 11-13:00 and 17-19:00. After 7 days of randomization, fresh stool and serum were collected for 16S rRNA gene sequencing and untargeted metabolomics analysis respectively. Meanwhile, routine blood test indicators and metabolic indicators were recorded. Finally, data from 65 patients in the SF group and 69 patients in the CF group were used for intention-to-treat analysis. There was no difference in the Shannon index between the SF group and CF group [2.5 (1.7-3.4) vs. 2.6 (1.5-3.5), P =0.934]. However, at the genus level, the abundances of Erysipelotrichaceae_UCG-003 and Howardella increased in the SF group. Some metabolic indicators (the albumin level, total cholesterol level and total bile acid level) and the increases in lymphocyte counts in the SF group were different from those in the CF group (P <0.05). In untargeted metabolomic analysis, 58 differentially abundant metabolites between the two groups were found. The pathway with the highest enrichment factors was primary bile acid biosynthesis according to the Kyoto Encyclopedia of Genes and Genomes Database classification. Regarding adverse events, the gut tolerance, average glucose and incidence of hyperglycemia and hypoglycemia were similar between the SF group and CF group. The mortality rate in the SF group was lower than that in the CF group, but there was no statistical difference (9.2% vs. 13.0%, P=0.484). SF did not increase the diversity of gut microbiota in critically ill patients. However, it did alter the abundances of some gut microbes and affect some metabolites. Its clinical significance requires further exploration. In addition, the gut tolerance and safety of SF were similar to that of CF. www. gov, registration number NCT04443335. Registered 21 June, 2020.

Host metabolism balances microbial regulation of bile acid signalling.

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2-4, immune responses5-7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.

Real-world effectiveness and safety of bulevirtide monotherapy for up to 96 weeks in patients with HDV-related cirrhosis.

Bulevirtide (BLV) 2 mg/day is EMA approved for treatment of compensated chronic hepatitis due to Delta virus (HDV) infection, however real-life data in large cohorts of patients with cirrhosis are lacking. Consecutive HDV-infected patients with cirrhosis starting BLV 2 mg/day since September 2019 were included in a European retrospective multicenter real-life study (SAVE-D). Patient characteristics before and during BLV treatment were collected. Virological, biochemical, combined responses, adverse events and liver-related events (HCC, decompensation, liver transplant) were assessed. 244 patients with HDV-related cirrhosis receiving BLV monotherapy for a median of 92 (IQR 71-96) weeks were included: at BLV start, median (IQR) age was 49 (40-58) years, 61% men, ALT 80 (55-130) U/L, liver stiffness measurement (LSM) 18.3 (13.0-26.3) kPa, platelets 94 (67-145) x 103/mm3, 54% with esophageal varices, 95% Child Pugh score A, 10% HIV-coinfected, 92% on NUC, median HDV RNA 5.4 (4.1-6.5) Log10 IU/mL, HBsAg 3.8 (3.4-4.1) Log10 IU/mL. At weeks (W)48 and 96, virological, biochemical and combined responses were observed in 65% and 79%, 61% and 64%, 44% and 54% of patients, respectively. AST, GGT, albumin, IgG and LSM values significantly improved throughout treatment. Serum bile acid levels increased in most patients, only 10% patients reported mild and transient pruritus, independently of bile acid levels. The W96 cumulative risk of de-novo HCC and decompensation was 3.0% (95% CI 2-6%) and 2.8% (95% CI 1-5%), respectively. Thirteen (5%) patients underwent liver transplantation (n=11 for HCC, n=2 for decompensation). BLV 2 mg/day monotherapy up to 96 weeks was safe and effective in patients with HDV-related cirrhosis. Virological and clinical responses increased over time. Liver-related complications were few.

