The pathophysiology of acute viral diseases is complex. It is characterized by strong inflammatory responses driven by immune cells, leading to tissue damage. Currently available in vitro models mainly recapitulate the viral life cycle but fail to model immune cell-mediated pathogenesis. Here we build macrophage-augmented organoids (MaugOs) by integrating macrophages into primary organoids that are cultured from human liver tissues. We test the infections of two RNA viruses, hepatitis E virus and SARS-CoV-2, and one DNA virus, monkeypox virus, which either primarily or secondarily affect the human liver. In all three models of acute viral diseases, MaugOs recapitulate infection and the resulting inflammatory response, although to different levels. We use this system to dissect the multifunctional role of human bile on hepatitis E virus replication and the inflammatory response through distinct mechanisms of action. We also show that MaugOs recapitulate features of inflammatory cell death triggered by hepatitis E virus infection when integrated with pro-inflammatory macrophages. Furthermore, we demonstrate a proof of concept in MaugOs for development of multitarget therapeutics that simultaneously target the virus, inflammatory response and the resultant inflammatory cell death.

To investigate and validate the mechanism of LXTHF in the treatment of IHC through network pharmacology, molecular docking technology, and animal experiments. The overall methodology included the identification of the major active ingredients of LXTHF using the ultra-performance liquid chromatography (UPLC) technique. Subsequently, network pharmacology was utilized to analyze and predict the interaction between the corresponding targets of LXTHF and IHC. Furthermore, an ANIT-induced rat model was established, and the serum and liver tissues were collected to assess the hepatoprotective effects of LXTHF, and a serum untargeted metabolomics test was performed. Finally, the precision of the results was verified at the molecular level through molecular docking, immunohistochemistry, and RT-qPCR. There were 162 active ingredients and 213 targets associated with LXTHF-IHC that were detected. The animal experiments have shown that LXTHF reversed the levels of liver function indexes in the ANIT group, which markedly performed anti-inflammatory, hepatoprotective, and enzyme-lowering effects. Combining the results of network pharmacology and metabolomics, we found that LXTHF could scavenge free radicals, suppress oxidative stress, and regulate the levels of bile acid in the serum by participating in the methionine cycle. Our results preliminarily suggested that LXTHF has a favorable anticholestatic effect in the ANIT-induced rat model, and the methionine and cysteine metabolic pathway plays an important role in this process.

The liver disorders caused by alcohol abuse are termed alcoholic-related liver disease (ALD), including alcoholic steatosis, alcoholic steatohepatitis, alcoholic hepatitis, and alcoholic cirrhosis, posing a significant threat to human health. Currently, ALD pathogenesis has not been completely clarified, which is likely to be related to the direct damage caused by alcohol and its metabolic products, oxidative stress, gut dysbiosis, and exosomes.

The existing studies suggest that both the gut microbiota and exosomes contribute to the development of ALD. Moreover, there exists an interaction between the gut microbiota and exosomes. We discuss whether this interaction plays a role in the pathogenesis of ALD and whether it can be a potential therapeutic target for ALD treatment.

Chronic alcohol intake alters the diversity and composition of gut microbiota, which greatly contributes to ALD's progression. Some approaches targeting the gut microbiota, including probiotics, fecal microbiota transplantation, and phage therapy, have been confirmed to effectively ameliorate ALD in many animal experiments and/or several clinical trials. In ALD, the levels of exosomes and the expression profile of microRNA have also changed, which affects the pathogenesis of ALD. Moreover, there is an interplay between exosomes and the gut microbiota, which also putatively acts as a pathogenic factor of ALD.

The liver is simultaneously impacted by environmental challenges and modulates the response to these insults. Efforts to understand the effects of stressors on the activity of the liver typically consider one type of challenge (e.g., nutrition, toxin, disease), profile targeted molecules, or study the hepatic disruptions in one sex. The present study characterized hepatic changes in the metabolome of females and males exposed to the nutritional challenge of fasting and inflammatory signals elicited by the viral mimetic Poly(I:C). The hepatic metabolome of pigs was profiled using untargeted liquid chromatography-mass spectrometry analysis enabling the quantification of metabolites. The analysis of pathways enriched among metabolites showing sex-by-distress interactions revealed molecular processes affected by fasting and immune stresses in a sex-specific manner, including SLC-mediated transmembrane transport, the urea cycle, and G-protein coupled receptor signaling. Metabolites differentially abundant across sex-distress groups in the previous pathways included creatine, taurine, and glycine derivatives. Pathways over-represented among metabolites significantly affected by distress included glucose homeostasis, the Krebs cycle, and the metabolism of water-soluble vitamins, with key metabolites including S-adenosylmethionine, histidine, glycerophosphocholine, and lactic acid. These results indicate that 24-h fasting, and low-grade systemic inflammation modulate the liver metabolism. The detection of metabolic disruption that varies with sex enforces the need to develop therapies that can restore hepatic homeostasis in females and males.

Epidemiological evidence links osteoarthritis to fetal origins. Our study shows prenatal caffeine exposure (PCE) in rats predisposes adult offspring to osteoarthritis, associated with elevated intrauterine glucocorticoid levels. Previous research indicates that chenodeoxycholic acid (CDCA), a bile acid, can slow osteoarthritis progression when administered intra-articularly. This study explored if disrupted bile acid metabolism in cartilage affects osteoarthritis risk in adult offspring with PCE. Our findings indicate that the expression of MMP3/MMP13 was upregulated, while endogenous CDCA levels were reduced in the cartilage of PCE-exposed offspring. Furthermore, we observed a persistent reduction in H3K27ac levels at the CYP7B1 promoter and its expression in the cartilage of PCE offspring from fetus to adulthood. Moreover, a sub-physiological level of CDCA promoted NF-κB phosphorylation and the expression of MMP3/MMP13 in chondrocytes in vitro. High levels of glucocorticoids reduced H3K27ac levels and CYP7B1 expression in the promoter region of CYP7B1 through the glucocorticoid receptor and histone deacetylase 4, consequently leading to decreased CDCA levels. In summary, our findings suggest that intrauterine low-expression programming of CYP7B1, induced by elevated glucocorticoid levels, reduces local CDCA levels in the cartilage of PCE offspring, ultimately leading to increased matrix degradation and susceptibility to osteoarthritis.

