Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as Xylanibacter rodentium, as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored in vitro and in vivo. In vitro, TDCA prevented myotube atrophy, whereas in vivo hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.

Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD.

C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro.

In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export.

Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.

Bile acids are a family of signaling molecules synthesized in the liver and metabolized by gut bacteria. As metabolites of the intestinal microbiota, bile acids bind to various receptors, and affect the metabolism and immune function of the host, including glucose and lipid metabolism, energy homeostasis, and inflammatory response. Conversely, bile acids also shape the composition of the gut microbiota. Given their critical role in physiological regulation, disrupted bile acid signaling is closely linked to metabolic diseases. Consequently, therapeutic strategies targeting bile acids are increasingly being explored. The size, composition, and function of the bile acid pool can be modulated through direct treatments (e.g., bile acid replacement therapy, administration of bile acid receptor agonists/antagonists) or indirect treatments (e.g., gut microbiota modulation, probiotic supplementation), providing new ideas for preventing and treating metabolic diseases.

Cholestatic liver diseases are characterized by intrahepatic accumulation of bile acids (BAs), exacerbating liver inflammation, and fibrosis. Dimethyl fumarate (DMF) is a clinically approved anti-inflammatory drug that demonstrated protective effects in several experimental models of liver injury. Still, its effect on BA homeostasis and liver fibrosis has not been thoroughly studied. Herein, we hypothesized that DMF could improve BA homeostasis and mitigate the progression of cholestasis-induced liver fibrosis. The DMF was administered to mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholestasis for 4 wk. The content of individual BAs in the plasma, liver, bile, intestine, and feces was measured using the LC-MS method alongside the analysis of liver phenotype and related executive and regulatory pathways. The DMF slowed down the progression of DDC-induced liver fibrosis by suppressing hepatic stellate cell and macrophage activation and by reducing c-Jun N-terminal kinase phosphorylation. Notably, DMF reduced BA cumulation in the plasma and liver of cholestatic mice by increasing BA fecal excretion via their reduced Bacteroidetes phyla-mediated deconjugation in the intestine. In addition, DMF was identified as the antagonist of the mouse farnesoid X receptor in enterocytes. In conclusion, DMF alleviates DDC-induced cholestatic liver injury through pleiotropic action leading to significant anti-inflammatory and antifibrotic activity of the agent. In addition, DMF mitigates BA retention in the liver and plasma by increasing their fecal excretion in cholestatic mice. These findings suggest that DMF warrants further investigation as a potential therapeutic agent for human chronic fibrosing cholestatic liver disorders.NEW & NOTEWORTHY Chronic cholestatic cholangiopathies present a therapeutic challenge due to their complex pathophysiology, where the accumulation of bile acids plays a crucial role. In this study, we found that dimethyl fumarate attenuated cholestatic liver damage in a murine model through its significant anti-inflammatory and antifibrotic activity supported by reduced bile acid accumulation in the plasma and liver via their increased fecal excretion.

Balantidium coli (B. coli) is a prevalent intestinal parasite in monkeys, significantly impacting their health. Previous studies have demonstrated that B. coli infection in pigs leads to severe dysregulation of the gut microbiota. However, there has been no report on the alterations in fecal microbiota and metabolites in rhesus monkeys infected with B. coli. In order to investigate the differences in gut microbiota and metabolites between healthy rhesus monkeys and those infected with B. coli, we conducted gene sequencing and gas chromatography-mass spectrometry (GC-MS) analysis of fecal samples from 6 healthy rhesus monkeys and 5 rhesus monkeys infected with B. coli. The results revealed significant differences in the composition of gut microbiota between rhesus monkeys infected with B. coli and healthy ones (p < 0.01). The abundance of Campylobacterota was significantly increased (p < 0.01), while the abundance of Bacteroidota was significantly decreased (p < 0.05). Prevotella 9 was the dominant genus in both groups, showing a significant increase in the infected group (p < 0.05). At the species level, Brachyspira hampsonii was significantly increased in the infected group (p < 0.01), whereas Prevotella copri, which was the dominant species in both groups, showed a significant decrease in the infected group (p < 0.05). Metabolomics studies indicated a significant decrease in levels of metabolites such as dihydrolipoamide, 9(Z),11(E)-Conjugated Linoleic Acid, and 8,9-DiHETrE within fecal samples from rhesus monkeys infected with B. coli (p < 0.05). Correlation analysis of the microbiome and metabolome suggested a close relationship between differential microbiota and metabolites. In conclusion, this study suggests that the colonization of B. coli is associated with dysbiosis of the monkey gut microbiota. This study provides a new insight that using intestinal microbes instead of antibiotics to treat balantidiosis can also serve as a reference for further research on the relationship between gut microbiota and metabolomics in host infections by other protozoa.