Goose Deoxycholic Acid Ameliorates Liver Injury in Laying Hens with Fatty Liver Hemorrhage Syndrome by Inhibiting the Inflammatory Response

Fatty liver hemorrhagic syndrome (FLHS) in laying hens is a nutritional and metabolic disease involving liver enlargement, hepatic steatosis, and hepatic hemorrhage as the primary symptoms. The syndrome is prone to occur during the peak laying period of laying hens, which has resulted in significant economic losses in the laying hen breeding industry; however, the specific pathogenesis of FLHS remains unclear. Our group and previous studies have shown that bile acid levels are significantly decreased during the development of fatty liver and that targeted activation of bile acid–related signaling pathways is beneficial for preventing and treating fatty liver. In this study, we generated a FLHS laying hen model by feeding hens a high-energy, low-protein diet, with goose deoxycholic acid (CDCA) given as an intervention. HE staining, fluorescence quantitative PCR, and ELISA were used to evaluate the effects of CDCA on pathological changes and inflammatory responses in the liver. The results showed that hepatic hemorrhage in FLHS laying hens was reduced after CDCA treatment. Furthermore, fat vacuoles and transaminase levels decreased significantly. In addition, expression levels of M1-type macrophage markers and polarization products were significantly reduced, and the expression of pro-inflammatory regulatory factors related to the JAK-STAT signaling pathway, LPS-TLR4-Myd88–NF-kB signaling pathway, and NLRP3 inflammasomes decreased significantly as well. Expression levels of M2-type macrophage markers and polarization products increased significantly, as did the expression of anti-inflammatory regulators related to the JAK-STAT signaling pathway. These results suggest that CDCA ameliorates liver injury in laying hens with FLHS by inhibiting macrophage M1-type polarization and the resulting pro-inflammatory response, thereby promoting M2-type macrophage polarization and an anti-inflammatory response.

Probiotic interventions with highly acid-tolerant Levilactobacillus brevis strains improve lipid metabolism and gut microbial balance in obese mice.

Many studies have shown that specific lactic acid bacteria (LAB) strains can delay obesity, offering a viable alternative to medications and surgeries. However, the mining and development of highly effective LAB strains for obesity control is still limited. In this study, the naturally highly acid-tolerant and gamma-aminobutyric acid-producing Levilactobacillus brevis D17 and its glnR deletion strain were used to investigate their anti-obesity effects. In an 8-week mouse experiment, L. brevis D17 and its glnR-deletion strain D17ΔglnR significantly reduced weight gain by 28.4% and 29.1%, respectively, improving abnormal serum indicators and glucose metabolism caused by a high-fat diet. Furthermore, L. brevis D17 and its glnR-deletion strain D17ΔglnR successfully colonized in the gut. Both D17 and D17ΔglnR interventions significantly restored the relative abundance of Muribaculaceae, Ileibacterium valens, Lactobacillus, Faecalibaculum, Bifidobacterium globosum, Akkermansia muciniphila, and Romboutsia ilealis, whereas they significantly reduced potentially harmful bacteria like Leptogranulimonas, Flintibacter, and Alistipes. Additionally, L. brevis intervention effectively decreased the levels of primary bile acids and increased secondary bile acids in the gut, thus balancing bile acid metabolism. The transcriptional analysis suggested that D17 and D17ΔglnR interventions may activate the AMPK signaling pathway in the liver to inhibit lipogenesis, activate the cAMP pathway to promote lipolysis, and inhibit pro-inflammatory macrophage infiltration to block inflammatory responses. These results indicate that L. brevis D17 and its glnR-deletion mutant strain D17ΔglnR show great potential in combating obesity. Moreover, these results also provide insights into the underlying mechanism behind their anti-obesity properties.

Alpha-1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid-Inducible Manner.

The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha-1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids. AAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence-activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton-X extraction. Inclusion composition was evaluated through mass-spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)-supplemented chow for 7 days. MS identified the key endoplasmic reticulum chaperone 78 kDa glucose-regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA-mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates. Our results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage. NCT02929940.

Application of physiologically based (PBK) modeling to quantify the effect of the antibiotic tobramycin on bile acid levels in human plasma.

Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats. Kinetic parameters to define the effects of tobramycin on intestinal bile acid transport were determined in vitro using a Caco-2 cell layer Transwell model for studying the intestinal translocation of 4 model bile acids including glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA), the latter as a model for unconjugated bile acids (uBA). Kinetic constants for the effect of tobramycin on intestinal microbial deconjugation were taken from previous in vitro studies using anaerobic fecal incubations. The PBK model simulations predicted that exposure to tobramycin at the dose level also used in the previous 28day rat study would reduce human plasma Cmax levels of GCA, GCDCA, GDCA, and DCA by 42.4%, 27.7%, 16.9%, and 75.8%. The reduction of conjugated bile acids is governed especially via an effect on ASBT-mediated intestinal uptake, and not via the effect of tobramycin on intestinal conjugation, likely because deconjugation happens to a large extent in the colon which has limited subsequent bile acid reuptake. The results reflect that oral exposure to xenobiotics that are not or poorly bioavailable can affect systemic bile acid homeostasis. Altogether, the PBK model appears to provide a 3R compliant tool to evaluate the effect of oral exposure to xenobiotics on host bile acid homeostasis via effects on intestinal bile acid deconjugation and reuptake.

Bile acids in follicular fluid: potential new therapeutic targets and predictive markers for women with diminished ovarian reserve

ObjectiveTo investigate the changes in bile acid (BA) metabolites within the follicular fluid (FF) of patients with diminished ovarian reserve (DOR) and to identify novel diagnostic markers that could facilitate early detection and intervention in DOR patients.DesignA total of 182 patients undergoing assisted reproductive technology (ART) were enrolled and categorized into the normal ovarian reserve (NOR) group (n = 91) or the DOR group (n = 91) to measure BA levels in FF. To identify the changes in granulosa cells (GCs), we collected GCs from an additional 7 groups of patients for transcriptome sequencing.SettingReproductive medicine center within a hospital and university research laboratory.PopulationA total of 182 patients undergoing assisted reproductive technology were enrolled and categorized into the NOR group (n = 91) or the DOR group (n = 91).MethodsIn this study, BA metabolites in FF of DOR and NOR patients were analyzed in detail by targeted metabolomics, and the correlation between BA levels in FF and clinical indicators was discussed. Then, we constructed a diagnostic model for DOR using the random forest algorithm based on five different BAs. Additionally, we performed a functional enrichment analysis on differentially expressed genes (DEGs) in GCs from both DOR and NOR patients.Main outcome measuresBA levels in FF and their correlation with clinical indicators; the areas under the curve (AUCs) of the random forest diagnostic model for DOR; and the DEGs and corresponding functional enrichment results of GC RNA analysis.Result (s)The levels of lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid and cholic acid in FF of DOR group were lower than those of NOR group. And significant reductions in total, primary, secondary, and unconjugated BA levels were observed in the DOR group. The above five BAs levels were closely related to indicators of ovarian reserve. The AUC of the diagnostic model based on the above five BAs was 0.964. Based on transcriptome sequencing data from two groups of GCs, a total of 482 up-regulated and 654 down-regulated DEGs were identified. Gene ontology analysis revealed that the metabolic and biosynthetic processes of fatty acids, steroids, and cholesterol were enriched in these DEGs, whereas Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of fatty acid and ovarian steroidogenesis.Conclusion(s)The levels of multiple BA metabolites in FF are significantly lower than those in patients with DOR and are closely related to the evaluation of ovarian reserve function.

Levels of Bile Acid Metabolism Are Associated With Alterations of Gut Microbes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.

Rol de la alteración del eje microbiota-intestino-hígado en la enfermedad hepática esteatósica asociada a disfunción metabólica

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of liver morbidity worldwide, including conditions such as hepatocellular carcinoma and the need for liver transplantation, with a particularly high prevalence in Latin America. The pathogenesis of MASLD is multifactorial, involving both genetic and environmental factors, including dysfunction of the gut-liver axis. The mechanisms involved in the progression of liver disease to cirrhosis are not yet fully understood. Recently, the intestinal microbiota has been recognized as playing a crucial role in disease progression by modulating systemic and hepatic inflammatory responses. In MASLD patients, microbial dysbiosis contributes to intestinal barrier dysfunction, increasing intestinal permeability and facilitating the translocation of microbial products to the liver, thereby exacerbating inflammation and hepatic damage. Additionally, alterations in bile acid levels and microbial metabolites further reinforce this pathological cycle. Therapeutic strategies aimed at restoring microbial balance—such as fecal microbiota transplantation, probiotics, prebiotics, and synbiotics—have shown promising results in modulating the microbiota-gut-liver axis and slowing MASLD progression. Further studies are needed to fully understand their impact on the pathophysiology of MASLD and to strengthen their integration into current therapeutic protocols for this disease.