Farnesoid X receptor (FXR), predominantly expressed in the liver and intestine, plays a crucial role in regulating bile acid (BA) metabolism. However, the specific contributions of FXR in different tissues to BA homeostasis remain unclear. To elucidate the comprehensive roles of FXR, we developed a novel double tissue-specific knockout (KO) mouse model of Fxr in both liver and intestine (FxrΔL/ΔIN). Notably, FxrΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with Fxr whole body KO mice (Fxr-/-). However, FxrΔL mice only showed elevated hepatic BA concentration, whereas FxrΔIN displayed remarkably increased BA concentration in feces. Fxr deletion increased the BA synthesis genes mRNA level, such as Cyp7a1 and Cyp8b1, but reduced the expression of FXR downstream target genes Shp and Fgf15. These findings provide a valuable model to underscore the pivotal functions of tissue-specific FXR in maintaining BA homeostasis. Moreover, these insights facilitate the development of FXR-targeted therapeutic strategies for the BA dysregulation disease treatment.NEW & NOTEWORTHY We successfully developed a double tissue-specific Fxr knockout (DKO) mouse model, which provides a novel tool for investigation of FXR functions in the liver and intestine. Unlike whole body KO, the DKO model excludes the FXR impact on other tissues. FxrΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with Fxr-/- mice. We established a powerful tool for therapeutic strategies for bile acid metabolism disorders associated with FXR.

Cholestatic liver injury (CLI) is a liver dysfunction closely associated with oxidative stress and bile acid (BA) metabolic disorders, but effective therapies are lacking.The use of ursolic acid (UA) and α-Tocopherol succinate (VES) together for treating CLI is promising due to their respective effects on regulating bile acid metabolism and providing antioxidant activity.

In this study, we synthesized drug-drug nanocrystals (UA-NSps) composed of UA and VES to treat CLI and evaluated their synergistic therapeutic effects by regulating bile acid metabolism and inhibiting oxidative stress in ANIT-induced CLI mice.

Our investigation demonstrated that UA-NSps exhibited high drug-loading capacity, spherical morphology, and improved dissolution and oral bioavailability. In the ANIT model, UA-NSps effectively restored liver function, as evidenced by histopathological and biochemical improvements. Mechanistically, UA-NSps enhanced Nrf2 nuclear translocation, upregulated Nrf2 and HO-1, reduced pro-inflammatory cytokines, and ameliorated mitochondrial damage. Moreover, UA-NSps alleviated the bile acid metabolism disorders by upregulating the transcriptional activity of UGT2B1, BSEP, and MRP2, as well as the protein expression of nuclear receptors and metabolic enzymes PXR,CYP3A4, and UGT1A1. Our study presents a novel drug-drug nanocrystal strategy that enhances the therapeutic efficacy against CLI by inhibiting oxidative stress and regulating bile acid metabolism.

Background/Objectives: Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. Methods: A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats' serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. Results: Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. Conclusions: Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components.

The aging of population coupled with unhealthy dietary habits among residents has led to a rise in the incidence of cardiovascular and metabolic diseases (CVMDs). Extensive research has highlighted the role of gut microbiota-derived metabolites in CVMDs. Among these metabolites, phenylacetylglutamine (PAGln), a meta-organismal prothrombotic metabolite, has been proved to promote the progression of CVMDs. This bacterial derived metabolite is a byproduct of amino acid comes from phenylalanine (Phe) in the diet. There are increasing evidence showing that the level of PAGln is associated with the risk of developing CVMDs. To provide a comprehensive understanding of the role of PAGln in CVMDs, this review delves into the production and metabolic pathways of PAGln and discusses the links of PAGln and the pathogenesis of CVMDs.

Loperamide, a widely used antidiarrheal agent, frequently induces constipation alongside other adverse effects. This study explored hesperidin's therapeutic potential in alleviating loperamide-induced constipation and its underlying mechanisms. Constipation models were established in HFD- or NFD-fed mice via loperamide administration (5 mg/kg/day). Hesperidin (100 mg/kg/day) significantly increased fecal weight and moisture in constipated mice. Biochemical analyses revealed elevated cholic acid/chenodeoxycholic acid ratios in serum and liver tissues of loperamide-treated HFD mice, indicating bile acids dysregulation. qRT-PCR and Western blot results demonstrated that hesperidin downregulated hepatic expression of cholesterol/bile acids biosynthesis genes (e.g., Hmgcr, Cyp7a1, Ch25h), which were overexpressed in constipated mice. Concurrently, hesperidin enhanced the expression of transporters (Abcg5, Abcb11, Abcc2) responsible for biliary cholesterol and bile acids efflux. Furthermore, hesperidin upregulated hepatic nuclear receptors (FXR/SHP), key regulators of bile acids homeostasis. Hesperidin alleviates loperamide-induced constipation through two parallel mechanisms: decreasing hepatic cholesterol accumulation and enhancing bile acids excretion. This dual action results from coordinated regulation of biosynthesis enzymes and transport proteins. This study highlights hesperidin's potential as an adjunct therapy to counteract loperamide-related constipation.