The consumption of an unbalanced diet, such as a high-fat diet, is strongly associated with hyperlipidemia and significantly contributes to the development of cardiovascular and cerebrovascular diseases, which are the leading causes of death worldwide. Globally, about 17.9 million people die of cardiovascular disease each year (WHO 2023). Probiotics have emerged as a promising intervention to alleviate hyperlipidemia. Therefore, this study investigates the effects of Lactobacillus fermentum 166 (LF-166), isolated from yak yogurt in the Sichuan Tibetan area, on lipid metabolism in the liver and gut microbiota of high-fat-diet-induced hyperlipidemic mice. The results revealed that the Lactobacillus fermentum 166 (LF-166) treatment reduced the body weight and decreased the blood and liver lipid levels in these mice. Based on the histopathological findings, LF-166 could alleviate liver steatosis and colon injury. Additionally, 16S rRNA sequencing of the mice's colonic contents showed that LF-166 reduced the Firmicutes/Bacteroidetes (F/B) value and enhanced the richness and diversity of the gut microbiota. LF-166 regulated hepatic lipid metabolism through the up-regulation of the genes Lxr, Ampkα, Fxr, Hsl, and Atgl and the down-regulation of C/ebpα and Pparγ in the liver; it also regulated intestinal lipid metabolism by up-regulating Abcg5 and Abcg8 in the ileum and down-regulating the expression of the genes Npc1l1, Asbt, and Ibabp. Thus, LF-166 may inhibit hyperlipidemia progression by modulating the expression of key genes involved in hepatic lipid metabolism, influencing the intestinal microbiota through the liver-gut axis, and regulating systemic lipid metabolism.

The prevalence and adverse outcomes of metabolic dysfunction associated with steatotic liver disease (MAFLD) are increasing. The changes in the gut microbiota and metabolites associated with metabolic dysfunction-associated steatohepatitis (MASH) are regarded as an essential part of the progression of MAFLD. This study aimed to identify the gut microbiota and metabolites involved in the development of MAFLD in patients.

This study enrolled 90 patients (healthy controls, HC: n = 30; MASH: n = 30; MASH-related cirrhosis, MC: n = 30), and their fecal samples were collected for 16S rRNA sequencing and non-targeted LC-MS/MS metabolomics analysis. Data preprocessing and statistical analyses were performed using QIIME2 software, Pynast, QIIME2 package, Progenesis QI, and R program.

The abundance of Prevotellaceae at the family level and Prevotella at the genus level was lower in the MASH and NC samples than in the HC samples. Both Prevotellaceae and Prevotella showed the strongest correlation with MASH progression via random forest analysis. Untargeted metabolomics was used to quantitatively screen for discrepant metabolites in the stool samples from the three groups. Linolenic acid (LA)-related metabolite levels were significantly lower in MASH and NC samples. Associations between Prevotella- or LA-related metabolites and liver function were discovered. A high abundance of Prevotella was associated with LA-related metabolites and MASH.

This study identified that gut microbiota and metabolites are associated with MASH-related metabolic dysfunction. LA and Prevotella are depleted during MASH progression, and additional supplementation with Prevotella may be a potential strategy for the future treatment of MAFLD.

