Search Results (353)

Animal bile has been used for millennia in traditional Chinese medicine as a cough suppressant and bronchodilator. As the primary functional constituents of bile, bile acids (BAs) are believed to mediate these physiological effects. Although the role of BAs in enterohepatic circulation is well-characterized, and recent advances have highlighted their immunomodulatory functions, their pathophysiological significance in the respiratory system has been largely overlooked. This review synthesizes emerging evidence on the multidimensional roles of BAs and their receptor-mediated signaling pathways, with a focus on their contribution to the pathogenesis of major respiratory diseases such as asthma, pulmonary fibrosis, and lung injury. Full article

Cholestasis is an important clinical manifestation of primary sclerosing cholangitis (PSC), leading to liver injury, fibrosis and liver failure. The gut microbiota influences the pathogenesis of cholestatic liver disease by modulating metabolic and immune responses. Our study established a PSC mouse model with a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and Lactobacillus helveticus R0052 intervention to assess the protective effects of probiotics on the disease. In addition, we investigated the microbiome and transcriptome alterations resulting from L. helveticus R0052 intervention to explore associations between gut microbiota and host metabolism. The results showed that L. helveticus R0052 reduced liver injury and inflammation, and ameliorated cholestasis in DDC-fed mice. These beneficial effects were accompanied by alterations in hepatic FXR-Cyp7a1 and ileal FXR-Fgf15 signaling pathways, modified bile-acid homeostasis, as well as changes in the gut microbiota and their metabolites. Overall, our research findings provide an experimental basis for the potential application of L. helveticus R0052 in the prevention of cholestasis. Full article

Inflammatory stress can disrupt gut microbial communities and bile acid (BA) metabolism in weaned piglets; whether dietary proanthocyanidins (PACs) can alleviate such alterations remains unclear. Eighteen 21-day-old Duroc × Landrace barrows were randomly assigned to control (CON), lipopolysaccharide-challenged (LPS), and LPS-challenged PAC-supplemented (LPS + PAC; 250 mg/kg diet) groups for a 21-day trial. Fecal microbiota and serum BAs were assessed by 16S rRNA gene sequencing and targeted liquid chromatography–tandem mass spectrometry, respectively. LPS challenge increased the relative abundance of Fusobacteriota and enriched several taxa associated with inflammatory dysbiosis, including Proteobacteria, Enterobacteriaceae, and Escherichia-Shigella. Compared with the LPS group, PAC supplementation was associated with a lower relative abundance of Firmicutes and higher relative abundances of Mitsuokella and Dorea. LPS challenge reduced the serum concentrations of several primary and secondary BAs and increased the concentrations of sulfated BAs. PAC supplementation was associated with lower concentrations of several BAs but a higher glycoursodeoxycholic acid (GUDCA) concentration than LPS alone. GUDCA was negatively correlated with several LPS-enriched taxa. These findings indicate that PAC supplementation was associated with changes in selected fecal bacterial taxa and serum BA concentrations during LPS challenge. Whether these microbial and BA changes are causally related requires further investigation. Full article

Hepatitis B virus (HBV) infection can lead to hepatitis B, which may eventually progress to cirrhosis or hepatocellular carcinoma (HCC). Host lipid metabolism plays a critical role in HBV replication, and HBV infection also impairs lipid homeostasis. The solute carrier family 27 member 5 (SLC27A5) gene, which encodes a long-chain fatty acid transporter and bile acid–CoA ligase, has been reported to be associated with cirrhosis and HCC. However, whether SLC27A5 influences HBV infection or replication remains unclear. In this study, the SLC27A5 gene was overexpressed or silenced in HepAD38 cells. Results show that SLC27A5 overexpressing suppresses HBV replication. Given the primary role of SLC27A5 in bile acid metabolism, we hypothesized that SLC27A5 might inhibit HBV replication via regulating the FXR/SREBP1C/FASN/ACC1 signaling pathway. Subsequent experiments confirmed that overexpression of SLC27A5 upregulated FXR expression levels and downregulated mRNA levels of the SREBP1C, FASN, and ACC1 genes. Consequently, lipid synthesis was suppressed in SLC27A5-overexpressing cells, with significantly reduced levels of lipid droplets and triglycerides. Furthermore, SLC27A5 might collaborate with Entecavir to inhibit HBV replication. In summary, we demonstrated that SLC27A5 inhibited HBV replication through regulating FXR/SREBP1C/FASN/ACC1 and decreasing lipid synthesis. Full article