Clostridium Scindens Protects Against Vancomycin-Induced Cholestasis and Liver Fibrosis by Activating Intestinal FXR-FGF15/19 Signaling.

Primary sclerosing cholangitis (PSC) is characterized by abnormal bile acid metabolites and altered gut microbiota, with no effective treatments available. Vancomycin, a glycopeptide antibiotic, has emerged as a promising candidate. However, the mechanism by which vancomycin impacts the progression of PSC remains unknown. Mice treated with vancomycin exhibit increased hepatic collagen deposition and injury, due to the inhibition of intestinal FXR-FGF15/19 axis and the elevation of bile acid levels. These effects are associated with the reduction in Clostridia XIVa, especially Clostridium scindens (C. scindens). Gavage of C. scindens alleviates vancomycin-induced bile acid accumulation and liver fibrosis via activating intestinal FXR-FGF15/19 signaling. Similar effects are observed in mice treated with engineered Escherichia coli Nissle 1917 that are capable of expressing bile acid 7α-dehydratas (BaiE) from C. scindens (EcN-BaiE). Activating intestinal FXR-FGF15/19 signaling by fexaramine (Fex) or recombinant protein FGF19 reverse vancomycin-induced liver injury and fibrosis. These results demonstrate that long-term oral vancomycin exacerbates cholestatic liver injury, while C. scindens mitigates this effect by activating the intestinal FXR-FGF15/19 signaling pathway. This underscores the importance of monitoring bile acid levels in PSC patients receiving vancomycin treatment and suggests that C. scindens may serve as a potential therapeutic approach for PSC patients.

Bifidobacterium longum subsp. longum relieves loperamide hydrochloride-induced constipation in mice by enhancing bile acid dissociation.

Bifidobacterium species are known for their efficacy in alleviating constipation. This study aimed to compare the constipation-relieving effects of different Bifidobacterium species (Bifidobacterium longum subsp. longum, Bifidobacterium bifidum, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium longum subsp. infantis, and Bifidobacterium adolescentis) and to explore the underlying mechanisms from both the bacterial and host perspectives. We evaluated six Bifidobacterium species for their physiological properties, including growth rate, oligosaccharide utilization, osmotic pressure resistance, cell adhesion, and bile acid dissociation capability. Mice with severe constipation induced by loperamide hydrochloride were treated with these bacteria at a density of 109 CFU per mL for 17 days. Gastrointestinal indices such as fecal water content, time to first black stool defecation, and small intestine propulsion rate were measured to assess constipation relief. Microbiome and metabolome (bile acid and tryptophan) analyses were conducted to elucidate the differences in constipation relief among the species. Our results demonstrated that Bifidobacterium longum subsp. longum exhibited superior physiological traits, including rapid growth, extensive oligosaccharide utilization, and high bile salt dissociation capacity. Notably, only Bifidobacterium longum subsp. longum significantly ameliorated constipation symptoms in the mouse model. Furthermore, this strain markedly restored bile acid and short-chain fatty acid levels in the intestines of constipated mice and altered the composition of the intestinal microbiota. These findings suggest that the enhanced efficacy of Bifidobacterium longum subsp. longum in relieving constipation is associated with its ability to modulate intestinal physiology and microbiota structure and metabolism.

Exploring the Fecal Metabolome in Infants With Cow's Milk Allergy: The Distinct Impacts of Cow's Milk Protein Tolerance Acquisition and of Synbiotic Supplementation.

