The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs, along with the potential mechanisms involved. Twenty-one finishing pigs (Duroc×Landrace×Yorkshire [DLY]; average BW = 144.38 ± 8.92 kg) were assigned to three dietary treatments, with each treatment containing seven replicates, each consisting of one pig. The three dietary treatments included: a basic diet, a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid (HDCA), and a basic diet supplemented with 500 mg/kg of lithocholic acid (LCA). The trial lasted for 28 d. Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism. The results suggested that HDCA tended to decrease backfat thickness in finishing pigs (P = 0.094) and reduced the size of lipid droplets in 3T3-L1 adipocytes (P = 0.012), whereas LCA increased backfat thickness (P = 0.016) and induced larger lipid droplets in the abdominal adipose tissue (P = 0.003). Furthermore, HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase (HSL) gene in backfat of pigs (P < 0.05) and increased the protein expression of phosphorylated HSL (p-HSL) in vitro (P = 0.093). Compared to HDCA, LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs (P < 0.05) and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase (P < 0.05). In conclusion, HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs, while LCA promoted lipid synthesis and increased backfat thickness of pigs. The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.

Nonalcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, poses a substantial global health burden. Metformin is known for its protective effects in NAFLD, but the role of gut microbiota in the underlying mechanisms remains unclear. In this study, metformin was found to mitigate methionine-choline deficient (MCD) -diet induced NAFLD through reshaping the gut microbiota to increase ursodeoxycholic acid (UDCA) level, thereby inhibiting farnesoid X receptor (FXR) accompanied with activated autophagy. Specifically, using dirty cage experiments and 16S rRNA sequencing, it identified that metformin could reshape microbiota to release liver injury as confirmed by the results of histopathology and biochemical index detection. Furthermore, the bile acids were found to be altered by metformin, in which, the UDCA, a FXR natural inhibitor, was observed a significantly increase. Meanwhile, the inhibited FXR and activated autophagy in metformin-treated mice were captured using western blot, qRT-PCR and immunofluorescence analysis. In addition, the benefit of UDCA against NAFLD was demonstrated in UDCA treated mice. Further investigation with FXR siRNA introduced to HepG2 cells revealed that inhibiting FXR can reduce oleic acids induced cell injury with the autophagy activation. In conclusion, this study highlights metformin's potential to ameliorate NAFLD by reshaping gut microbiota, thereby upregulating UDCA in the liver and restoring cholesterol synthesis capacity, possibly via inhibiting FXR to activate autophagy.

This study aimed to investigate the effects of a diet supplemented with different levels of oleic acid (OA) on growth performance, serum biochemical parameters, nutrient utilization, and intestinal lipid metabolism in Pekin ducks. A total of 350 fourteen-d-old male ducks were randomly assigned to the following five isonitrogenous and heteroenergetic dietary treatment groups: 0.00% (control), 0.25%, 0.50%, 0.75%, and 1.00% OA groups. The experiment lasted 28 days. The findings indicated that neither growth performance nor nutrient utilization was affected by OA supplementation (P > 0.05). The 0.50% OA group displayed the lowest serum triglyceride (TG) levels among all treatment groups, with significantly lower values compared to both the 0.25%=% and 0.75% OA groups (P < 0.05). Moreover, the activities of lipid droplet (LD)-degrading enzymes in the jejunal mucosa, such as adipose triglyceride lipase (ATGL), showed a significant inverse linear relationship (P < 0.05); carboxylesterase 2 (CES2) activity exhibited a proportional dose-dependent increase (P < 0.05); and lysosomal acid lipase (LAL) activity was negatively correlated with the increased concentration of OA in the diet (P < 0.05). Moreover, the mRNA expression levels of the LD formation-related genes PLIN2 were significantly higher in the 0.50% OA group compared to the 0.25% and 0.75% OA groups (P < 0.05). The mRNA expression of LD degradation-related genes, the PNPLA2 expression in the 0.25%, 0.50%, and 0.75% OA groups and LPL expression in all OA groups were downregulated (P < 0.05) when compared with those in the control group. These results suggested that dietary supplementation with OA, especially at a level of 0.50%, may decrease the serum TG content and promote lipid deposition in the jejunum in Pekin ducks by regulating the formation and degradation of enterocyte LDs.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

This study aims to investigate the diagnostic potential of bile acid profiles combined with lipid parameters in metabolic dysfunction-associated steatotic liver disease (MASLD).

This study employed LC-MS technology to analyze the serum bile acid profiles of 186 male patients with MASLD and 80 male non-MASLD patients. According to whether the serum samples exhibit dyslipidemia, the subjects were divided into four groups. Subsequently, a series of analyses were conducted, including univariate analysis, the Spearman correlation test, multinomial logistic regression, restricted cubic spline regression, and ROC curve analysis.

The bile acid profiles of serum samples with dyslipidemia exhibit significant differences compared to those of normal serum samples. The bile acids, which include total deoxycholic acid (DCA), secondary bile acids (SBA), unconjugated bile acids (UCBA), 12α-hydroxylated bile acids (12HBA), total bile acids (TBA), primary bile acids (PBA)/SBA, and glycine-conjugated bile acids (GCBA)/taurine-conjugated bile acids (TCBA), demonstrate a non-linear correlation with the logarithmic ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C). The ROC analysis indicates that, in populations with normal lipid levels, bile acid indicators such as GLCA and 12HBA demonstrate a superior ability to distinguish between MASLD and non-MASLD compared to populations with abnormal lipid levels and the overall population. Their diagnostic performance significantly surpasses that of existing MASLD diagnostic models.

The combination of bile acid profiles and lipid indicators holds significant diagnostic potential in MASLD.