The broad Degenerin/epithelial sodium channel (DEG/ENaC) family includes a subfamily of bile acid-sensing ion channels (BASICs). While their biophysical properties are extensively studied in mammals, the presence and function of BASICs in invertebrates remain largely unexplored. Here, we present the first functional evidence of invertebrate BASICs, revealing conserved features and evolutionary adaptations across bilaterian species. Using electrophysiological and pharmacological approaches, we show that invertebrate BASICs exhibit species-specific bile acid sensitivity profiles and differing responses to channel blockers, amiloride, and diminazene, while retaining shared properties like inhibition by calcium ions and selective permeability of sodium ions. For example, the acorn worm Schizocardium californicum BASIC displays broad bile acid sensitivity similar to mammals, while the brachiopod Novocrania anomala BASIC is activated solely by ursodeoxycholic acid (UDCA) in our experiments. Mutagenesis of the conserved D444 residue in the pore-lining region confirms its critical role in gating. Combined functional and phylogenetic analysis suggests BASICs emerged early in bilaterian evolution, evolving from channels that were merely modulated by bile acids, like their acid-sensing ion channel cousins, into channels that are activated by bile acids. Tissue-specific expression patterns imply roles in bile acid-dependent sodium absorption or environmental sensing of bile acid-like compounds. Given the absence of endogenous bile acids in invertebrates, we propose that invertebrate BASICs may detect environmental compounds, contributing to ecological interactions. This study enhances our understanding of the evolutionary, functional, and ecological roles of BASICs, with implications for future research into their native ligands.

High-fat diet (HFD) was suggested to be associated with several retinal diseases, including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Nevertheless, our understanding of the mechanisms governing retinal lipid metabolic homeostasis remains limited, with little attention focused on the influence of HFD on different retinal cell types. To address this gap, we established a high-fat model using mice fed with HFD for a duration of 6 months. Then, we conducted a comparative analysis of the retinal lipidome and proteome between normal diet (ND) and HFD-fed mice to explore the impacts of HFD on retinal lipid metabolism and gene expression network. Furthermore, we also investigated the impacts of HFD on retina in single-cell resolution by single-cell transcriptome sequencing.

We found that a long-term HFD significantly altered the lipid composition of the retina, with a dramatically elevated cholesterylesters (CE), phosphatidylcholine (PC), and phosphatidylglycerol (PG) level and a decreased eicosanoid level. Proteomic analysis revealed that the primary bile acid biosynthesis pathway was over-activated in HFD retinas. By using single-cell transcriptome analysis, we identified different regulation of gene expression in MG and rod cells in a high-fat environment, whereas the previously identified activation of the bile acid synthesis pathway was predominantly found in MG cells, and may be regulated by alternative pathways of bile acid synthesis, suggesting the critical roles of MG cells in retinal lipid metabolism.

Taken together, by multi-omics studies, we unveiled that HFD leading to the development of retinal diseases may be regulated by alternative pathways of bile acid synthesis, and our study will shed light on the treatment of these diseases.

Cirrhosis complications are often triggered by bacterial infections with multidrug-resistant organisms. Alterations in the gut and oral microbiome in decompensated cirrhosis (DC) influence clinical outcomes. We interrogated: (i) gut and oral microbiome community structures, (ii) virulence factors (VFs) and antimicrobial resistance genes (ARGs) and (iii) oral-gut microbial overlap in patients with differing cirrhosis severity.

Fifteen healthy controls (HCs), as well as 26 patients with stable cirrhosis (SC), 46 with DC, 14 with acute-on-chronic liver failure (ACLF) and 14 with severe infection without cirrhosis participated. Metagenomic sequencing was undertaken on paired saliva and faecal samples. 'Salivatypes' and 'enterotypes' based on genera clustering were assessed against cirrhosis severity and clinical parameters. VFs and ARGs were evaluated in oral and gut niches, and distinct resistotypes identified.

Salivatypes and enterotypes revealed a greater proportion of pathobionts with concomitant reduction in autochthonous genera with increasing cirrhosis severity and hyperammonaemia. Increasing overlap between oral and gut microbiome communities was observed in DC and ACLF vs. SC and HCs, independent of antimicrobial, beta-blocker and gastric acid-suppressing therapies. Two distinct gut microbiome clusters harboured genes encoding for the PTS (phosphoenolpyruvate:sugar phosphotransferase system) and other VFs in DC and ACLF. Substantial ARGs (oral: 1,218 and gut: 672) were detected (575 common to both sites). The cirrhosis resistome was distinct, with three oral and four gut resistotypes identified, respectively.

The degree of oral-gut microbial community overlap, frequency of VFs and ARGs all increase significantly with cirrhosis severity, with progressive dominance of pathobionts and loss of commensals. Despite similar antimicrobial exposure, patients with DC and ACLF have reduced microbial richness compared to patients with severe infection without cirrhosis, supporting the additive pathobiological effect of cirrhosis.

This research underscores the crucial role of microbiome alterations in the progression of cirrhosis in an era of escalating multidrug resistant infections, highlighting the association and potential impact of increased oral-gut microbial overlap, virulence factors, and antimicrobial resistance genes on clinical outcomes. These findings are particularly significant for patients with decompensated cirrhosis and acute-on-chronic liver failure, as they reveal the intricate relationship between microbiome alterations and cirrhosis complications. This is relevant in the context of multidrug-resistant organisms and reduced oral-gut microbial diversity that exacerbate cirrhosis severity, drive hepatic decompensation and complicate treatment. For practical applications, these insights could guide the development of targeted microbiome-based therapeutics and personalised antimicrobial regimens for patients with cirrhosis to mitigate infectious complications and improve clinical outcomes.

Flaxseed-derived peptide IPPF has been reported to effectively inhibit cholesterol micellization and reduce cholesterol accumulation in vitro. However, its effects on hepatic cholesterol accumulation and related dysfunction-associated steatotic liver disease (MASLD) in vivo, along with the underlying mechanisms and specific molecular targets, remain unclear. This study investigated the impact of IPPF on hepatic cholesterol accumulation to ameliorate MASLD and its potential mechanisms in vivo. Six-week-old male C57BL/6J mice were fed a high-cholesterol, high-fat diet and treated with different doses of IPPF via oral gavage for six weeks. IPPF intervention significantly reduced hepatic cholesterol levels and oxidative stress damage while increasing fecal cholesterol and bile acid excretion. Non-targeted metabolomics analysis revealed that IPPF primarily affected pathways related to ABC transporters and bile acid metabolism. IPPF intake upregulated the mRNA expression of Abcg5/8 and Cyp7a1 in the liver. Molecular docking, dynamics and Surface plasmon resonance (SPR) simulations demonstrated that IPPF binds strongly to ABCG5/8 and CYP7A1, forming stable complexes. Furthermore, cholesterol accumulation and MASLD in HepG2 cells induced by palmitic acid (PA) was alleviated by IPPF, but this effect was partly stopped when CYP7A1 or ABCG5/8 was inhibited. In conclusion, flaxseed-derived peptide IPPF targets CYP7A1 and ABCG5/8, promoting cholesterol conversion and excretion, thereby reducing hepatic cholesterol accumulation and offering a potential nutritional treatment for MASLD. IPPF can be used as a novel dietary cholesterol-lowering functional ingredient. This study provides a scientific basis and new perspective for the development of cholesterol-lowering functional foods and dietary supplements.