Cow's milk allergy (CMA) is one of the most prevalent food allergies in early childhood, often treated via elimination diets including standardamino acid-based formula or amino acid-based formula supplemented with synbiotics (AAF or AAF-S). This work aimed to assess the effect of cow's milk (CM) tolerance acquisition and synbiotic (inulin, oligofructose, Bifidobacterium breve M-16V) supplementation on the fecal metabolome in infants with IgE-mediated CMA. The CMA-allergic infants received AAF or AAF-S for a year during which fecal samples were collected. The samples were subjected to metabolomics analyses covering gut microbial metabolites including SCFAs, tryptophan metabolites, and bile acids (BAs). Longitudinal data analysis suggested amino acids, BAs, and branched SCFAs alterations in infants who outgrew CMA during the intervention. Synbiotic supplementation significantly modified the fecal metabolome after 6 months of intervention, including altered purine, BA, and unsaturated fatty acid levels, and increased metabolites of infant-type Bifidobacterium species: indolelactic acid and 4-hydroxyphenyllactic acid. This study offers no clear conclusion on the impact of CM-tolerance acquisition on the fecal metabolome. However, our results show that 6 months of synbiotic supplementation successfully altered fecal metabolome and suggest induced bifidobacteria activity, which subsequently declined after 12 months of intervention.

Associations of plasma acylcarnitine and bile acid levels with incidence of coronary heart disease in Chinese adults

Objective: To explore the associations of plasma acylcarnitine and bile acid levels with the risk of incident coronary heart disease (CHD) in Chinese adults. Methods: The baseline survey of China Kadoorie Biobank (CKB) took place in 10 areas across China during 2004-2008, and the first resurvey took place from July to October 2008, with collection of data via questionnaire, physical examination and blood samples. The current study was based on 2 159 individuals with targeted mass spectrometry metabolomic measurements from the first resurvey of CKB. The associations of acylcarnitines and bile acids with incident CHD were assessed using Cox proportional hazards regression models. Unweighted metabolites scores were constructed to assess the overall effect of acylcarnitines and bile acids on incident CHD. The impact of metabolites on the performance of CHD prediction model was evaluated with the receiver operating characteristic (ROC) area under the curve (AUC). Follow-up for CHD incidence was censored on December 31, 2018. Results: The mean age of the participants was (53.1±9.8) years and 754 were males (34.9%). During (10.5±0.1) years of follow-up, 140 cases of CHD were recorded. Four metabolites including acylcarnitines C3-OH, C5:1, C5:1-DC, and deoxycholic acid (DCA) showed associations with CHD incidence and the HR (95%CI) were 1.474 (1.230-1.767), 0.761 (0.637-0.909), 0.773 (0.650-0.918), and 1.309 (1.113-1.539), respectively [false discovery rate (FDR)0.05]. All metabolite scores, including short-chain, medium-chain, long-chain acylcarnitines, primary and secondary bile acids scores were associated with the risk of CHD (FDR0.05). Compared to the traditional models, the addition of DCA or 4 key metabolites increased the AUC of the predictive model from 0.803 (0.761-0.845) to 0.812 (0.772-0.852) and 0.817 (0.778-0.857), respectively (all P0.05). Conclusions: Acylcarnitine and bile acid levels are associated with the risk of CHD, and DCA or 4 key metabolites can improve the predictive ability for CHD incidence.

PDZK1 gene transfer ameliorates lipopolysaccharide-induced cholestasis in rats by rescuing hepatic ABC transporters.

Lipopolysaccharide (LPS) causes inflammatory cholestasis in sepsis. We investigated the role of PDZK1 in the repression of ABC transporters in LPS-induced cholestasis. Lentiviral gene transfer of PDZK1 to rats was conducted to explore its influence on cholestasis induced by LPS. And the effect of lentivirus-mediated shRNA targeting PDZK1 on ABC transporters in rat liver BRL-3A cells was evaluated. Lentiviral vector encoding rat PDZK1 was administered to rats by tail intravenous injection. Obviously elevated serum total bile acid (TBA) level and liver biochemical markers in cholestatic rats were decreased by the Lv-PDZK1 delivery. Also Lv-PDZK1 delivery stimulated the suppressed hepatic ABC transporters expression. In vitro, after the lentiviral vector LV3/PDZK1 shRNA transfection, no expression of PDZK1 and mild expression of ABC transporters were detected in BRL-3A cells by Western blotting. Our results indicate that the lentiviral-mediated hepatocyte PDZK1 expression ameliorates LPS-induced cholestasis in rats by rescuing hepatic ABC transporters expression.