The aim of this review is to explore the potential of new regenerative medicine approaches in the treatment of cholestatic liver fibrosis. Cholestatic liver diseases, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and biliary atresia (BA), due to the accumulation of bile, often progress to liver fibrosis, cirrhosis, and liver failure. When the disease becomes severe enough to require liver transplantation. Deeply understanding the disease's progression and fibrosis formation is crucial for better diagnosis and treatment. Current liver fibrosis treatments mainly target the root causes and no direct treatment method in fibrosis itself. Recent advances in regenerative medicine offer a potential approach that may help find the ways to target fibrosis directly, offering hope for improved outcomes. We also summarize, analyze, and discuss the current state and benefits of regenerative medicine therapies such as mesenchymal stem cell (MSC) therapy, induced pluripotent stem cells (iPSCs), and organoid technology, which may help the treatment of cholestatic liver diseases. Focusing on the latest research may reveal new targets and enhance therapeutic efficacy, potentially leading to more effective management and even curative strategies for cholestatic liver diseases.

Hepatic complications are the major health issues associated with dietary intake of calorie saturated food e.g. high-fat diet (HFD). Recent studies have revealed the beneficial effects of probiotics in HFD fed mice with hepatic complications. Some probiotic Lactic acid bacteria (LAB) e.g. Lactobacillus plantarum have drawn our attention in managing hepatic complications. Here, we aim to elucidate the protective effects of L. plantarum KAD strain, isolated from ethnic fermented food 'Kinema' in HFD-fed mice as, a preventive approach. Eighteen Swiss albino mice were equally divided into 3 groups: Normal Diet (ND), negative control (HFD), and HFD-fed with oral L. plantarum KAD supplementation (LP). All the experimental groups were subjected to specific diet according to grouping for eight weeks. After completion of the regime, subjects were anesthetized and sacrificed. Organs, blood, and fecal samples were collected and stored appropriately. Physical indices, including body weight gain, organ co-efficients were calculated along with assessment of glycemic, lipidomic, hepatic, oxidative stress, inflammatory, and histological parameters. Gut microbiota analysis was performed using 16s V3-V4 fecal metagenomic profiling, and sequencing were done using Illumina Miseq system. Oral administration of L. plantarum KAD is found to significantly (p<0.05) restore metabolic health by normalizing glycemic, lipidomic, hepatic parameters, oxidative stress and inflammatory parameters. Moreover, LP group (7.08±0.52 mg/g) showed significantly (p<0.001) decreased hepatic triglyceride level compared to HFD group (20.07±1.32 mg/g). L. plantarum KAD improved the adipocytic, and colonic histomorphology with significantly better scoring pattern. LP group (1.83±0.41) showed a significantly (p<0.001) reduced hepatic score compared to negative control group (5.00±0.63), showing reduced hepatosteatosis, and immune infiltration. The strain modulated gut health by altering its microbial composition positively towards normalization. In conclusion, the results of the experiment suggest that prophylactic L. plantarum KAD administration has beneficial effects on the onset of HFD induced hepatic complications in mice. Further studies are needed, on this strain for its clinical use as dietary supplement.

Liver disease is among the top ten causes of death globally. With studies suggesting a link between gut microbiota (GM) and liver disease.

We selected summary statistics data from the largest available whole-genome association study (n = 13,266) of GM by the MiBioGen consortium as the exposure, and obtained liver disease-related data from IEU Open GWAS and The NHGRI-EBI GWAS Catalog. A two-sample Mendelian Randomization (MR) analysis employing various methods, to establish the causal relationship between GM and five liver diseases. Meanwhile, single-cell RNA sequencing data were used to examine Prevotella-related genes expression under healthy and disease liver.