The incidence of Barrett esophagus (BE) and gastroesophageal adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BAs) support fat digestion and undergo microbial metabolism in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. When activated, FXR can inhibit cancer-related processes, and thus, it is an appealing therapeutic target. Here, we assess the effect of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression.

L2-IL1B mice (mouse model of BE and GEAC) under different diets, and L2-IL1B-FXR KO-mice were characterized. L2-IL1B-derived organoids were exposed to different BAs and to the FXR agonist obeticholic acid (OCA). The BA profile in serum and stool of healthy controls and patients with BE and GEAC was assessed.

Here we show that a high-fat diet accelerated tumorigenesis in L2-IL1B mice while increasing BA levels and altering the composition of the gut microbiota. Although upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine BE organoids and L2-IL1B mice with OCA notably ameliorated the phenotype.

GEAC carcinogenesis appears to be partially driven via loss or inhibition of FXR on progenitor cells at the gastroesophageal junction. Considering that the resulting aggravation in the phenotype could be reversed with OCA treatment, we suggest that FXR agonists have great potential as a preventive strategy against GEAC progression.

Florfenicol (FF), a third-generation chloramphenicol antibiotic widely used in food-producing animals, has become a "pseudopersistent" environmental contaminant, raising concerns about its potential ecological and human health impacts. However, its bioaccumulation behavior and hepatotoxic mechanisms remain poorly understood. This study aims to address these gaps with a 28-day exposure experiment in adult zebrafish at 0.05 and 0.5 mg/L FF. Multiomic analyses (metabolomics, lipidomics, and transcriptomics), combined with histological and mitochondrial function assessments, were employed. Higher bioaccumulation was observed at 0.05 mg/L, potentially due to metabolic saturation at higher concentrations. Histological analysis revealed significant hepatic steatosis (>5 % steatosis area), indicative of moderate nonalcoholic fatty liver disease (NAFLD). Multiomic data demonstrated global dysregulation in energy metabolism, including marked alterations in lipids (accumulation of toxic sphingolipids, excessive fatty acids, and acylglycerol), amino acids, tricarboxylic acid cycle intermediates, and nucleotides. Crucially, mitochondrial dysfunction was identified as a central mechanism, with impaired respiratory chain activities, adenosine triphosphate depletion, elevated reactive oxygen species, and oxidative stress promoting NAFLD progression. These findings highlight mitochondrial impairment and oxidative stress as key drivers of FF-induced hepatotoxicity, providing novel insights into its toxicological mechanisms and emphasizing the ecological risks posed by antibiotic pollution in aquatic systems.

This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.

After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.

Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUCinf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (Cmax) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted Cmax within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The Cmax and AUCinf were overestimated in HI patients and the trend to reduction of Cmax with minimal change in AUCinf with increasing severity of HI was not well captured. Decreasing Simcyp® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.

Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.

NCT number: NCT04226833.

The gut microbiota (GM), the set of microorganisms that colonizes our intestinal tract, can undergo many changes, some of which are age related. Several studies have shown the importance of maintaining a healthy GM for a good quality of life. In the elderly, maintaining a good GM may become a real defense against infection by pathogens, such as C. difficile. In addition to the GM, bile acids (BAs) have been shown to provide an additional defense mechanism against the proliferation of pathogenic bacteria and to regulate bacterial colonization of the gut. BAs are molecules produced in the host liver and secreted with the bile into the digestive tract, and they are necessary for the digestion of dietary lipids. In the gut, host-produced BAs are metabolized by commensal bacteria to secondary BAs. In general GM and host organisms interact in many ways. This review examines the relationship between GM, BAs, aging, and possible new approaches such as dietary interventions, administration of ursodesoxycholic acid/tauroursodesoxycholic acid (UDCA/TUDCA), and probiotics to enrich the microbial consortia of the GM in the elderly and achieve a eubiotic state necessary for maintaining good health. The presence of Firmicutes and Actinobacteria together with adequate levels of secondary BAs would provide protection and improve the frailty state in the elderly. In fact, an increase in secondary BAs has been observed in centenarians who have reached old age without serious health issues, which may justify their active role in achieving longevity.

Advanced glycation end products (AGEs) in processed foods are closely linked to intestinal injury. However, the long-term effects of exposure to free Nɛ-carboxymethyl lysine (CML), a prevalent AGE molecule, on intestinal barrier integrity have been rarely evaluated. This study investigated the temporal effects of CML exposure on intestinal barrier permeability in C57BL/6N mice at diet-related doses over 12, 14, and 16 weeks. No significant changes were observed at 12 weeks, but CML exposure significantly increased intestinal permeability at 14 and 16 weeks, accompanied by elevated serum LPS levels, colonic histological damage, and reduced tight junction protein expression at 16 weeks. CML exposure also altered gut microbiota composition and intestinal bile acid (BA) profiles, specifically reducing TDCA, GDCA, and GCDCA levels. Given the important role of colonic BA receptor signaling in maintaining the intestinal barrier integrity, the impact of CML on BA receptor signaling was assessed. CML exposure significantly downregulated BA receptor TGR5-YAP signaling in mice, while no significant effects were observed in vitro, suggesting that the changes observed in TGR5-YAP signaling in vivo may not result from the direct effects of CML. Spearman's correlation analysis revealed strong associations between altered gut microbiota, BA levels, TGR5-YAP signaling, and intestinal barrier injury. This study highlighted the chronic health risks of long-term CML intake and provided new insights into the links between CML-induced intestinal toxicity, gut microbiota, BA profiles, and BA receptor signaling.