Practical Considerations for Odevixibat Treatment in Patients with Progressive Familial Intrahepatic Cholestasis: A Single-Center Case Series.

Background: Patients with progressive familial intrahepatic cholestasis (PFIC) experience cholestasis-associated symptoms, including severe pruritus. Odevixibat is an ileal bile acid transporter inhibitor indicated for treatment of PFIC in the European Union and for the treatment of pruritus in PFIC in the United States. The aim of the current study was to characterize the real-world effectiveness and safety of odevixibat in patients with PFIC. Methods: This retrospective study included 9 patients with PFIC treated with odevixibat in a single center in Tübingen, Germany. Data were recorded using case report forms. Results: Of the 9 patients (PFIC1, n = 2; PFIC2, n = 7), 5 had improved serum bile acid levels, pruritus, liver function tests, and sleep with odevixibat treatment. Two siblings with periodic relapses of PFIC symptoms also had improved pruritus and sleep within 4 months of treatment. Two siblings with complete loss of bile salt export pump (BSEP) protein did not respond to treatment; both underwent liver transplantation (indications: hepatocellular carcinoma [HCC] manifestation [n = 1] and severe failure to thrive and refractory pruritus [n = 1]). Four patients reported abdominal complaints that were transient or responded to dose reduction; no other safety issues were reported. Conclusions: In this case series, clinical benefits were observed in most patients with PFIC1 and PFIC2 treated with odevixibat. In patients with periodic relapse of PFIC symptoms, ≥3 months of treatment with odevixibat may be required for symptom control. Patients with complete loss of BSEP did not have consistent symptom relief and require careful monitoring. Effectiveness and feasibility results from our cohort demonstrate potential for long-term benefits with odevixibat in real-world treatment of patients with PFIC.

Nicotinamide Mononucleotide Alleviates Bile Acid Metabolism and Hormonal Dysregulation in Letrozole-Induced PCOS Mice.

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.

Bulevirtide Monotherapy Is Safe and Well Tolerated in Chronic Hepatitis Delta: An Integrated Safety Analysis of Bulevirtide Clinical Trials at Week 48.

The safety and tolerability of bulevirtide (BLV), a novel entry inhibitor of hepatitis delta virus, were evaluated in an integrated analysis of clinical trial results from patients with chronic hepatitis delta (CHD). Week 48 on-treatment clinical and laboratory results from two Phase 2 trials (MYR203 [NCT02888106] and MYR204 [NCT03852433]) and one Phase 3 trial (MYR301 [NCT03852719]) were pooled (N = 269). Patients were grouped as follows: BLV 2 mg (n = 64), BLV 10 mg (n = 115), pegylated interferon-alfa (n = 39) and control (n = 51). The control group consisted of patients assigned to the delayed treatment group in Study MYR301. Adverse events (AEs) that occurred more frequently with BLV 2 mg and BLV 10 mg versus control included increased total bile acid levels (20% and 17% vs. 0%), injection-site reactions (16% and 20% vs. 0%), headache (16% and 17% vs. 0%), pruritus (11% and 10% vs. 0%) and eosinophilia (9% and 4% vs. 0%). Increases in total bile acid levels were observed with BLV without clear correlation with AEs, such as pruritus, eosinophilia or vitamin D deficiency. Grade 3 or 4 study drug-related AEs occurred in a higher proportion of patients receiving pegylated interferon-alfa (51%) than with BLV 2 or 10 mg (3% and 4%, respectively). There were no serious AEs related to BLV, and no patients discontinued BLV due to an AE. Neither hepatic decompensation nor death occurred. BLV monotherapy was safe and well tolerated through 48 weeks of treatment in patients with CHD. NCT02888106, NCT03852433 and NCT03852719.