Hyperlipidemia is a lipid metabolism disorder that, in severe cases, can lead to conditions such as hypertension, coronary heart disease, and cirrhosis. Previous studies have identified Ilicis Rotundae Cortex (IRC) crude extract as having the potential to regulate blood lipids. However, whether the triterpenoids therein are the principal agents responsible for hypolipidemic effects and their specific mechanisms of action remain unexplored. This study aimed to investigate the effects of total triterpenoids (TT) extract derived from IRC on hyperlipidemia and to elucidate their potential mechanisms.

TT extract was first prepared and characterized to assess their hypolipidemic activity in cell models. A hyperlipidemia mouse model was established by using C57BL/6 J mice fed a high-fat, high-sugar, and high-cholesterol diet for 8 weeks. TT extract was administered as a prophylactic intervention for 4 weeks to evaluate its impact on blood lipid levels, liver lipid metabolism, and liver function. Based on progressive analysis, this study integrated serum non-targeted metabolomics analysis strategy and bile acids-targeted metabolomics analysis strategy. It was combined with modern molecular biology techniques to reveal the mechanism by which TT extract ameliorated the symptoms of hyperlipidemia through a cascade approach.

TT extract treatment significantly reduced lipid levels in hyperlipidemic mice. Notably, TT extract down-regulated bile acid levels, particularly bile acids as FXR antagonists such as T-β-MCA, β-MCA, TUDCA, and UDCA. This effect is likely mediated through alterations in the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways. TT extract administration led to decreased expression of CYP7A1 and CYP7B1, resulting in reduced bile acid levels in vivo. Additionally, FXR expression was upregulated in both the liver and ileum, potentially activating FGF15 in the ileum, which in turn transmits signals to the liver and modulates SHP and BSEP expression. These changes contribute to the regulation of bile acid synthesis, metabolism, and excretion. In vitro experiments also demonstrated that TT extract influenced the protein expression of FXR and FGF19.

Our findings demonstrate that TT extract from IRC has hypolipidemic effects. This study is the first to reveal the mechanism by which TT extract improves hyperlipidemia from the perspective of the hepatic-intestinal axis and bile acid metabolism. Its underlying mechanism is related to activating the intestinal FXR-FGF15/19 signaling pathway, which transmits signals to the liver, thereby affecting the hepatic FXR-SHP signaling pathway. This results in improved bile acid metabolism, ultimately reducing hepatic injury and ileal inflammation to exert hypolipidemic effects.

Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.

Environmental stressors can induce heritable traits in organisms across phyla, with distinct epigenetic alterations in gametes and phenotypic outcomes across several generations. However, the mechanisms underlying such intergenerational inheritance, mainly from the germline to the germline and from the germline to the soma, are enigmatic, given that postfertilization embryos and germline cells reprogram the epigenome in each generation to gain their cellular identity. Here, we report stable germline transmission of differential DNA methylation alterations (epimutations) and their associations with nonalcoholic fatty liver disease (NAFLD) in medaka exposed to a model estrogenic chemical but a ubiquitous environmental contaminant, bisphenol A (BPA).

Ancestral BPA exposure in the F0 generation led to advanced NAFLD in the unexposed grandchildren generation (F2) of medaka. The F2 liver transcriptome and histopathology revealed a severe NAFLD phenotype in females. Whole-genome bisulfite sequencing of the sperm and liver revealed a gradual shift in promoter methylation from F0 sperm (hypomethylated) to F1 sperm (mix of hypo- and hypermethylated) and F2 liver (predominantly hypermethylated). Many differentially methylated promoters (DMPs) overlapped in F0 sperm, F1 sperm, and F2 liver, regardless of sex. In females, stable transmission of 1511 DMPs was found across three generations, which are associated with protein-coding genes, miRNAs, and others and linked to NAFLD and nonalcoholic steatohepatitis (NASH). Among them, 27 canonical genes maintained consistently hypermethylated promoters across three generations, with significant downregulation of their expression and enrichment in NAFLD-related pathways, mainly fat digestion, glycerolipid metabolism, and steroid biosynthesis.

The present results demonstrate stable inter- and transgenerational germline-to-germline and germline-to-soma transmission of environmentally induced DNA epimutations with F0 and F1 gametic epimutations, predicting the F2 liver phenotype-a clear transgenerational passage of the disease phenotype in medaka.

MicroRNAs (miRNAs), small and noncoding RNAs that regulate gene expression through hybridization to messenger RNA, play a crucial role in the prevention or progression of non-alcoholic fatty liver disease (NAFLD). There is an urgent demand for the improvement of diagnostic tools and effective pharmacotherapies for the treatment of NAFLD, which can advance to cirrhosis and liver cancer. MiRNAs act as regulatory factors and noninvasive diagnostic agents for NAFLD, enabling the staging of the disorder, prognosis, and identification of pharmaco-therapeutic targets. NAFLD causes alterations in the expression patterns of hepatocyte miRNAs, with some specific miRNAs related to the upgrade from NAFLD to non-alcoholic steatohepatitis (NASH). These miRNAs can activate certain signaling cascade and exacerbate or improve NAFLD, additionally, act as hepatocellular signals or second messengers that transmit information between the liver and other systems. This study provides a comprehensive review of the most important miRNAs and their involvement in the pathophysiology and cellular signaling pathways related to NAFLD.

Depression is a widely recognized neuropsychiatric disorder. Recent studies have shown a potential correlation between bile acid disorders and depression, highlighting the importance of maintaining bile acid balance for effective antidepressant treatment. Schisandrol B (SolB), a primary bioactive compound from Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd.etWils, is pivotal in regulating bile acid homeostasis via pregnane X receptor (PXR) in cholestasis. However, the potential of SolB in alleviating depression-like symptoms, its pharmacological effects, and the underlying mechanisms remain to be fully elucidated.

We confirmed the effect of SolB against depression induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) in mice. The role of SolB in bile acid homeostasis in depression was analyzed using the metabolomic. Gene analyses and 16S rRNA sequencing were employed to investigate the involvement of PXR. Experiments with Pxr-/- mice were conducted to confirm the essential role of the PXR pathway in SolB's antidepressant effects.