Recent research has highlighted concerns regarding the hepatotoxicity of Bisphenol S (BPS), particularly its potential transgenerational effects. In this study, we investigated the effects of perinatal BPS exposure on female offspring (F1) by exposing pregnant Sprague-Dawley (SD) rats (F0) to 0.05 and 20 mg/kg BPS from gestational day 6 to postnatal day 21. Results showed that perinatal BPS exposure resulted in increased body weight, higher liver coefficient, and impaired liver function in female rat offspring (F1). Untargeted metabolomics analysis revealed suppression of the primary bile acid biosynthesis pathway, and network toxicology predicted cholesterol metabolism and bile secretion as key pathways, suggesting altered cholesterol and bile acid homeostasis in the liver of female offspring. Validation studies demonstrated activation of cholesterol synthesis, as shown by upregulation of sterol regulatory element-binding protein 2 (SREBP2), squalene epoxidase (SQLE), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Furthermore, the down-regulated expression levels of acetyl-CoA acetyltransferase 1 (ACAT1), ATP-binding cassette sub-family G member 8 (ABCG8), and ATP-binding cassette sub-family G member 5 (ABCG5) indicated that pathways associated with cholesterol conversion, including cholesterol esterification, transport, and secretion as very low-density lipoprotein cholesterol (VLDL-C), were suppressed. Specifically, reduced transcription of ACAT1, ABCG8, and ABCG5, which are involved in cholesterol esterification and cholesterol efflux, was observed. This imbalance was associated with hepatic cholesterol accumulation and hepatotoxicity, although whether cholesterol accumulation was a cause or a consequence of liver injury remained unclear. In summary, our findings demonstrate that perinatal BPS exposure disrupted hepatic cholesterol homeostasis, which was associated with cholesterol accumulation and hepatotoxicity in F1 female rats. Full article

Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a major public health concern. The pediatric form of MASLD differs from the adult phenotype in its pathophysiology and exhibits distinct histopathological characteristics. This study aimed to characterize serum metabolomic alterations associated with pediatric MASLD and to identify metabolic signatures that may provide further insight into the disease phenotype. To this end, untargeted metabolomic analysis was performed on serum samples from 21 pediatric MASLD patients and 22 healthy controls using liquid chromatography coupled with high-resolution quadrupole time-of-flight mass spectrometry (LC-MS/QTOF). Univariate statistical analysis was performed using the Mann–Whitney U-test with false discovery rate (FDR) correction, while multivariate analysis employed principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA). Multivariate analysis in the positive ionization mode demonstrated clear separation between the MASLD and control groups (R²Y = 0.972, Q² = 0.823, CV-ANOVA p-value = 2.387 × 10⁻¹⁰). A total of 46 annotated metabolites differed significantly between the groups. The most pronounced alterations involved bile acid and sterol metabolism, including increased 12α-hydroxy-3-oxocholadienic acid and decreased conjugated primary bile acids, including taurine and glycine conjugates. In addition, increased levels of free carnitine and short-chain acylcarnitines, together with alterations in free and oxidized fatty acids, suggested disturbances in fatty acid metabolism. The metabolomic profile also revealed broad disruption of glycerophospholipid metabolism, characterized primarily by decreased lysophosphatidylcholines and lysophosphatidylethanolamines. In conclusion, the metabolomic profile of pediatric MASLD indicates pronounced systemic metabolic alterations, primarily involving lipid and fatty acid metabolism, bile acid and sterol metabolism, and amino acid-related pathways. The coordinated pattern of these changes suggests alterations across multiple interconnected metabolic processes, highlighting the complex metabolic phenotype of pediatric MASLD. The identified metabolic signatures provide a basis for further investigation and warrant validation in larger, independent cohorts to determine their biological and potential clinical relevance. Full article