Liver hepatocellular carcinoma (LIHC) is a prevalent and lethal malignancy with a complex molecular landscape. Fibrosis and ferroptosis are implicated in LIHC progression, yet their roles remain to be elucidated. The present study investigated the expression and prognostic significance of calcitonin receptor (CALCR), a gene that intersects the pathways of fibrosis and ferroptosis, across LIHC and other types of cancer. Data were obtained from The Cancer Genome Atlas and the Molecular Signatures Database. LIHC patients were classified into two clusters based on fibrosis‑related gene expression using ConsensusClusterPlus. Single‑sample gene set enrichment analysis was employed to quantify fibrosis and ferroptosis levels. Correlation, survival and nomogram analyses were performed to assess the prognostic value of CALCR. Additionally, single‑cell RNA sequencing data from the Tumor Immune Single Cell Hub 2 (TISCH2) and pan‑cancer analyses of genomic heterogeneity features were incorporated. The present study also identified a putative regulatory role for CALCR in LIHC cell migration, proliferation and apoptosis. CALCR was identified as a significant prognostic marker for LIHC. Patients with high CALCR expression exhibited shortened overall survival (OS) and disease‑specific survival (DSS). Specifically, the hazard ratios (HRs) for OS and DSS were 1.76 [95% confidence interval (CI): 1.23=2.49) and 1.77 (95% CI: 1.13=2.78], respectively, with corresponding P‑values of 0.002 for OS and 0.013 for DSS. Analyses of immune cell infiltration revealed a more complex immune environment in patients with low CALCR expression, suggesting differential responses to immunotherapy. Furthermore, in HepG‑2 and HuH‑7 cells, small interfering (si)‑CALCR increased apoptosis while reducing proliferation and migration compared with si‑negative control. CALCR serves as a significant prognostic biomarker for LIHC, influencing both molecular pathways and the immune landscape. Its expression is associated with improved survival outcomes and distinct genomic features, positioning it as a potential therapeutic target and predictor of immunotherapy efficacy.

The pregnane X receptor (PXR), a ligand-activated nuclear receptor, regulates the transcription of several genes that encode many enzymes and transporters related to drug metabolism. PXR also performs an important role as a physiological sensor in the modulation of endobiotic metabolism for hormones, bile acids, cholesterol, fatty acids, and glucose. Dysregulation of these PXR-mediated pathways is implicated in the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributing to the complex interplay of factors involved in chronic liver disease development and exacerbation affecting millions worldwide. This review highlights the current knowledge of PXR expression and its role in endobiotic metabolism related to MASH development, which is associated with diverse causes and dire outcomes. This review focuses on elucidating the molecular pathways associated with PXR activation directly or indirectly and PXR interaction with other regulatory factors. Although there is still much to comprehend about the intricate details of these pathways, the conclusion is drawn that PXR exerts a crucial role in the pathological and physiological pathways of hepatic cellular processes, which holds promise as a potential pharmacological target for exploring novel therapeutic approaches for MASH treatment and/or prevention. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR) plays a fundamental role in regulating gene expression involved in xenobiotic and endobiotic metabolism. Dysregulation of PXR-mediated pathways is related to the development of metabolic dysfunction-associated steatohepatitis. The ligand-independent pathways regulating PXR hepatic functions through phosphorylation shed light on possible indirect molecular mechanisms and pathways that regulate PXR activity and function. Understanding these pathways may provide insight into new pharmaceutical interventions for metabolic dysfunction-associated steatohepatitis development.

A high-fat diet (HFD) is often associated with hepatic lipid metabolism disorders, leading to dysfunction in multiple body systems. Ginsenosides derived from Panax ginseng have been reported to possess potential effects in ameliorating lipid metabolism disorders; however, their underlying mechanisms remain insufficiently explored. This study aims to investigate the bioactivities of ginsenosides in combating lipid metabolism disorders and obesity, with a focus on their mechanisms involving the cholesterol metabolism signaling pathway and gut microbiota. Our results demonstrated that ginsenoside treatment significantly reduced overall body weight, body weight changes, liver weight, and eWAT weight, as well as alleviated hepatic steatosis and dyslipidemia in HFD-fed rats, without affecting food intake. These effects were dose-dependent. Furthermore, 16S rRNA sequencing revealed that ginsenosides significantly increased the relative abundance of Akkermansia muciniphila, Blautia, Eisenbergiella, Clostridium clusters XI, XVIII, and III, while decreasing the relative abundance of Clostridium subcluster XIVa and Dorea. In addition, ginsenoside treatment significantly regulated the expression of hepatic genes and proteins involved in the cholesterol metabolism signaling pathway (FXR, CYP7A1, CYP7B1, CYP27A1, ABCG5, ABCG8, Insig2, and Dhcr7), potentially inhibiting hepatic cholesterol biosynthesis while promoting cholesterol transport to HDL and its excretion via bile and feces. Notably, levels of 7-dehydrocholesterol (7-DHC) and 27-hydroxycholesterol (27-OHC) were reduced, while 5β,6β-epoxycholesterol (5,6β-epoxy) levels were elevated following ginsenoside treatment, indicating significant modulation of oxysterols by ginsenosides. Moreover, bile acid enterohepatic circulation was regulated through the enhancement of hepatic FXR-CYP7A1 signaling and intestinal FXR-FGF15 signaling in HFD-fed rats treated with ginsenosides, which was closely linked to gut microbiota composition. Collectively, our findings suggest that ginsenosides alleviate hepatic lipid metabolism disorders by modulating gut microbiota and the cholesterol metabolism signaling pathway in HFD-fed rats.