SolB treatment significantly increased sucrose consumption in the SPT and the locomotor activity in the OFT, while decreasing immobility time in the FST and TST in mice exposed to CRS and CUMS. Additionally, SolB treatment significantly preserved the integrity of the dendritic spine, elevated synaptic protein PSD95 levels, and augmented CREB/BDNF expression. Metabolomic and gene analyses indicated that SolB treatment significantly facilitated bile acid metabolism, promoted intestinal bile acid efflux, decreased hippocampal levels of the secondary bile acids DCA and TLCA, and upregulated expression of the PXR target proteins CYP3A11, SULT2A1, MRP2, and OATP1B1 in the liver, and MRP2 and MDR1 in hippocampus, which are integral to bile acid homeostasis. 16S rRNA sequencing revealed that SolB reduced the abundance of the bile salt hydrolase (BSH)-producing bacteria Lactobacillus johnsonii and Bacteroides fragilis and subsequently decreased the production of TLCA and DCA. Moreover, SolB failed to protect against depression induced by CRS in Pxr-null mice, suggesting that the antidepressant effect of SolB was PXR-dependent.

These results provide direct evidence of the antidepressant effect of SolB via activation of PXR to regulate bile acid homeostasis in the brain-liver-gut axis, suggesting that SolB may serve as a novel potential target for preventing and treating depression.

Recent research indicates that the intestinal microbial community, known as the gut microbiota, may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). To understand this relationship, this study used a comprehensive bibliometric analysis to explore and analyze the currently little-known connection between gut microbiota and NAFLD, as well as new findings and possible future pathways in this field.

To provide an in-depth analysis of the current focus issues and research developments on the interaction between gut microbiota and NAFLD.

In this study, all data were collected from the Web of Science Core Collection, and the related searches were completed on one day (February 21, 2024). The data were stored in plain text format to facilitate subsequent analysis. VOSviewer 1.6.20 and CiteSpace 6.1R6 Basic were used for knowledge graph construction and bibliometric analysis.

The study included a total of 1256 articles published from 2013 to 2023, and the number of published papers demonstrated an upward trend, reaching a peak in the last two years. The University of California, San Diego held the highest citation count, while Shanghai University of Traditional Chinese Medicine in China led in the number of published works. The journal "Nutrients" had the highest publication count, while "Hepatology" was the most frequently cited. South Korean author Suk Ki Tae was the most prolific researcher. The co-cited keyword cluster labels revealed ten major clusters, namely cortisol, endothelial dysfunction, carbohydrate metabolism, myocardial infarction, non-alcoholic steatohepatitis, lipotoxicity, glucagon-like peptide-1, non-islet dependent, ethnicity, and microRNA. Keyword outbreak analysis highlighted metabolic syndrome, hepatic steatosis, insulin resistance, hepatocellular carcinoma, cardiovascular disease, intestinal permeability, and intestinal bacterial overgrowth as prominent areas of intense research.

Through the quantitative analysis of relevant literature, the current research focus and direction of gut microbiota and NAFLD can be more clearly understood, which helps us better understand the pathogenesis of NAFLD, and also opens up innovative solutions and strategies for the treatment of NAFLD.

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in bile acid metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and bile acid remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, enabling us to construct a secondary bile acid production gene catalog. This catalog greatly expanded the distribution of secondary bile acid production genes across 11 phyla, encompassing bacteria, archaea, and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between secondary bile acids (SBAs) and gastrointestinal and hepatic disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), and nonalcoholic fatty liver disease (NAFLD), further elucidating disease-specific alterations in secondary bile acid production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating secondary bile acid production in humans, given its closely aligned secondary bile acid production gene composition. This gene catalog provides a comprehensive and reliable foundation for future studies on microbial bile acid metabolism, offering new insights into the microbial contributions to health and disease.

Bile acid metabolism is an important function in both host and environmental microorganisms. The existing functional annotations from single source pose limitations on cross-habitat analysis. Our construction of a systematic secondary bile acid production gene catalog encompassing numerous high-quality reference sequences propelled research on bile acid metabolism in the global microbiome, holding significance for the concept of One Health. We further highlighted the potential of the microbiota-secondary bile acid axis as a target for the treatment of hepatic and intestinal diseases, as well as the varying feasibility of using animal models for studying human bile acid metabolism. This gene catalog offers a solid groundwork for investigating microbial bile acid metabolism across different compartments, including humans, animals, plants, and environments, shedding light on the contributions of microorganisms to One Health.

As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.

Rapamycin (Rapa) is an inhibitor of mTOR complex, and its therapeutic effect on liver function was examined in non-alcoholic fatty liver disease (NAFLD) rats here. And the possible mechanism of Rapa in NAFLD was preliminarily elucidated based on the non-targeted metabolomics analysis. Adult male SD rats were fed with a high-fat and high-cholesterol diet (HFD) to establish NAFLD model. For Rapa group, 0.8 mg/(kg.d) Rapa was given to the HFD rats. Ultra-performance liquid chromatography and Q-Tof-mass spectrometry (UPLC and Q-TOF/MS) analysis were applied for the identification of metabolites in the serum of rats, which were annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG). NAFLD rats presented with disturbed liver function, lipid metabolism and oxidative stress, but Rapa exerted a mitigating influence on the disorders. The metabolite profile data identified 579 metabolites that varied remarkably between the Rapa and HFD groups, with the main classes of amino acids and peptides, benzene, lipids and fatty acids. The differential metabolites were mainly involved in biosynthesis of cofactors, bile secretion, and glycerophospholipid metabolism were mainly enriched. In conclusion, Rapa has a potential protective effect against HFD-induced NAFLD, its hepatoprotective effect may achieved through mediating bile secretion and glycerophospholipid metabolism.