Ischemic stroke accounts for 87% of all strokes and remains a leading cause of mortality and morbidity worldwide, yet therapeutic options remain limited. Emerging evidence on the gut-brain axis and microbial metabolites as modulators of stroke outcome has positioned tauroursodeoxycholic acid (TUDCA), a taurine-conjugated secondary bile acid, as a candidate neuroprotective agent. Here, we evaluated the effects of intravenous TUDCA (100 mg/kg) in male C57BL/6 mice subjected to transient middle cerebral artery occlusion (tMCAO) or permanent distal middle cerebral artery occlusion (dMCAO), administered either one hour before or after stroke induction. Infarct size, neurological score, and IgG extravasation served as primary outcome measures, and blood-brain barrier (BBB) integrity was further assessed using a human iPSC-derived BBB organ-on-chip system. TUDCA did not significantly reduce infarct volume, improve neurological outcome, or attenuate BBB leakage in either in vivo model, nor did it preserve barrier permeability or ZO-1 expression in vitro under normoxic or hypoxic conditions. These findings indicate that, under the conditions tested, TUDCA does not influence the development of ischemic brain injury or features of BBB integrity, and that further optimization of dosing and administration strategies is required to fully evaluate its therapeutic potential in ischemic stroke. Full article

Advanced glycation end products (AGEs), stable glycation/glycoxidation products generated during thermal processing, accumulate in foods and pose health risks. Current mitigation strategies primarily focus on inhibiting AGEs formation rather than reducing already formed products, highlighting the need for effective approaches to reduce pre-formed AGEs. In this study, a food-grade lactic acid bacterium (LAB) capable of efficiently reducing fluorescent AGEs was isolated from naturally fermented foods using AGEs as the primary nitrogen source. From 1213 presumptive LAB isolates, three candidates with fluorescent AGEs reduction rates exceeding 50% were obtained, among which strain HNGD-YC1 exhibited the highest activity and was selected for further characterization. The strain was identified as Lactiplantibacillus plantarum through morphological, phylogenetic, and whole-genome ANI analyses and demonstrated favorable in vitro probiotic-related properties, including acid and bile salt tolerance, as well as a genomic safety profile. Whole-genome sequencing revealed candidate genes encoding proteases, glycoside hydrolases, and carbohydrate esterases, suggesting a putative multi-enzymatic mechanism involved in the reduction of fluorescent AGEs, which warrants further experimental validation. In food matrix applications, fermentation with HNGD-YC1 reduced fluorescent AGEs by 68.70% in spray-dried milk powder and 56.39% in roasted pork powder, while also reducing multiple other protein oxidation products and partially recovering the protein secondary structure parameters. These findings establish HNGD-YC1 as a promising candidate, providing a novel approach for developing low-AGEs fermented products. Full article

Exocrine pancreatic insufficiency (EPI) is a chronic gastrointestinal disease in dogs that is caused by the insufficient synthesis and secretion of pancreatic digestive enzymes by the exocrine pancreas. Previous studies have described intestinal dysbiosis in dogs with EPI and dysbiosis is often associated with bile acid dysmetabolism. This study aimed to measure the concentration of a variety of bile acids in the serum of dogs with EPI. Serum was collected from 50 dogs with a serum canine trypsin-like immunoreactivity (cTLI) concentration of less than 1 µg/L, strongly suggesting EPI, and 50 non-EPI control dogs with a serum cTLI concentration within the reference interval. Half of the dogs with EPI and half the non-EPI control dogs were German shepherd dogs and half were dogs of other breeds. There were significant differences in serum bile acid concentrations between non-EPI control dogs and dogs with EPI. Dogs with EPI had significantly higher serum concentrations of both primary and total bile acids. This study shows that EPI in dogs is associated with bile acid dysmetabolism. Full article

Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis and an important active constituent of bear bile. Whole-cell microbial conversion of inexpensive lithocholic acid (LCA) offers a promising alternative to conventional chemical synthesis owing to its high regioselectivity and mild reaction conditions, yet the fermentation process of Fusarium equiseti HG18 (CCTCC M2023160), a natural fungal catalyst for LCA 7β-hydroxylation, has not been systematically engineered for scalable production. This study developed a whole-cell process for UDCA production by F. equiseti HG18. Systematic optimization by single-factor experiments, Plackett–Burman design and Box–Behnken response surface methodology raised the shake-flask UDCA titer from 0.19 to 0.59 mg mL⁻¹. Scale-up in a 3 L stirred-tank bioreactor shortened the fermentation time from 144 h in shake-flask cultivation to 96 h in the bioreactor under optimized operating conditions (pH 8.5, aeration 2.5 L min⁻¹, and agitation 200 rpm). Experiments across a range of initial LCA loadings revealed a progressive decline in UDCA molar yield at elevated substrate concentrations, consistent with substrate-related inhibitory effects, and this loading-dependent behavior was used to design a two-stage fed-batch feeding strategy. Under the optimized condition (2.0 mg mL⁻¹ LCA fed at 0 and 48 h), UDCA titer reached 1.71 mg mL⁻¹, corresponding to a volumetric productivity of 17.8 mg L⁻¹ h⁻¹ and a UDCA molar yield of 41%. This study establishes a laboratory-scale whole-cell bioprocess for UDCA production from LCA using a wild-type fungal catalyst, integrating statistical medium optimization, bioreactor process development, and substrate-feeding strategies. The findings provide a practical framework for improving fungal whole-cell steroid biotransformation and highlight the potential of wild-type fungal platforms for scalable biocatalytic production. Full article

The intestinal microbiome has emerged as a clinically significant modulator of outcomes across multiple domains of cancer care. In hematopoietic stem cell transplantation (HSCT), loss of microbial diversity and depletion of short-chain fatty acid-producing commensals are independently associated with graft-versus-host disease (GvHD), bloodstream infections, transplant-related mortality, and overall survival. Mechanistic studies have identified interconnected pathways—including butyrate-mediated epithelial protection, tryptophan-derived aryl hydrocarbon receptor signaling, bile acid metabolism, and Paneth cell–intestinal stem cell interactions—through which microbial communities regulate intestinal barrier integrity and immune homeostasis. These insights have provided the biological rationale for therapeutic strategies aimed at restoring microbial ecology. Fecal microbiota transplantation (FMT) has demonstrated promising clinical activity in steroid-refractory acute GvHD, with one meta-analysis reporting a pooled clinical remission rate of 64% (95% CI, 51–77%) across prospective single-arm studies, and proprietary live biotherapeutic products (LBPs) such as MaaT013 met the primary endpoint of the single-arm phase III ARES trial, achieving a day-28 gastrointestinal overall response rate of 62%; however, the CHMP adopted a negative opinion on its conditional marketing authorization application in June 2026, citing limitations of the single-arm design, and a re-examination is pending. In parallel, gut microbiome composition has been associated with immune checkpoint inhibitor (ICI) response, and early-phase FMT studies suggest that microbiome modulation may restore sensitivity to anti-PD-1 therapy in some patients with refractory melanoma and may enhance treatment responses in first-line ICI settings; however, these findings derive primarily from small, uncontrolled or early-phase studies. Defined single-strain approaches, notably Clostridium butyricum MIYAIRI 588 (CBM588), have shown encouraging secondary clinical efficacy signals in two small, randomized phase I trials in metastatic renal cell carcinoma, including significantly prolonged progression-free survival in one trial and a higher objective response rate in another; however, neither trial met its prespecified primary microbiome endpoint of increased Bifidobacterium spp. abundance. Emerging evidence further links antibiotic-induced dysbiosis to impaired chimeric antigen receptor T-cell (CAR-T) therapy outcomes, while short-chain fatty acids have been identified as direct enhancers of CAR-T cell effector function. This review synthesizes the current evidence for microbiome-based therapeutics across HSCT, GvHD, ICI therapy, CAR-T cell therapy, and infection prevention, and addresses cross-cutting translational challenges including antibiotic stewardship, donor selection, safety in immunocompromised populations, and pharmacomicrobiomics. While randomized controlled trial data remain limited and many approaches are investigational, the convergence of mechanistic, observational, and early interventional evidence positions microbiome restoration as a promising frontier in precision oncology. Full article

Bile acid (BA) dysmetabolism is implicated in canine chronic inflammatory enteropathy (CIE), but fasting serum profiles across treatment-response groups remain poorly characterized. This exploratory observational study analyzed pretreatment serum from dogs subsequently classified as food-responsive enteropathy (FRE; n = 8) or immunosuppressant-responsive enteropathy (IRE; n = 5), with four unmatched purpose-bred Beagle controls. Targeted LC–MS/MS, performed using a published canine serum method, provided results for 15 BA species. All samples were analyzed in one batch by an analyst blinded to subsequent group assignment. Eight species quantifiable in every dog and ten derived variables were compared using Kruskal–Wallis tests with Benjamini–Hochberg correction across 18 omnibus tests. Cholic acid and unconjugated primary BA concentrations were higher in IRE than in controls and FRE. The total primary-to-secondary BA ratio showed a monotonic group ordering (control < FRE < IRE; H = 13.76, p = 0.0010, q = 0.0092; epsilon-squared = 0.840), with all Bonferroni-corrected pairwise comparisons significant. A post hoc four-scenario sensitivity analysis comprising the submitted zero-substitution analysis and three LOD/LOQ-based alternatives reproduced the same 18-test FDR-significant set and the same ratio inference. This analysis tests robustness to censored-value handling but is not independent validation. The findings suggest group-associated serum BA patterns, but the small sample, clinical heterogeneity, and unmatched controls preclude diagnostic or treatment-predictive interpretation. Full article

Background/Objectives: Glucagon-like peptide-1 (GLP-1), which is released by enteroendocrine L-cells, is the primary incretin hormone and plays a pivotal role in glucose regulation, appetite control, and metabolic health. While GLP-1 receptor agonists offer significant therapeutic benefits, there is a growing interest in identifying foods that can increase endogenous GLP-1 production through physiological processes. However, the physiological impact of modulating GLP-1 through diet is modest compared with activating GLP-1 receptors pharmacologically. This narrative review summarizes the latest reports on how specific food matrices and gut microbiota-dependent pathways influence GLP-1 release, emphasizing their importance in precision nutrition. Methods: Literature published between 2001 and 2026 was reviewed, including experimental, clinical, and translational studies examining the effects of foods on GLP-1 secretion, L-cell activation, nutrient-sensing receptors, microbial metabolites, and metabolic outcomes. Evidence was synthesized for food categories such as fermented dairy products, fermented vegetables, whole grains, legumes, fiber-rich root vegetables, berries, grapes, green tea, turmeric and oily fish. Results: Foods modulate endogenous GLP-1 secretion through complementary pathways involving L-cell stimulation and the activation of receptors, including FFAR2, FFAR3, GPR119, TGR5 and FFAR4 (GPR120), as well as the production of microbial metabolites. Fermented dairy products, kimchi, kefir, Jerusalem artichokes, chicory root, oats, garlic, onions, berries, grapes, green tea and oily fish support incretin regulation through microbial fermentation, the generation of short-chain fatty acids (SCFAs), bile acid signalling and the release of bioactive compounds. These food matrices shape metabolite profiles more effectively than isolated nutrients, highlighting the importance of the interaction between whole foods and the gut microbiota. Conclusions: Foods rich in fermentable substrates, polyphenols, bioactive peptides and omega-3 fatty acids are promising dietary modulators of physiological GLP-1 activity. Taking into account microbiome characteristics, metabolic phenotype and individual postprandial responses could facilitate the development of personalized nutrition strategies to help prevent and manage obesity, type 2 diabetes and related cardiometabolic disorders. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic disorder characterized by dysregulated lipid handling and bile acid signaling, processes controlled by PPARs and FXR. We report that RT206, a 2-aryloxy-3-phenyl-propanoic acid derivative, combines partial PPARα/γ agonism with positive allosteric modulation of FXR. Transactivation assays and endogenous gene-expression profiling confirmed activation of PPARα/γ-responsive genes. RT206 showed no intrinsic FXR agonism, yet it robustly potentiated FXR-dependent gene transcription in HepG2 cells in the presence of structurally distinct orthosteric agonists. Grating-coupled interferometry revealed weak interaction with apo-FXR that was enhanced by orthosteric ligands, consistent with cooperative ternary complex formation. Docking and molecular dynamics supported a model in which RT206 engages the non-orthosteric FXR S2 site, while orthosteric agonists occupy the S1 primary pocket. Comparison with guggulsterone revealed distinct predicted S2 interaction patterns associated with divergent transcriptional outcomes in vitro. In fatty acid-loaded HepG2 cells, RT206 combined with FXR agonists modulated FXR- and PPAR-regulated metabolic genes and modestly reduced neutral-lipid accumulation. These findings identify RT206 as a proof-of-principle scaffold that integrates partial PPARα/γ agonism with ligand-dependent potentiation of FXR activity and support its further evaluation in more advanced liver models. Full article

The yak is an iconic ruminant of the Qinghai-Tibet Plateau, yet segment-specific variation in its intestinal microbial functional potential and bile acid profiles under different feeding systems remains insufficiently characterized. Six healthy adult male yaks with similar body weights (320 ± 30 kg) were assigned to grazing (G) or stall-feeding (S) systems, with three animals per group, for a 90-day trial comprising a 10-day adaptation period and an 80-day formal experimental period. The individual yak was considered the experimental unit, and intestinal segments sampled from the same animal were treated as repeated observations. Liver tissue and digesta from the duodenum, ileum, cecum, and colon were analyzed using targeted bile acid metabolomics and shotgun metagenomics. Principal coordinate analysis based on Bray-Curtis dissimilarities showed segment-associated clustering of microbial communities, with PCo1 and PCo2 explaining 65.5% and 18.9% of the total variation, respectively. ANOSIM identified a significant intestinal-segment effect on microbial community composition (R = 0.2208, BH-FDR = 0.0144), whereas the overall feeding-system effect was not significant (R = 0.3747, BH-FDR = 0.1200). No statistically significant feeding-system differences were detected in Shannon, Simpson, Chao1, or ACE indices within individual intestinal segments (BH-FDR ≥ 0.800), and PERMDISP detected no significant differences in within-group dispersion (BH-FDR ≥ 0.1682). Bacillota and Bacteroidota were the dominant phyla. Descriptive functional profiling showed higher mean ileal abundances of GH2 (0.0035 vs. 0.0026), GH3 (0.0029 vs. 0.0024), and GH43 (0.0021 vs. 0.0013) in grazing yaks, whereas the starch-associated GH13 family showed its highest mean abundance in the colon of stall-fed yaks. These metagenomic patterns represent predicted genomic functional potential rather than gene expression, enzyme activity, or metabolic flux. Cecal total bile acid concentration showed a nominal between-group difference (unadjusted Welch’s p = 0.0109), but this difference did not remain significant after correction across the five anatomical sites (BH-FDR = 0.0545). In the colon, stall-fed yaks had a lower conjugated-to-unconjugated bile acid ratio and a higher secondary-to-primary bile acid ratio than grazing yaks (BH-FDR < 0.05). Feeding-system-associated descriptive patterns were observed in predicted microbial functional profiles, whereas statistically supported between-group differences were limited mainly to selected colonic bile acid ratios. Given the limited animal-level replication, these findings should be considered exploratory. Full article