The IVW analysis indicate a causal relationship between GM and liver diseases, with Prevotella exhibiting a protective effect in all five liver diseases: Alcoholic liver disease (OR:0.81,95% confidence interval:0.66-1.00,P IVW = 0.0494); Cirrhosis (OR: 0.85,95% confidence interval: 0.73-0.99,P IVW = 0.0397); Hepatic failure, not elsewhere classified (OR:0.60,95% confidence interval:0.37-0.95,P IVW = 0.0305); Benign neoplasm:Liver (OR:0.39,95% confidence interval:0.2-0.75,P IVW = 0.0046); Malignant neoplasm of liver, primary (OR:0.41, 95% confidence interval:0.18-0.93,P IVW = 0.0334). The single-cell results suggest differential expression of Prevotella-related genes between liver disease patients and healthy individuals.

Our MR results show a causal relationship between the GM and liver disease. Prevotella displays a notable protective effect. This finding may enhance the precision of GM-based therapies and offer new insights for clinical research.

Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.

The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment.

Pregnane X receptor (PXR) is essential in the regulation of liver homeostasis, and the gut microbiota is closely linked to liver physiologic and pathologic status. We previously found that activation of PXR significantly promotes liver enlargement through interaction with yes-associated protein (YAP). However, whether gut microbiota contributes to PXR-induced hepatomegaly and the involved mechanisms remain unclear. In this study, C57BL/6 mice were administered the mouse-specific agonist pregnenolone 16α-carbonitrile (PCN) for 5 days. Depletion of gut microbiota was achieved using broad-spectrum antibiotics (ABX) and fecal microbiota transplantation (FMT) was performed to restore the gut microbia. The composition of gut microbiota was analyzed by 16S rRNA sequencing, while the expression of PXR, YAP, and their downstream target genes and proteins were assessed. The results indicated that PCN treatment altered the composition and abundance of specific bacterial taxa. Furthermore, depletion of gut microbiota using ABX significantly attenuated PCN-induced hepatomegaly. FMT experiments further demonstrated that the fecal microbiota from PCN-treated mice could induce liver enlargement. Mechanistic studies revealed that ABX treatment impeded the PXR and YAP activation induced by PCN, as evidenced by decreased expression of PXR, YAP, and their downstream targets. Moreover, alterations in PXR and YAP activation were likely contributing to hepatomegaly in recipient mice following FMT from PCN-treated mice. Collectively, the current study demonstrated that gut microbiota is involved in PCN-induced hepatomegaly via regulating PXR and YAP activation, providing potential novel insights into the involvement of gut microbiota in PXR-mediated hepatomegaly. SIGNIFICANCE STATEMENT: This work describes that the composition of gut microbiota is altered in mouse pregnane X receptor (PXR) agonist pregnenolone 16α-carbonitrile (PCN)-induced hepatomegaly. Treatment with an antibiotic cocktail depletes the intestinal microbiota, leading to the impairment of liver enlargement caused by PCN. Additionally, fecal microbiota transplantation from PCN-treated mice induces liver enlargement. Further study revealed that gut microbiota is involved in hepatomegaly via regulating PXR and yes-associated protein activation.

Mastitis is an inflammatory disease of the mammary gland with a high incidence in lactating animals, significantly impacting their health and breastfeeding. Moreover, mastitis adversely affects milk quality and yield, resulting in substantial economic losses for the dairy farming industry. Forsythiaside A (FTA), a phenylethanol glycoside analog extracted from Forsythia, exhibits notable anti-inflammatory and antioxidant properties. However, its protective effects and specific mechanisms against mastitis remain unclear. In this study, a lipopolysaccharide (LPS)-induced mouse mastitis model was used to investigate the protective effect of FTA on LPS-induced mastitis and its potential mechanism using histological assays, Western blot, qRT-PCR, FITC-albumin permeability test, 16s rRNA gene sequencing analysis and non-targeted metabolomics assays to investigate the protective effect of FTA on LPS-induced mastitis model and its potential mechanism. The results demonstrated that FTA significantly mitigated LPS-induced mouse mastitis by reducing inflammation and apoptosis levels, modulating the PI3K/AKT/mTOR signaling pathways, inducing autophagy, and enhancing antioxidant capacity and the expression of tight junction proteins. Furthermore, FTA increased the abundance of beneficial microbiota while decreasing the levels of harmful microbiota in mice, thus counteracting the gut microbiota disruption induced by LPS stimulation. Intestinal metabolomics analysis revealed that FTA primarily regulated LPS-induced metabolite alterations through key metabolic pathways, such as tryptophan metabolism. This study confirms the anti-inflammatory and antioxidant effects of FTA on mouse mastitis, which are associated with key metabolic pathways, including the restoration of gut microbiota balance and the regulation of tryptophan metabolism. These findings provide a novel foundation for the treatment and prevention of mammalian mastitis using FTA.

Chronic kidney disease (CKD) is worldwide healthcare burden with growing incidence and death rate. Emerging evidence demonstrated the compositional and functional differences of gut microbiota in patients with CKD. As such, gut microbial features can be developed as diagnostic biomarkers and potential therapeutic target for CKD.

To eliminate the outcome bias arising from factors such as geographical distribution, sequencing platform, and data analysis techniques, we conducted a comprehensive analysis of the microbial differences between patients with CKD and healthy individuals based on multiple samples worldwide. A total of 980 samples from six references across three nations were incorporated from the PubMed, Web of Science, and GMrepo databases. The obtained 16S rRNA microbiome data were subjected to DADA2 processing, QIIME2 and PICRUSt2 analyses.

The gut microbiota of patients with CKD differs significantly from that of healthy controls (HC), with a substantial decrease in the microbial diversity among the CKD group. Moreover, a significantly reduced abundance of bacteria Faecalibacterium prausnitzii (F. prausnitzii) was detected in the CKD group through linear discriminant analysis effect size (LEfSe) analysis, which may be associated with the alleviating effects against CKD. Notably, we identified CKD-depleted F. prausnitzii demonstrated a significant negative correlation with three pathways based on predictive functional analysis, suggesting its potential role in regulating systemic acidbase disturbance and pro-oxidant metabolism.

Our findings demonstrated notable alterations of gut microbiota in CKD patients. Specific gut-beneficial microbiota, especially F. prausnitzii, may be developed as a preventive and therapeutic tool for CKD clinical management.

Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation.

The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS).

FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite.

FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Prevotella copri is an abundant member of the human gastrointestinal microbiome, whose relative abundance has curiously been associated with positive and negative impacts on diseases, such as Parkinson's disease and rheumatoid arthritis. Yet, the verdict is still out on the definitive role of P. copri in human health, and on the effect of different diets on its relative abundance in the gut microbiome. The puzzling discrepancies among P. copri studies have only recently been attributed to the diversity of its strains, which substantially differ in their encoded metabolic patterns from the commonly used reference strain. However, such strain differences cannot be resolved by common 16S rRNA amplicon profiling methods. Here, we scrutinize P. copri, its versatile metabolic potential, and the hypotheses behind the conflicting observations on its association with diet and human health. We also provide suggestions for designing studies and bioinformatics pipelines to better research P. copri.

Primary sclerosing cholangitis (PSC), a rare chronic cholestatic liver disease, is characterized by intrahepatic or extrahepatic strictures accompanied by biliary fibrosis. So far, there are no effective therapies to slow down the progression of this disease. Farnesoid X receptors (FXRs) are ligand-activated transcription factors involved in the control of bile acid (BA) synthesis and enterohepatic circulation. Therefore, targeting FXRs holds promise as a potential approach for treating PSC. Pediococcus pentosaceus Li05 is a probiotic that was isolated from healthy volunteers and has previously been shown to have an anti-inflammatory effect in DSS-induced colitis. In this study, we established a 3,5-diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced cholestasis mouse model and investigated the effects of Pediococcus pentosaceus Li05 on PSC. Our findings revealed that administration of Li05 significantly attenuated liver damage, hepatic inflammation, and fibrosis, as well as bile duct hyperplasia. Li05 activated the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways to decrease the expression of Cyp7a1. In addition, the Li05-modulated gut microbiota structure especially improved the abundance of 7α-dehydroxylation bacteria like Eubacterium. The intervention of Li05 also improved the intestinal barrier and reduced bacterial endotoxin translocation. Based on these findings, Li05 shows promise for future application as a therapeutic strategy for cholestasis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by inflammation and fibrosis of the bile ducts. Cholestasis may lead to hepatic inflammation and fibrosis, and amelioration of cholestasis may allow recovery from inflammatory and fibrotic pathological damage. Prevotella copri (P. copri) interventions have been reported to significantly improve cholestasis and liver fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced PSC mouse models. Even though P. copri treatment alone cannot bring about recovery from DDC-induced inflammation, it increases the abundance of Lactobacillus murinus (L. murinus) compared with DDC treatment, which has been reported to have anti-inflammatory effects. The abundance of L. murinus still not recovering to a normal level may underlie hepatic inflammation in P. copri + DDC mice. Separate or combined interventions of P. copri and L. murinus were used to investigate the molecular mechanism underlying the improvement in PSC inflammation and fibrosis. P. copri and L. murinus significantly reduced the hepatic inflammatory cell aggregation and inflammatory factor expression as well as the hepatic collagen content and fibrin factor expression in the PSC mice. Further analysis of phosphorylation and dephosphorylation levels revealed that treating the PSC mice with the P. copri and L. murinus combined intervention inhibited the activity of the DDC-activated TGF-β1/Smad pathway, thereby reducing liver inflammation and fibrosis. The combination of P. copri and L. murinus inhibits the TGF-β1/Smad pathway and reduces inflammation and fibrosis in PSC.

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid-microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway.

Forsythia fruit, edible fruit of Forsythia suspensa (Thunb.) Vahl, which has been found to be effective in treating cholestasis. However, its key component for alleviating cholestasis has not been determined. In this study, four representative active ingredients in forsythia fruit were selected. Through network pharmacology and molecular docking technology, we tried to find the key component for its treatment of cholestasis. Furthermore, the model of cholestasis in mice was established to verify the protective effect of the key component on cholestasis. Network pharmacology and molecular docking showed that forsythoside A (FTA) is the key component of forsythia fruit in the treatment of cholestasis. In vivo experiments revealed that FTA treatment could alleviate liver injury, dysfunction, and collagen deposition induced by cholestasis in mice. At the same time, FTA treatment inhibited inflammatory factor release and fibrosis-related factor expression. In addition, FTA treatment also reduced MMP-2, TLR4, MYD88, NF-κB p65, and p-NF-κB p65 protein expression. In conclusion, FTA, a key component of forsythia fruit, alleviated liver damage and fibrosis caused by cholestasis via inhibiting the TLR4/NF-κB pathway, extracellular matrix accumulation, and inflammatory cytokine expression. The research results could provide a scientific reference for the development of forsythia fruit as a drug or functional food to prevent and treat cholestasis.

Biliary diseases are a group of disease affecting biliary tract, including immune-mediated primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). With limited treatment options, PBC and PSC may lead to liver cirrhosis.

Emerging evidence has shown the participation of gut microbiota in the etiology of PBC and PSC. Patients with PBC and PSC exhibit alterations in gut microbiota composition. Dysfunctional gut barrier facilitates the translocation of possible pathogenic bacteria and derived metabolites. Along with molecular mimicry between host and bacterial antigen, these factors result in aberrant auto-immune activation, and subsequently lead to liver injury. Though the precise mechanism has not been fully elucidated, studies investigating the role of gut microbiota in pathogenesis of PBC and PSC have inspired novel biomarkers and therapeutic strategies.

In this review, recent evidence on the alteration of intestinal microbiota and possible mechanistic and therapeutic applications are discussed, predominantly focusing on PSC and PBC.

The gut microbiota is a complex ecosystem that has coevolved with the human body for hundreds of millions of years. In the past 30 years, with the progress of gene sequencing and omics technology, the research related to gut microbiota has developed rapidly especially in the field of digestive system diseases and systemic metabolic diseases. Mechanical, biological, immune, and other factors make the intestinal flora form a close bidirectional connection with the liver and gallbladder, which can be called the "gut-liver-biliary axis." Liver and gallbladder, as internal organs of the peritoneum, suffer from insidious onset, which are not easy to detect. The diagnosis is often made through laboratory chemical tests and imaging methods, and intervention measures are usually taken only when organic lesions have occurred. At this time, some people may have entered the irreversible stage of disease development. We reviewed the literature describing the role of intestinal flora in the pathogenesis and biotherapy of hepatobiliary diseases in the past 3-5 years, including the dynamic changes of intestinal flora at different stages of the disease, as well as the signaling pathways involved in intestinal flora and its metabolites, etc. After summarizing the above contents, we hope to highlight the potential of intestinal flora as a new clinical target for early prevention, early diagnosis, timely treatment and prognosis of hepatobiliary diseases. GRAPHICAL ABSTRACT.

Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.

Background: Liver fibrosis is a common outcome of the pathological progression of chronic liver disease; however, no specific and effective therapeutic agent has been approved for its treatment. We investigated the effects of Kuhuang on liver fibrosis and the underlying mechanisms of action. Materials and methods: To induce hepatic fibrosis, either 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet was administered, or bile duct ligation (BDL) surgery was performed on C57BL/6 mice. Kuhuang was orally administered to mice for 7 days before and after bile duct ligation or 4 weeks with a DDC diet. Hematoxylin and eosin, Sirius red staining, and immunohistochemical analyses were performed to evaluate hepatic pathology. Hepatic interferon-β (IFN-β) levels were measured using an enzyme-linked immunosorbent assay. RNA sequencing was performed to examine the gene expression profiles of liver tissues. The mRNA expression of inflammatory, profibrotic, and bile acid (BA)-related genes was further validated by qRT-PCR. A targeted metabolomics assay revealed the alteration of the hepatic bile acid (BA) composition. The composition of the gut microbiota was determined via 16S rRNA sequencing. Results: Treatment with Kuhuang attenuated liver fibrosis and reduced the inflammatory response in bile duct ligation and DDC mouse models. In addition, the hepatic IFN signaling pathway was activated following Kuhuang treatment. Kuhuang treatment also significantly decreased hepatic levels of both primary and secondary BAs. In addition, Kuhuang treatment altered gut microbiota composition, with an increased abundance of interferon-inducing Akkermansia and decreased abundance of bile salt hydrolase-producing Lactobacillus, Clostridium, and Bifidobacterium. Furthermore, the abundance of Akkermansia was positively correlated with the hepatic mRNA expression levels of Ifna4, Ifnb, and Isg15, whereas that of Lactobacillus, Clostridium _- sensu _- stricto _- 1, and Bifidobacterium was positively correlated with levels of bile acid synthesis-related genes. Conclusion: Our results suggest that Kuhuang plays a protective role during the progression of liver fibrosis, potentially by altering the composition of the gut microbiota, which consequently activates interferon signaling and inhibits bile acid synthesis in the liver.

Obesity is a risk factor for many chronic diseases and its rising prevalence the last couple of decades is a healthcare concern in many countries. Obesity is a multifactorial problem that is not only limited in its causation by diet and lack of exercise. Genetics but also environmental factors such as the gut microbiome should similarly be taken into account. A plethora of articles have been published, that from various different angles, attempt to disentangle the complex interaction between gut microbiota and obesity. Examples range from the effect of the gut microbiota on the host immune system to the pathophysiological pathways in which microbial-derived metabolites affect obesity. Various discordant gut microbiota findings are a result of this complexity. In this review, in addition to summarizing the classical role of the gut microbiome in the pathogenesis of obesity, we attempt to view both the healthy and obesogenic effects of the gut microbiota as a consequence of the presence or absence of collective guilds/trophic networks. Lastly, we propose avenues and strategies for the future of gut microbiome research concerning obesity.

Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.