The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components, such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin, have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds, such as lipopolysaccharides and muropeptides, can have opposing effects on endocrine control of host metabolism, where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites, such as short-chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol, can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Overproduction of uric acid caused by increased expression and/or enhanced activity of xanthine oxidase (XO) is one of the major etiologies of hyperuricemia, which had a significant sex differences. As an important enzyme involved in production of reactive oxygen species and uric acid, activity of XO is highly correlated with hyperuricemia and its complications. However, the mechanisms underlying XO dysregulation remain unclear, and sex difference in the prevalence of hyperuricemia has been well known. To explore the potential role of intestinal farnesoid X receptor (FXR) on XO regulation and production, and the mechanisms of sex differences in this pathological process. Two hundred and sixty-one dyslipidemia participants and intestine-specific FXR-knockout mice were used to study the relationship between the intestinal FXR and the serum uric acid level. Western blotting, quantitative real-time PCR, and dual-luciferase reporter assay, were applied to clarify the regulatory role of FXR deficiency on XO. Special inhibitors, agonists, siRNA, sex hormones were used to investigate the mechanism of sex difference in FXR deficiency induced hyperuricemia in cell and animal model. Serum fibroblast growth factor 19 (FGF19) levels were lower in hyperuricemia patients in a sex difference manner. Increased local TNFα level driven by intestinal FXR deficiency/inhibition induced overexpression and hyperactivity of intestinal XO, leading to elevated intestinal uric acid synthesis, and subsequently resulting in hyperuricemia. We found that estrogens inhibited XO expression and activity, whereas androgens enhanced XO activity, leading to the sex difference in FXR deficiency induced hyperuricemia. Infliximab treatment eliminated the sex difference in uric acid levels in intestinal FXR-knockout mice. This study demonstrated the role of intestinal FXR in the pathogenesis of hyperuricemia, and partially elucidated the mechanisms underlying the sex differences of hyperuricemia.

Global incidence of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is on the rise while treatments remain elusive. MASLD is a disease of dysregulated systemic and hepatic metabolism. Current understanding of disease pathophysiology as it relates to metabolome changes largely comes from studies on animal models and human plasma. However, human tissue data are crucial for transitioning from mechanisms to clinical therapies. The close relationship between MASLD and comorbidities like obesity, type 2 diabetes and dyslipidemia make it difficult to determine the contribution from liver disease itself. Here, we review recent metabolomics studies in liver tissue from human MASLD patients, which have predominately focused on lipid metabolism, but also include bile acid, tricarboxylic acid (TCA) cycle, and branched chain amino acid (BCAA) metabolism. Several clinical trials are underway to target various of these lipid-related pathways in MASLD. Although only the β-selective thyroid hormone receptor agonist resmetirom has so far been approved for use, many metabolism-targeting pharmaceuticals show promising results for halting disease progression, if not promoting outright reversal. Ultimately, the scarcity of human tissue data and the variability of confounding factors, like obesity, within and between cohorts are impediments to the pathophysiological understanding required for efficient development of metabolic treatments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by hepatic steatosis associated with metabolic abnormalities. Recent research has shed light on the intricate interplay among interleukin-1 receptor 1 (IL1R1), gut microbiota, and bile acids in the pathogenesis of MASLD. This review aims to provide a comprehensive overview of the current understanding of the role of IL1R1, gut microbiota, and bile acids in MASLD, exploring their interrelationships and potential mechanisms. We summarize the evidence supporting the involvement of IL1R1 in inflammation, discuss the influence of gut microbiota on bile acid metabolism and its influence on liver health, and elucidate the bidirectional interactions among IL1R1 signaling, gut microbiota composition, and bile acid homeostasis in MASLD. Furthermore, we highlight emerging therapeutic strategies targeting these interrelated pathways for the management of MASLD.

Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.

Ischemic-type biliary lesions (ITBL) are a major cause of graft loss and even mortality after liver transplantation (LT). The underlying cellular mechanisms for ITBL remain unclear. Gut microbiota has been found to be closely related to complications after LT. Here, using gut microbiome compositions, we found patients with ITBL had a higher abundance of bacteria associated with bile salt metabolism. These bacteria are reported to convert cholic acid (CA) into deoxycholic acid (DCA), consistent with our data that there were higher DCA concentrations and DCA/CA ratio in patients with ITBL than patients without ITBL. Using an in vitro model, human intrahepatic biliary epithelial cells (HIBEC) subjected to DCA showed a higher apoptosis rate, lower viability, and higher levels of cleaved-caspase3 than CA at the same concentration. DCA also changed the morphology of mitochondria and farnesoid X receptor (FXR) expression. Interestingly, DCA-induced apoptosis rate was significantly reduced in HIBEC when the FXR or BAX gene was knocked down, suggesting that DCA-induced apoptosis was dependent on FXR-mitochondrial pathway. Furthermore, increasing DCA/CA ratio in a bile acid-feeding mouse model resulted in cholangiocyte apoptosis and impaired liver function. The patients with ITBL also showed an increased proportion of TUNEL-positive biliary epithelial cells than those without ITBL. These suggest that changes in the gut microbiota following LT may enhance the conversion of CA to DCA, and may contribute to biliary damage via FXR-mitochondrial apoptosis pathway, providing new ideas for the early monitoring and treatment of ITBL.

The purpose of this study was to examine the hepatic bacterial composition and metabolome characteristics of patients with NAFLD using 16S rDNA sequencing and metabolomics. The results of the study revealed substantial differences in hepatic bacterial composition and metabolites between the NAFLD group and the control group. These differences were used to identify potential biomarkers that could be employed to diagnose NAFLD.

Liver tissues from 13 patients in the NAFLD group and 12 patients in the control group were collected for microbiota examination.