Cisplatin (CP), a widely used antineoplastic agent, is a leading cause of drug-induced liver injury (DILI) due to its hepatotoxic effects. Licorice (GC), an established remedy in traditional Chinese medicine (TCM), has shown promise in addressing liver diseases and DILI. Nonetheless, the specific active components and underlying mechanisms of GC in mitigating CP-induced liver injury remain inadequately investigated.

This study examined the active components and efficacy of GC in addressing CP-induced hepatotoxicity, focusing on its mechanisms related to bile acid metabolism and gut microbiota regulation.

Utilizing a CP-induced rat liver injury model, this study evaluated changes in liver coefficient, liver function indices, and pathological morphology while assessing the efficacy of GC for both prevention and treatment of CP-induced liver injury. Subsequently, UPLC-Q-TOF-MS qualitatively analyzed GC's blood-entering components, elucidating its pharmacodynamic material basis. Network pharmacology analysis identified potential pathways and targets of GC's blood components in relation to CP-induced liver injury. Furthermore, metabolomics and 16S rRNA sequencing were employed to clarify the pharmacodynamic mechanisms of GC in modulating bile acid metabolism and gut microbiota, offering insights into its preventive and therapeutic roles.

The pharmacodynamic results revealed that GC significantly reduced liver function biomarkers and improved pathological changes in liver tissue. UPLC-Q-TOF-MS analysis identified 16 blood-entering components as potential pharmacodynamic agents of GC for preventing and treating CP-induced liver injury. Network pharmacology analysis suggested a link between GC's efficacy and the bile acid metabolic pathway. Furthermore, metabolomics analysis, immunoblotting, and 16S rRNA sequencing demonstrated that GC regulated bile acid metabolites in both liver and feces, enhanced FXR and BSEP expressions in the liver, and decreased CYP27A1 expression. Additionally, GC mitigated CP-induced intestinal dysbiosis by altering the abundance of gut microbiota.

UPLC-Q-TOF-MS performed a qualitative analysis of 16 blood-entering components linked to GC, providing a basis for further exploration of the pharmacodynamic material underpinning GC. The protective role of GC in CP-induced liver injury appears connected to enhanced bile acid metabolism and restoration of gut microbiota balance.

Type 2 diabetes mellitus (T2DM) has become a public health problem worldwide. There is growing interest in finding drugs to treat T2DM from herbal medicine. Berberidis Cortex is a traditional Tibetan herb commonly used in the treatment of T2DM, and alkaloids are its main active components. However, the anti-diabetic mechanisms of the total alkaloids of Berberidis Cortex (TBC) remain unclear.

The aim of this study was to evaluate the anti-T2DM efficacy of TBC and reveal the mechanisms behind its effects.

UPLC-Q-Exactive Orbitrap MS technology was employed to qualitatively identify alkaloid components in TBC. T2DM rat models were induced by high-fat diet combined with streptozotocin, and then treated with different doses of TBC (43.5, 87, 174 mg/kg/d) for 40 days. Biochemical parameters, such as fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated serum protein (GSP), homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), alongside H&E and PAS staining were used to evaluate the anti-diabetic activity of TBC. More importantly, metagenomics, transcriptomics, targeted metabolomics, and Western blot analysis were integrated to reveal the underlying mechanisms of TBC for T2DM treatment.

TBC significantly reduced the levels of FBG, OGTT, GSP, HOMA-IR, TC, TG, and LDL-C, and improved the histopathological alterations of pancreatic and liver tissues in T2D rats. It also reduced serum levels of lipopolysaccharide (LPS) and several pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Gut microbiome analysis by metagenomics proved that TBC could improve gut microbiota dysbiosis, including an increase in some beneficial bacteria (e.g., Bifidobacterium pseudolongum and Lactobacillus acidophilus) and a decrease in some harmful bacteria (e.g., Marvinbryantia and Parabacteroides). Western blot analysis found that TBC significantly up-regulated the expression of three intestinal barrier related tight junction proteins (ZO-1, occludin, and claudin-1), and effectively suppressed several key proteins in the TLR4/MyD88/NF-κB inflammatory cascade, including TLR4, MyD88 and p-NF-κB p65. Moreover, hepatic transcriptomics analysis further revealed the regulatory role of TBC on gluconeogenesis related genes, such as Pgc, and Creb1. Targeted metabolomics and Western blot analysis showed that TBC improved BAs dysregulation in T2DM rats, specifically increasing TCDCA and CA levels, thereby activating several proteins in the FXR/FGF15 signaling axis (i.e., FXR, FGF15 and FGFR4), and then decreased the expression of p-CREB1 and PGC-1α to inhibit liver gluconeogenesis.

TBC can significantly improve hyperglycemia, insulin resistance, hyperlipidemia, and inflammation in T2DM rats. The mechanism is related to the regulation of multiple links, including improving gut microbiota dysbiosis, protecting the intestinal barrier by up-regulating the expression of three tight junction proteins, reducing inflammation by inhibiting the LPS/TLR4/MyD88/NF-κB pathway, and inhibiting liver gluconeogenesis by regulating BAs/FXR/FGF15 and CREB1/PGC-1α signaling pathways.

Organ damage caused by electric shock has attracted great attention. Some animal investigations and clinical cases have suggested that electric shock can induce liver injury. This study aimed to investigate the potential mechanism of liver injury induced by electric shock.

Healthy male C57BL/6J mice aged 6-8 weeks were romandly divided into two groups: control group and electric shock group. Mice in the electric shock group were shocked on the top of the skull with an electric baton (20 kV) for 5 sec, while mice in the control group were exposed to only the acoustic and light stimulation produced by the electric baton. The effect of electric shock on liver function was evaluated by histological and biochemical analysis, and a metabolomics and transcriptomics study was performed to investigate how electric shock might induce liver damage. All data of this study were analyzed using a two-tailed unpaired Student's t-test in SPSS 22.0 Statistical Package.