The bacterial DNA profiles of the liver were significantly different between NAFLD patients and controls. NAFLD patients exhibited an enrichment of Enterobacterales, Mycobacteriales, Pseudomonadales, Flavobacteriales and Xanthomonadales, Sphingomonadales, Lysobact, which was characterised by a lack of erales. At the genus level, the abundance values of Escherichia-Shigella, Rhodococcus, and Chryseobacterium in the NAFLD group were significantly elevated, while the abundance values of Stenotrophomonas, Lawsonella and Sphingobium were significantly reduced. A total of 402 distinct metabolites were identified between the two groups, with 78 metabolites that were up-regulated and 14 metabolites that were down-regulated. The enrichment of metabolic pathways indicated that linoleic acid metabolism was the most significant contributor to the metabolic differences, and lipid metabolism was substantially differentiated. The hepatic metabolite levels were substantially correlated with the changes in hepatic microflora, as demonstrated by the correlation analysis.

Differences in pathogenesis and host physiological function of NAFLD may be attributed to the hepatic flora and metabolomic characteristics. In the future, this presents new opportunities for the investigation of prospective diagnostic and therapeutic targets for NAFLD.

This study aims to investigate the alterations in serum bile acid profiles among individuals with fatty liver (including non-alcoholic fatty liver (NAFL) and alcoholic fatty liver (AFL) and evaluate their clinical significance when combined with liver enzyme levels.

A cohort of 110 individuals with fatty liver (including non-alcoholic fatty liver 58 individuals and alcoholic fatty liver 52 individuals) was selected from the Department of Gastroenterology at Wenzhou People's Hospital between January 2021 and December 2022, while a control group of 66 healthy individuals was recruited from the hospital's health examination center during the same period. Clinical data and blood samples were collected from all participants. Serum bile acid profiles were quantified using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Statistical analysis was conducted in conjunction with liver enzyme indicators.

In the NAFL group, GCA, TCA, and TCDCA levels were significantly elevated compared to the control group, with GCA (AUC 0.754, sensitivity 0.707, specificity 0.712), TCA (AUC 0.770, sensitivity 0.724, specificity 0.712), and TCDCA (AUC 0.782, sensitivity 0.810, specificity 0.652) showing strong diagnostic value. In the AFL group, TCDCA, TCA, GCA, TUDCA, and GUDCA were significantly elevated, with AUC values ranging from 0.848 to 0.912. Among these, TUDCA had the highest sensitivity (0.885) and specificity (0.773) for AFL diagnosis. TUDCA (sensitivity 0.615, specificity 0.897) was the key bile acid distinguishing AFL from NAFL, with an optimal cut-off of 36.33 nmol/L. These bile acids show significant diagnostic potential for differentiating NAFL and AFL.

The bile acid profiles in both NAFL and AFL patients show changes, which hold potential clinical significance and may serve as serum biomarkers to differentiate NAFL from AFL.

Yes-associated protein 1 (YAP1) regulates the survival, proliferation, and stemness of cells, and contributes to the development of metabolic dysfunction associated fatty liver disease (MAFLD). However, the regulatory role of intestinal YAP1 in MAFLD still remains unclear.

Terminal ileal specimens were used to compare intestinal YAP1 activation in patients with and without MAFLD. Mice targeted for knocking out YAP1 in the intestinal epithelium were fed a high-fat diet (HFD) for 8 consecutive weeks. In a separate group, the mice were fed an HFD supplemented with the bile acid binder cholestyramine (CHO) or a low-fat diet with deoxycholic acid (DCA). Immunofluorescence, Immunohistochemistry, Western blot, RT-qPCR, ELISA, 16S rDNA sequencing, tissue and enteroid culture techniques were used to evaluate the effects of an HFD or DCA on the gut‒liver axis in mice or humans.

Intestinal YAP1 was activated in both humans with MAFLD and mice fed an HFD. In in vivo studies, YAP1 knockout in intestinal epithelial cells of mice alleviated the hepatic steatosis induced by an HFD, and mitigated the adverse effects of HFD on the gut‒liver axis, including the upregulation of lipopolysaccharide (LPS) and inflammation levels, enrichment of intestinal Gram-negative bacteria, and inhibition of intestinal stem cell (ISC) differentiation into the goblet and Paneth cells. High-fat feeding (HFF) produced high concentrations of DCA. The consumption of DCA mimics these HFF-induced changes, and is accompanied by the activation of Abelson tyrosine-protein kinase 1 (ABL1) and its direct substrate, YAP1, in the terminal ileum. In vitro studies further confirmed that DCA upregulated the tyrosine phosphorylation of YAP1Y357 in ISC by activating ABL1, which inhibited the differentiation of ISCs into secretory cells.

Our findings reveal that the activation of the ABL1‒YAP1 axis in ISCs by DCA contributes to hepatic steatosis through the gut‒liver axis, which may provide a potential intestinal therapeutic target for MAFLD.

The wide application of copper oxide nanoparticles (CuO NPs) in various fields such as medicine, food, agriculture, and animal husbandry can result in direct or indirect oral exposure of CuO NPs to the human body. Therefore, the research on the biosafety of CuO NPs is crucially important. However, previous research mainly concentrated on CuO NPs-induced oxidative stress, rather than the dysregulation of metabolic homeostasis. Our current finding indicates that CuO NPs can enter the systemic circulation and accumulate in the liver by being adopted by the colon and disrupting the intestinal barrier. Subsequently, CuO NPs can impair bile acid (BA) homeostasis through increased reabsorption of bile acids (BAs), ultimately leading to non-alcoholic fatty liver disease (NAFLD). Additionally, the direct stimulation from CuO NPs, damage to the gut barrier, and disruption of BA homeostasis can also disrupt microbial homeostasis in the intestines, including alterations in the composition and biological functions of gut microbiota, thereby triggering NAFLD. These findings deepen our understanding of the biosafety of CuO NPs and provide evidence for their role in disrupting physiological homeostasis.

The mechanisms underlying the ameliorative effects of polyunsaturated fatty acids (PUFAs) on metabolic disorders induced by a high-fat diet (HFD) remain poorly unclear. In this study, we investigated the anti-hyperlipidemic effects of Trichosanthes kirilowii Maxim. (T. kirilowii) seed oil rich in conjugated linolenic acid in HFD-induced hyperlipidemic rats, by the gut microbiome, cecum bile acids (BAs), and serum metabolomics. The results showed that T. kirilowii seed oil improved dyslipidemia, hepatic steatosis, oxidative stress, and inflammatory responses in HFD-induced rats. Meanwhile, T. kirilowii seed oil inhibited sterol regulatory element-binding protein 1c (SREBP-1c) mediated fatty acid synthesis and upregulated cholesterol 7-alpha hydroxylase (CYP7A1) mediated hepatic cholesterol metabolism to exert hypolipidemic effects. The administration of high dose T. kirilowii seed oil (THD) improved gut microbiota dysbiosis, increased the relative abundance of beneficial bacteria Romboutsia and unidentified_Oscillospiraceae, and decreased the relative abundance of Christensenellaceae_R-7 group, Phascolarctobacterium, and Bacteroides in HFD-induced rats. T. kirilowii seed oil reduced the accumulation of cecum primary BAs in HFD-induced rats. In addition, THD reversed the HFD-induced changes in 24 serum metabolites including leucine, isoleucine, acetylcarnitine, and glucose. Metabolic pathway enrichment analysis of the differential metabolites revealed that valine, leucine and isoleucine metabolism, butanoate metabolism, citrate cycle, and glycolysis were potential metabolic pathways involved in the anti-hyperlipidemic effects of T. kirilowii seed oil. In conclusion, this study found that dietary T. kirilowii seed oil alleviated gut microbiota dysbiosis and improved metabolic disorders in hyperlipidemic rats. This provides new insights into the anti-hyperlipidemic mechanism by which other families of PUFAs are derived from different plants.

The pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 "Jing Tint 6" laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.

The importance of the gut microbiome for human health and well-being is generally accepted, and elucidating the signaling pathways between the gut microbiome and the host offers novel mechanistic insight into the (patho)physiology and multifaceted aspects of healthy aging and human brain functions.

The gut microbiome is tightly linked with the nervous system, and gut microbiota are increasingly emerging as important regulators of emotional and cognitive performance. They send and receive signals for the bidirectional communication between gut and brain via immunological, neuroanatomical, and humoral pathways. The composition of the gut microbiota and the spectrum of metabolites and neurotransmitters that they release changes with increasing age, nutrition, hypoxia, and other pathological conditions. Changes in gut microbiota (dysbiosis) are associated with critical illnesses such as cancer, cardiovascular, and chronic kidney disease but also neurological, mental, and pain disorders, as well as chemotherapies and antibiotics affecting brain development and function.

Dysbiosis and a concomitant imbalance of mediators are increasingly emerging both as causes and consequences of diseases affecting the brain. Understanding the microbiota's role in the pathogenesis of these disorders will have major clinical implications and offer new opportunities for therapeutic interventions.

Bile acids (BAs) are significantly altered in the liver and serum of patients with nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms of these changes, particularly BA alternative pathways (BAP) responsible for non12-OH BAs, remain unclear. RNA-seq data were initially analyzed to reveal the changes of gene expression in NASH patients. Targeted metabolomics were conducted on plasma from NASH mice induced by high-fat or western diet with CCl4 for 10-24 weeks. Liver tissues were examined using proteomics, RT-qPCR, and western blotting. An integrated approach was then employed to analyze protein interactions and network correlations. Analysis of RNA-seq data revealed the inhibition of CYP7B1 in NASH patients, indicating the dysregulation of BAP. In NASH mouse models, dysregulation of BA circulation was observed by increased plasma total BA (TBA) levels and decreased liver TBA, with liver swelling and histopathological changes. Targeted metabolomics revealed suppressed levels of non12-OH BAs, which inversely correlated with increased liver injury markers. The reduced mRNA and protein expression of Fxr and upregulation of Lxr signaling in livers suggested the suppressed BAP was modulated by Fxr-Lxr signaling. Moreover, BAP interactions predominantly implicated multiple metabolism disruptions, involving 7 hub proteins (Hk1, Acadsb, Pklr, Insr, Ldlr, Cyp27a1, and Cyp7b1), offering promising therapeutic targets for NASH. We presented the metabolic and proteomic map of BAP and its regulatory network in NASH progression. Therapeutic targeting of BAP or its co-regulatory proteins holds promise for NASH treatment and metabolic syndrome management.

Liver damage from nonalcoholic steatohepatitis (NASH) presents a significant challenge to the health and productivity of ruminants. However, the regulatory mechanisms behind variations in NASH susceptibility remain unclear. The gut‒liver axis, particularly the enterohepatic circulation of bile acids (BAs), plays a crucial role in regulating the liver diseases. Since the ileum is the primary site for BAs reabsorption and return to the liver, we analysed the ileal metagenome and metabolome, liver and serum metabolome, and liver single-nuclei transcriptome of NASH-resistant and susceptible goats together with a mice validation model to explore how ileal microbial BAs metabolism affects liver metabolism and immunity, uncovering the key mechanisms behind varied NASH pathogenesis in dairy goats.

In NASH goats, increased total cholesterol (TC), triglyceride (TG), and primary BAs and decreased secondary BAs in the liver and serum promoted hepatic fat accumulation. Increased ileal Escherichia coli, Erysipelotrichaceae bacterium and Streptococcus pneumoniae as well as proinflammatory compounds damaged ileal histological morphology, and increased ileal permeability contributes to liver inflammation. In NASH-tolerance (NASH-T) goats, increased ursodeoxycholic acid (UDCA), isodeoxycholic acid (isoDCA) and isolithocholic acid (isoLCA) in the liver, serum and ileal contents were attributed to ileal secondary BAs-producing bacteria (Clostridium, Bifidobacterium and Lactobacillus) and key microbial genes encoding enzymes. Meanwhile, decreased T-helper 17 (TH17) cells and increased regulatory T (Treg) cells proportion were identified in both liver and ileum of NASH-T goats. To further validate whether these key BAs affected the progression of NASH by regulating the proliferation of TH17 and Treg cells, the oral administration of bacterial UDCA, isoDCA and isoLCA to a high-fat diet-induced NASH mouse model confirmed the amelioration of NASH through the TH17 cell differentiation/IL-17 signalling/PPAR signalling pathway by these bacterial secondary BAs.

This study revealed the roles of ileal microbiome and its secondary BAs in resilience and susceptibility to NASH by affecting the hepatic Treg and TH17 cells proportion in dairy goats. Bacterial UDCA, isoDCA and isoLCA were demonstrated to alleviate NASH and could be novel postbiotics to modulate and improve the liver health in ruminants. Video Abstract.

Pleurotus eryngii, an edible mushroom recognized for its potent polysaccharides, demonstrates significant regulatory effects on metabolic processes. β-glucan (WPEP) derived from P. eryngii has been noted for its therapeutic potential, exhibiting notable benefits in alleviating colonic inflammation and restructuring gut microbiota in mice treated with dextran sodium sulfate (DSS). This study focuses on utilizing DSS-induced colitis mice to explore the efficacy and underlying mechanisms of WPEP in ameliorating colitis, employing a metabolomics approach analyzing urine and serum. The findings reveal that WPEP administration effectively regulates metabolic imbalances in DSS mice, impacting purine metabolism, pentose and glucuronic acid interconversion, amino acid metabolism, primary bile acid biosynthesis, citric acid cycle, and lipid metabolism. Furthermore, WPEP demonstrates a capacity to modulate colitis by regulating diverse metabolic pathways, consequently influencing intestinal barrier integrity, motility, inflammation, oxidative stress, and immunity. These insights suggest that WPEP is a promising food component for managing inflammatory bowel diseases.

Background: The gut microbiota constitutes a complex microorganism community that harbors bacteria, viruses, fungi, protozoa, and archaea. The human gut bacterial microbiota has been extensively proven to participate in human metabolism, immunity, and nutrient absorption. Its imbalance, namely "dysbiosis", has been linked to disordered metabolism. Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the features of deranged human metabolism and is the leading cause of liver cirrhosis and hepatocellular carcinoma. Thus, there is a pathophysiological link between gut dysbiosis and MASLD. Aims and Methods: We aimed to review the literature data on the composition of the human bacterial gut microbiota and its dysbiosis in MASLD and describe the concept of the "gut-liver axis". Moreover, we reviewed the approaches for gut microbiota modulation in MASLD treatment. Results: There is consolidated evidence of particular gut dysbiosis associated with MASLD and its stages. The model explaining the relationship between gut microbiota and the liver has a bidirectional organization, explaining the physiopathology of MASLD. Oxidative stress is one of the keystones in the pathophysiology of MASLD and fibrosis generation. There is promising and consolidated evidence for the efficacy of pre- and probiotics in reversing gut dysbiosis in MASLD patients, with therapeutic effects. Few yet encouraging data on fecal microbiota transplantation (FMT) in MASLD are available in the literature. Conclusions: The gut dysbiosis characteristic of MASLD is a key target in its reversal and treatment via diet, pre/probiotics, and FMT treatment. Oxidative stress modulation remains a promising target for MASLD treatment, prevention, and reversal.

Background: Qinglian Hongqu decoction (QLHQD), a traditional Chinese herbal remedy, shows potential in alleviating metabolic issues related to nonalcoholic fatty liver disease (NAFLD). However, its precise mode of action remains uncertain. Objective: This study aims to evaluate the efficacy and mechanisms of QLHQD in treating NAFLD. Methods: This study utilized a NAFLD mouse model to assess the effects of QLHQD on lipid metabolism, including blood lipids and hepatic steatosis, as well as glucose metabolism, including blood glucose levels, OGTT results, and serum insulin. Network pharmacology, bioinformatics, and molecular docking were used to explore how QLHQD may improve NAFLD treatment. Key proteins involved in these mechanisms were validated via WB and immunohistochemistry. Additionally, the expression of downstream pathway targets was examined to further validate the insulin resistance mechanism by which QLHQD improves NAFLD. Results: Animal studies demonstrated that QLHQD alleviated lipid abnormalities, hepatic steatosis, blood glucose levels, the insulin resistance index, and the OGTT results in NAFLD mice (P < 0.05 or 0.01). Network pharmacology and bioinformatics analyses indicated that the effects of QLHQD on NAFLD might involve bile acid secretion pathways. Subsequent validation through Western blotting, immunohistochemistry, and qPCR demonstrated that QLHQD may influence fat metabolism and insulin sensitivity in NAFLD mice via the FXR/TGR5/GLP-1 signaling pathway. Conclusion: QLHQD significantly alleviates glucose and lipid metabolism disorders in a high-fat diet-induced NAFLD mouse model. Its mechanism of action may involve the activation of the FXR/TGR5/GLP-1 signaling pathway in the gut, which reduces lipid accumulation and insulin resistance.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-previously described as nonalcoholic fatty liver disease-continues to rise globally. Despite this, therapeutic measures for MASLD remain limited. Recently, there has been a growing interest in the gut microbiome's role in the pathogenesis of MASLD. Understanding this relationship may allow for the administration of therapeutics that target the gut microbiome and/or its metabolic function to alleviate MASLD development or progression. This review will discuss the interplay between the gut microbiome's structure and function in relation to the development of MASLD, assess the diagnostic yield of gut microbiome-based signatures as a noninvasive tool to identify MASLD severity, and examine current and emerging therapies targeting the gut microbiome-liver axis.

Hyperuricemia is prevalent globally and potentially linked to environmental pollution. As a typical persistent organic pollutant, phenanthrene (Phe) poses threats to human health through biomagnification. Although studies have reported Phe-induced toxicities to multiple organs, its impact on uric acid (UA) metabolism remains unclear. In this study, data mining on NHANES 2001-2016 indicated a positive correlation between Phe exposure and the occurrence of hyperuricemia in population. Subsequently, adolescent Balb/c male mice were orally exposed to Phe at a dosage of 10 mg/kg bw every second day for 7 weeks, resulting in dysfunction of intestinal UA excretion and disruption of the intestinal barrier. Utilizing intestinal organoids, 16S rRNA sequencing of gut microbiota, and targeted metabolomic analysis, we further revealed that an imbalance in bile acid metabolism derived from gut microbiota might mediate the intestinal barrier damage. Additionally, the tea extract theabrownin (TB) effectively improved Phe-induced hyperuricemia and intestinal dysfunction at a dose of 320 mg/kg bw per day. In conclusion, this study demonstrates that Phe exposure is positively associated with hyperuricemia and intestinal damage, which provides new insights into the toxic effects induced by Phe. Furthermore, the present study proposes that supplementation with TB would be a healthy and effective improvement strategy for patients with hyperuricemia and intestinal injury caused by environmental factors.

Mulberry leaf polysaccharides (MLP) are integral components of Mulberry leaves that confer hypoglycemic and hypolipidemic properties. This study investigated the efficacy of MLP in treating Type 2 Diabetes Mellitus (T2DM) and the underlying mechanisms related to gut microbiota-bile acids metabolism in T2DM rats. The findings revealed that MLP apparently reduced fasting blood glucose and lipid levels, ameliorated disorders in glucose and lipid metabolism, and mitigated insulin resistance. MLP enhanced the abundance of Prevotella, Ruminococcus, and Lactobacillus, thereby rectifying the gut microbiota dysbiosis in rats, which effectively restored gut microbiota homeostasis and composition. Furthermore, the data demonstrated that MLP modulated bile acid metabolism, as evidenced by reduced serum cholesterol levels, enhanced mRNA expression of hepatic cholesterol 7α- hydroxylase (Cyp7a1) and cholesterol 12α- hydroxylase (Cyp8b1), and ileal G protein-coupled bile acid receptor (Tgr5), while suppressing hepatic and ileal farnesoid X receptor (Fxr) mRNA expression in T2DM rats. Additionally, MLP upregulated the protein expression of hepatic CYP7A1 and CYP8B1, and ileal TGR5, while inhibiting FXR protein levels in the liver and ileum of T2DM rats. These results suggest that MLP can rectify disorders in glucose and lipid metabolism via the gut microbiota-bile acids metabolic pathway.

Coronary artery disease (CAD), a critical condition resulting from systemic inflammation, metabolic dysfunction, and gut microbiota dysbiosis, poses a global public health challenge. ALW-II-41-27, a specific inhibitor of the EphA2 receptor, has shown anti-inflammatory prosperities. However, the impact of ALW-II-41-27 on atherosclerosis has not been elucidated. This study aimed to examine the roles of pharmacologically inhibiting EphA2 and the underlying mechanism in ameliorating atherosclerosis. ALW-II-41-27 was administered to apoE-/- mice fed a high-fat diet via intraperitoneal injection. We first discovered that ALW-II-41-27 led to a significant reduction in atherosclerotic plaques, evidenced by reduced lipid and macrophage accumulation, alongside an increase in collagen and smooth muscle cell content. ALW-II-41-27 also significantly lowered plasma and hepatic cholesterol levels, as well as the colonic inflammation. Furthermore, gut microbiota was analyzed by metagenomics and plasma metabolites by untargeted metabolomics. ALW-II-41-27-treated mice enriched Enterococcus, Akkermansia, Eggerthella and Lactobaccilus, accompanied by enhanced secondary bile acids production. To explore the causal link between ALW-II-41-27-associated gut microbiota and atherosclerosis, fecal microbiota transplantation was employed. Mice that received ALW-II-41-27-treated mouse feces exhibited the attenuated atherosclerotic plaque. In clinical, lower plasma DCA and HDCA levels were determined in CAD patients using quantitative metabolomics and exhibited a negative correlation with higher monocytes EphA2 expression. Our findings underscore the potential of ALW-II-41-27 as a novel therapeutic agent for atherosclerosis, highlighting its capacity to modulate gut microbiota composition and bile acid metabolism, thereby offering a promising avenue for CAD.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive intracellular fat deposition in the hepatocytes, and the development is exacerbated by gut microbiota and bile acids metabolism disorders. Ilex hainanensis Merr. is a traditional medicine of the Zhuang nationality, historically esteemed for its efficacy in lowering blood pressure and lipid levels. This study aimed to investigate the pharmacodynamic effects in NAFLD mice and impacts on gut microbiota and bile acids (BAs) metabolism of I. hainanensis extract (IHA). 16 compounds were identified from IHA by HPLC-DAD-MS analysis. IHA significantly reduced body weight indexs, alanine transaminase (ALT) and aspartate transaminase (AST) activities, improved dyslipidemia and insulin resistance (IR), and effectively ameliorated hepatic steatosis in HFD-induced NAFLD mice. IHA also altered gut microbiota composition, particularly enhancing the abundance of bacteria involved in BAs metabolism, as well as augmented BAs synthesis in the liver and increased fecal excretion. In conclusion, our findings suggest that IHA holds promise in improving NAFLD conditions and modulating gut microbiota and BAs metabolism. These insights contribute to a deeper understanding of the mechanisms underlying IHA-mediated alleviation of lipid accumulation in NAFLD.