The electric shock group had significantly higher serum aspartate aminotransferase and alanine aminotransferase levels than the control group (p < 0.001), and the shock notably caused cytoplasmic swelling and vacuolization, mild inflammatory cell (mainly macrophages and monocytes) infiltration and acute focal necrosis in hepatocytes (p < 0.001). A total of 47 differential metabolites and 249 differentially expressed genes (DEGs) were detected using metabolomic and transcriptomic analyses. These differential metabolites were significantly enriched in primary bile acid biosynthesis (p < 0.05). Gene ontology functional analysis of the DEGs revealed that electric shock disturbed a key biological process involved in the inflammatory response in the mouse liver, and a significant number of DEGs were enriched in Kyoto Encyclopedia of Genes and Genomes-identified pathways related to inflammation, such as the interleukin-17, tumor necrosis factor and mitogen-activated protein kinase signalling pathway. Transcriptomic and metabolomic analyses revealed that bile acid metabolism disturbance including up-regulation of the taurochenodesoxycholic acid, chenodeoxycholic acid and taurocholic acid, and down-regulation of chenodeoxycholic acid clycine conjugate may contribute to the electric shock-induced inflammatory response.

Electric shock can induce liver inflammatory injury through the interleukin-17, tumor necrosis factor, and mitogen-activated protein kinase signaling pathway, and the bile acid metabolism disturbance including up-regulation of the taurochenodesoxycholic acid, chenodeoxycholic acid and taurocholic acid, and down-regulation of chenodeoxycholic acid clycine conjugate may contribute to inflammatory liver injury following electric shock.

Short-chain chlorinated paraffins (SCCPs) are pervasive organic pollutants recognized for their persistence and bio-toxicity. This study investigated the hepatotoxic mechanisms of SCCPs at environmentally relevant concentration (0.7 μg/kg). The results showed that SCCPs exposure in mice resulted in dysregulated blood and liver lipids, marked by elevated cholesterol levels. Additionally, liver function was compromised, as indicated by increased levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Histopathological examination of liver tissue post-SCCPs exposure revealed hepatocyte enlargement, vacuolar degeneration, and mild ballooning degeneration. Mechanistically, SCCPs induced mitochondrial abnormalities, evidenced by heightened Hoechst 33258 fluorescence, and augmented reactive oxygen species and malondialdehyde levels in liver tissue. This was accompanied by a reduction in total antioxidant capacity, culminating in elevated apoptosis markers, including cytochrome C and caspase-3. Moreover, SCCPs perturbed hepatocellular energy metabolism, characterized by increased glycolysis, lactic acid, and fatty acid oxidation, alongside a disruption in the tricarboxylic acid cycle and a decline in mitochondrial energy metabolic function. Furthermore, SCCPs exposure downregulated the expression of genes involved in bile acid synthesis (cyp27a1, fxr, and shp), thereby precipitating the cholesterol-bile acid metabolism disorders and cholesterol accumulation. Collectively, these findings underscore that SCCPs, even at environmentally relevant levels, can induce lipid dysregulation, mitochondrial disorders and cholesterol deposition in the hepatocytes, contributing to liver damage. The study's insights contribute to a comprehension of SCCPs-induced hepatotoxicity and may inform potential preventative and treatment targets for hepatic damage associated with SCCPs exposure.

There are few reliable biomarkers for gastrointestinal toxicity, and the further identification of such markers can improve the accuracy and speed of toxicological evaluations. This study aimed to evaluate the effectiveness of several recently proposed biomarkers-plasma citrulline, fecal calprotectin, fecal bile acid, and plasma miRNAs (miR-194 and -215)-in detecting intestinal toxicity. To this end, cysteamine hydrocholoride (cysteamine, 600 or 900 mg/kg, PO), indomethacin (10 mg/kg, PO), or 2,4-Dinitrobenzenesulfonic acid hydrate (DNBS, 20 mg/kg, IR) were administered to male Wistar rats to establish models of gastric/duodenal, jejunum/ileum, or colonic damage, respectively. Both novel biomarkers and traditional toxicological parameters were evaluated in these rat models. Standard in-life observations, such as fecal properties or body weight, were inadequate for monitoring intestinal toxicity, as there were few observable changes indicative of intestinal injury, especially in the cysteamine and indomethacin models. Plasma citrulline drastically decreased in cysteamine or indomethacin-treated rats, with a milder decrease in DNBS-treated animals. Fecal total bile acids and calprotectin levels increased only in rats treated with indomethacin or DNBS, but not with cysteamine. While plasma miR-194 remained unchanged across all models, miR-215 levels decreased after cysteamine treatment. Together, these results suggest that plasma citrulline and fecal calprotectin may be effective biomarkers for monitoring intestinal injury. Fecal TBA and plasma miR-215 also show potential as useful biomarkers, but further research is needed to confirm their efficacy. Specifically, plasma citrulline is indicative of damage from the stomach to the ileum, fecal total bile acids and calprotectin are indicative of damage from the jejunum to the rectum, and plasma miR-215 is indicative of damage from the stomach and the duodenum. Integrating these novel biomarkers with standard toxicological parameters will help in predicting actual intestinal sites of damage. This integration has the potential to improve the quality of toxicological evaluations. Our findings support the use of these biomarkers in clinical settings.

Breast cancer (BC), a major cause of death among women worldwide, has traditionally been linked to genetic and environmental factors. However, emerging research highlights the gut microbiome's significant role in shaping BC development, progression, and treatment outcomes. This review explores the intricate relationship between the gut microbiota and the breast tumor microenvironment, emphasizing how these microbes influence immune responses, inflammation, and metabolic pathways. Certain bacterial species in the gut either contribute to or hinder BC progression by producing metabolites that affect hormone metabolism, immune system pathways, and cellular signaling. An imbalance in gut bacteria, known as dysbiosis, has been associated with a heightened risk of BC, with metabolites like short-chain fatty acids (SCFAs) and enzymes such as β-glucuronidase playing key roles in this process. Additionally, the gut microbiota can impact the effectiveness of chemotherapy, as certain bacteria can degrade drugs like gemcitabine and irinotecan, leading to reduced treatment efficacy. Understanding the complex interactions between gut bacteria and BC may pave the way for innovative treatment approaches, including personalized microbiome-targeted therapies, such as probiotics and fecal microbiota transplants, offering new hope for more effective prevention, diagnosis, and treatment of BC.

High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.

Functional probiotics, particularly Lactobacillus delbrueckii subsp. lactis CKDB001, have shown potential as a therapeutic option for metabolic dysfunction-associated steatotic liver disease (MASLD). However, their effects have not been confirmed in in vivo systems. Here, we investigated the effects of L. delbrueckii subsp. lactis CKDB001 on insulin resistance, dyslipidemia, MASLD, and lipid metabolism in a murine model of high-fat diet (HFD)-induced obesity.

The mice were divided into four groups (n = 12 per group)-normal chow diet (NCD), high fat diet (HFD), HFD with L. delbrueckii subsp. lactis CKDB001 (LL), and HFD with resmetirom (positive control (PC), a thyroid receptor β agonist). The experimental animals were fed NCD or HFD for 12 weeks, followed by an additional 12-week oral treatment with LL or resmetirom.

LL supplementation reduced body weight, insulin levels, and HOMA-IR compared with those in the HFD group, indicating improved insulin sensitivity. Additionally, LL reduced serum triglyceride (TG) levels without affecting total cholesterol (TC) levels. HFD consumption increased liver weight and hepatic TG and TC levels, indicating ectopic fat accumulation; however, LL supplementation reversed these changes, indicating a liver-specific effect on cholesterol metabolism. Furthermore, LL administration attenuated NAFLD activity scores, reduced hepatic fibrosis, improved liver function markers (aspartate aminotransferase), and enhanced Adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. However, LL did not considerably affect the expression of genes related to lipid metabolism. In epididymal adipose tissue, LL treatment reduced leptin levels but had no effect on adiponectin; additionally, histological analysis showed an increase in adipocyte size, potentially linked to enhanced energy metabolism.

Collectively, these findings suggest that LL could be a promising therapeutic candidate for improving insulin sensitivity, reducing hepatic lipid accumulation, and mitigating MASLD.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease caused by insulin resistance (IR) and insufficient insulin secretion. Its characteristic pathophysiological processes involve the interaction of multiple mechanisms. In recent years, globally, the prevalence of T2DM has shown a sharp rise due to profound changes in socio-economic structure, the persistent influence of environmental factors, and the complex role of genetic background. It is worth noting that most T2DM patients show significant IR, which further exacerbates the difficulty of disease progression and prevention. In the process of extensively exploring the pathogenesis of T2DM, the dynamic equilibrium of gut microbes and its diverse metabolic activities have increasingly emphasized its central role in the pathophysiological process of T2DM. Bile acids (BAs) metabolism, as a crucial link between gut microbes and the development of T2DM, not only precisely regulates lipid absorption and metabolism but also profoundly influences glucose homeostasis and energy balance through intricate signaling pathways, thus playing a pivotal role in IR progression in T2DM. This review aims to delve into the specific mechanism through which BAs contribute to the development of IR in T2DM, especially emphasizing how gut microbes mediate the metabolic transformation of BAs based on current traditional Chinese medicine research. Ultimately, it seeks to offer new insights into the prevention and treatment of T2DM. Diet, genetics, and the environment intricately sculpt the gut microbiota and BAs metabolism, influencing T2DM-IR. The research has illuminated the significant impact of single herbal medicine, TCM formulae, and external therapeutic methods such as electroacupuncture on the BAs pool through perturbations in gut microbiota structure. This interaction affects glucose and lipid metabolism as well as insulin sensitivity. Additionally, multiple pathways including BA-FXR-SHP, BA-FXR-FGFR15/19, BA-FXR-NLRP3, BA-TGR5-GLP-1, BAs-TGR5/FXR signaling pathways have been identified through which the BAs pool significantly alter blood glucose levels and improve IR. These findings offer novel approaches for enhancing IR and managing metabolic disorders among patients with T2DM.

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.

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.

Increasing evidences indicate that the gut microbiota is involved in the development and therapy of gastrointestinal and hepatic disease. Imbalance of gut microbiota occurs in the early stages of diseases, and maintaining the balance of the gut microbiota provides a new strategy for the treatment of diseases. It has been reported that Parabacteroides distasonis is associated with multiple diseases. As the next-generation probiotics, several studies have demonstrated its positive regulation on the gastrointestinal and hepatic disease, including inflammatory bowel disease, colorectal cancer, hepatic fibrosis, and fatty liver. The function of P. distasonis and its metabolites mainly affect host immune system, intestinal barrier function, and metabolic networks. Manipulation of P. distasonis with natural components lead to the protective effect on enterohepatic disease. In this review, the metabolic pathways regulated by P. distasonis are summarized to illustrate its active metabolites and their impact on host metabolism, the role and action mechanism in gastrointestinal and hepatic disease are discussed. More importantly, the natural components can be used to manipulate P. distasonis as treatment strategies, and the challenges and perspectives of P. distasonis in clinical applications are discussed.

This study was performed to explore the beneficial protective impact of nicorandil (Nico) against lithocholic acid (LCA)-induced hepatotoxicity.

Mice received Nico (50 and 100 mg/kg. orally) for 7 days and LCA (125 mg/kg, i.p.) was injected for the last 4 days two times daily.

Nico improved both structural and functional abnormalities induced by LCA. Nico significantly decreased serum levels of transaminases, ALP, GGT and markedly elevated albumin levels. Additionally, Nico mitigated oxidative stress; it decreased contents of MDA and NO and increased GSH level and SOD activity. Moreover, Nico markedly decreased the elevated levels of TNF-α, JNK, Bax, Caspase-3 and iNOS, and increased the levels of eNOS in hepatic tissues. Furthermore, Nico substantially decreased the expression of NFκBp65 in hepatic tissues. Histopathological and transmission electron microscopy findings further supported these biomarkers.

Nico might be used as an adjuvant medication to prevent LCA-induced hepatotoxicity, pending further clinical research, through impeding oxidative stress, inflammation and apoptosis.

The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives.