Background Oxidative stress can impair intestinal barrier function and cause liver damage,resulting in reduced animal productivity.Paraquat(PQ)induces significant oxidative stress in weaned piglets.The antioxidant,ant...Background Oxidative stress can impair intestinal barrier function and cause liver damage,resulting in reduced animal productivity.Paraquat(PQ)induces significant oxidative stress in weaned piglets.The antioxidant,anti-inflammatory,and metabolic regulatory functions of taurine(Tau),a free amino acid that is widely distributed in the body,have been extensively studied.However,the mechanisms by which dietary Tau alleviates oxidative stress and gut-liver axis damage in weaned piglets remain unclear.Methods Forty weaned piglets(20 males and 20 females;6.41±0.11 kg;25 days old;Duroc×Landrace×Yorkshire)were used in a 2×2 factorial design to investigate the mechanism by which dietary Tau(0%or 0.4%)alleviates PQ-induced oxidative stress and gut-liver axis damage.We analyzed key biomarkers related to gut barrier function,mucosal damage repair,liver damage,gut-liver immunity,antioxidant capacity,systemic immune homeostasis,antioxidant levels,and gut microbiota diversity in piglets under normal and acute oxidative stress.In particular,we evaluated the coordinated regulation of gut-liver axis function mediated by Tau through the Nrf2/Keap1(antioxidant)and TLR4/NF-κB(immune modulation)signaling pathways.Partial least squares path modeling and molecular docking were used to explore the intrinsic relationship between PQ,Tau,and the gut-liver axis.Results PQ exposure impaired gut barrier function,increased the liver fibrosis area,and markedly affected gut microbial diversity(P<0.05).Tau effectively alleviated PQ-induced oxidative stress by activating the Nrf2/Keap1 pathway and inhibiting the TLR4/NF-κB pathway.This enhanced gut barrier function,promoted mucosal repair,and significantly suppressed the concentration and circulation of lipopolysaccharides in the blood,consequently reducing liver damage(P<0.05).This further facilitated the optimization of gut microbiota composition,thereby supporting the positive regulation of the gut-liver axis and improving systemic immune and antioxidant functions.Conclusions Tau improved the health status of weaned piglets under both normal and stressed conditions by modulating the Nrf2/Keap1 and TLR4/NF-κB pathways,offering a potential new nutritional strategy for alleviating gut-liver damage.展开更多
The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this a...The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this axis,mediated by gut microbiota dysbiosis,impaired intestinal barrier function,and pro-inflammatory signaling,contributes significantly to insulin resistance,hepatic steatosis,and systemic metabolic dysfunction.This review explores the underlying mechanisms by which microbial alterations,increased gut permeability,and inflammatory pathways influence hepatic insulin resistance and glucose metabolism.In addition to established mechanisms,emerging pathways involving neuroendocrine circuits,microbial metabolites,and immune mediators are discussed,offering deeper insight into gut-liver interactions in metabolic disease.The review also outlines therapeutic strategies targeting the gut-liver axis,including microbiota modulation,barrier function enhancement,and anti-inflammatory interventions,emphasizing their potential in advancing diabetes management.A conceptual framework is proposed to integrate these components into a precision medicine approach for metabolic regulation.Key challenges in clinical translation,including patient heterogeneity and the absence of reliable biomarkers to guide treatment decisions are also discussed to inform future research.By linking mechanistic understanding with therapeutic innovation,the review highlights the gut-liver axis as a promising target for personalized diabetes care.展开更多
Autoimmune liver disease overlap syndrome(OS)is a rare and clinically significant condition that has received limited attention in microbiome research.In their recent study,Wang et al combined 16S rRNA sequencing with...Autoimmune liver disease overlap syndrome(OS)is a rare and clinically significant condition that has received limited attention in microbiome research.In their recent study,Wang et al combined 16S rRNA sequencing with untargeted metabolomics to characterize the gut-liver axis in OS,identifying shared features of dysbiosis in autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC),and unique signatures,including enrichment of Klebsiella and Escherichia and depletion of aromatic amino acids.In this letter,we critically appraise these findings,emphasizing that OS should be considered a distinct immunometabolic phenotype rather than a simple mixture of AIH and PBC.We discuss the potential mechanistic relevance of the Fusicatenibacter-tyrosine relationship,highlight the clinical implications of integrating microbiota-metabolite analyses,and outline the limitations that future studies must address.展开更多
Recent research has indicated that sialic acid,such as free sialic acid(N-acetylneuraminic acid,Neu5Ac)and bound sialic acid(3ʹ-sialyllactose,3ʹ-SL),can ameliorate disorders associated with glycolipid metabolism,altho...Recent research has indicated that sialic acid,such as free sialic acid(N-acetylneuraminic acid,Neu5Ac)and bound sialic acid(3ʹ-sialyllactose,3ʹ-SL),can ameliorate disorders associated with glycolipid metabolism,although the underlying mechanisms have yet to be determined.We examined the effects of 3ʹ-SL on glycolipid metabolism in mice fed a high-fat diet.Male C57BL/6J mice were divided into 6 groups:2 model control groups(normal and high-fat diets)and 4 intervention groups(Neu5Ac,and low,moderate,and high-dose 3ʹ-SL).After 8 weeks of continuous gavage intervention,mice in the 3ʹ-SL intervention groups had lower body weight and total fat content;reduced fasting blood glucose,triglycerides,low-density lipoproteins and oxidized-low-density lipoproteins;and increased high-density lipoproteins,but no dosage-dependent of 3ʹ-SL intervention was found,moderate-dose 3ʹ-SL intervention as optimal for further exploration.3ʹ-SL intervention could increase respiratory exchange ratio,energy expenditure,and amount of exercise performed.3ʹ-SL increased the colonic abundances of Akkermansia,Lactobacillus,and Bacteroides,and reduced those of Erysipelatoclostridium,Faecalibaculum,and Aldercreutzia.Changes were also observed in colonic metabolites,and liver gene transcript and metabolites,which were mainly enriched in bile secretion,taurine and hypotaurine metabolism,and insulin resistance.Additionally,3ʹ-SL was observed to regulate genes associated with physiological rhythms,including Clock,Per2,Cry1,and Bhihe41.Collectively,our findings indicate that 3ʹ-SL can contribute to the prevention and control of disorders associated with glucose and lipid metabolism caused by high-fat diets.Compared with Neu5Ac,3ʹ-SL intervention can more effectively ameliorate intestinal flora disorders,enhance bile acid circulation,increase tissue energy expenditure,and reduce lipid synthesis,thereby promoting lipid-lowering effects mediated via the gut-liver axis,and can also enhance energy metabolism and alleviate disorders of glucolipid metabolism by altering physiological rhythms in high fat-diet mice.展开更多
Targeting the gut-liver axis has emerged as a promising strategy in the treatment of metabolic dysfunction-associated steatotic liver disease(MASLD),a condition that currently represents the most common cause of chron...Targeting the gut-liver axis has emerged as a promising strategy in the treatment of metabolic dysfunction-associated steatotic liver disease(MASLD),a condition that currently represents the most common cause of chronic liver disease worldwide.Within this axis,the duodenum serves not only as a site of nutrient absorption but also as a metabolic sensor capable of influencing systemic and hepatic homeostasis.We have read with great interest the recent study by Yu et al,investigating the effects of duodenal mucosal ablation(DMA)by irreversible electroporation in a rat model of MASLD.The authors reported remarkable reductions in hepatic lipid content,improvements in serum lipid profiles,and both structural and functional changes in the intestinal mucosa,including alterations in enteroendocrine signaling.These results corroborate the pivotal role of the gut-liver axis in the pathogenesis of MASLD and highlight the potential of minimally invasive approaches targeting the proximal intestine.In this letter,we discuss the broader implications of these findings,emphasizing the translational relevance of intestinal modulation strategies in the comprehensive treatment of MASLD.展开更多
The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and ...The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a “low bacterial richness” may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier (“leaky gut”), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy.展开更多
BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modul...BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modulating gut microbiota.Partially hydrolyzed guar gum(PHGG),a water-soluble dietary fiber,has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes.However,its effects on NAFLD remain to be fully elucidated.To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODS Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic(Ath)diet(a mouse model of NAFLD)for 8 wk,with or without 5%PHGG.Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium.Body weight,liver weight,macroscopic findings in the liver,blood biochemistry[aspartate aminotransferase(AST)and alanine aminotransferase(ALT),total cholesterol,triglyceride,free fatty acids,and glucose levels],liver histology,myeloperoxidase activity in liver tissue,mRNA expression in the liver and intestine,serum endotoxin levels in the portal vein,intestinal permeability,and microbiota and short-chain fatty acid(SCFA)profiles in the cecal samples were investigated.RESULTS Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels,liver fat accumulation,liver inflammatory(tumor necrosis factor-αand monocyte chemotactic protein-1)and fibrogenic(collagen 1a1 andαsmooth muscle actin)marker levels,and liver myeloperoxidase activity,which were significantly attenuated by PHGG treatment.Furthermore,the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor(TLR)4 and TLR9 expression,confirming that intestinal permeability was significantly elevated,as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran.PHGG treatment did not affect fatty acid metabolism in the liver.However,it decreased lipopolysaccharide signaling through the gut-liver axis.In addition,it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa.Treatment with PHGG markedly increased the levels of SCFAs,particularly,butyric acid,acetic acid,propionic acid,and formic acid,in the cecal samples.CONCLUSION PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.展开更多
Background:This study investigated the protective effects of L.reuteri ZJ617 on intestinal and liver injury and the underlying mechanisms in modulating inflammatory,autophagy,and apoptosis signaling pathways in a pigl...Background:This study investigated the protective effects of L.reuteri ZJ617 on intestinal and liver injury and the underlying mechanisms in modulating inflammatory,autophagy,and apoptosis signaling pathways in a piglet challenged with lipopolysaccharide(LPS).Methods:Duroc×Landrace×Large White piglets were assigned to 3 groups(n=6/group):control(CON)and LPS groups received oral phosphate-buffered saline for 2 weeks before intraperitoneal injection(i.p.)of physiological saline or LPS(25μg/kg body weight),respectively,while the ZJ617+LPS group was orally inoculated with ZJ617 for 2 weeks before i.p.of LPS.Piglets were sacrificed 4 h after LPS injection to determine intestinal integrity,serum biochemical parameters,inflammatory signaling involved in molecular and liver injury pathways.Results:Compared with controls,LPS stimulation significantly increased intestinal phosphorylated-p38 MAPK,phosphorylated-ERK and JNK protein levels and decreased IκBαprotein expression,while serum LPS,TNF-α,and IL-6 concentrations(P<0.05)increased.ZJ617 pretreatment significantly countered the effects induced by LPS alone,with the exception of p-JNK protein levels.Compared with controls,LPS stimulation significantly increased LC3,Atg5,and Beclin-1 protein expression(P<0.05)but decreased ZO-1,claudin-3,and occludin protein expression(P<0.05)and increased serum DAO and D-xylose levels,effects that were all countered by ZJ617 pretreatment.LPS induced significantly higher hepatic LC3,Atg5,Beclin-1,SOD-2,and Bax protein expression(P<0.05)and lower hepatic total bile acid(TBA)levels(P<0.05)compared with controls.ZJ617 pretreatment significantly decreased hepatic Beclin-1,SOD2,and Bax protein expression(P<0.05)and showed a tendency to decrease hepatic TBA(P=0.0743)induced by LPS treatment.Pretreatment of ZJ617 before LPS injection induced the production of 5 significant metabolites in the intestinal contents:capric acid,isoleucine 1TMS,glycerol-1-phosphate byproduct,linoleic acid,alanine-alanine(P<0.05).Conclusions:These results demonstrated that ZJ617 pretreatment alleviated LPS-induced intestinal tight junction protein destruction,and intestinal and hepatic inflammatory and autophagy signal activation in the piglets.展开更多
Viral B and C hepatitis are a major current health issue,both diseases having a chronic damaging effect on the liver and its functions.Chronic liver disease can lead to even more severe and life-threatening conditions...Viral B and C hepatitis are a major current health issue,both diseases having a chronic damaging effect on the liver and its functions.Chronic liver disease can lead to even more severe and life-threatening conditions,such as liver cirrhosis and hepatocellular carcinoma.Recent years have uncovered an important interplay between the liver and the gut microbiome:the gut-liver axis.Hepatitis B and C infections often cause alterations in the gut microbiota by lowering the levels of‘protective’gut microorganisms and,by doing so,hinder the microbiota ability to boost the immune response.Treatments aimed at restoring the gut microbiota balance may provide a valuable addition to current practice therapies and may help limit the chronic changes observed in the liver of hepatitis B and C patients.This review aims to summarize the current knowledge on the anatofunctional axis between the gut and liver and to highlight the influence that hepatitis B and C viruses have on the microbiota balance,as well as the influence of treatments aimed at restoring the gut microbiota on infected livers and disease progression.展开更多
The gut-liver axis denotes the intricate connection and interaction between gut microbiome and liver, in which compositional and functional shifts in gut microbiome affect host metabolism. Hepatic portal vein of the b...The gut-liver axis denotes the intricate connection and interaction between gut microbiome and liver, in which compositional and functional shifts in gut microbiome affect host metabolism. Hepatic portal vein of the blood circulation system has been thought to be the major route for metabolite transportation in the gut-liver axis, but the existence and importance of other routes remain elusive. Here, we perform metabolome comparison in blood circulation and mesenteric lymph systems and identify significantly shifted metabolites in serum and mesentery. Using cellular assays, we find that the majority of decreased metabolites in lymph system under high-fat diet are effective in alleviating metabolic disorders, indicating a high potential of lymph system in regulating liver metabolism. Among those, a representative metabolite, L-carnitine, reduces diet-induced obesity in mice. Metabolic tracing analysis identifies that L-carnitine is independently transported by the mesenteric lymph system, serving as an example that lymph circulation comprises a second route in the gut-liver axis to modulate liver metabolism. Our study provides new insights into metabolite transportation via mesenteric lymph system in the gut-liver axis, offers an extended scope for the investigations in host-gut microbiota metabolic interactions and potentially new targets in the treatment of metabolic disorders.展开更多
The gut microbiota is of growing interest to clinicians and researchers.This is because there is a growing understanding that the gut microbiota performs many different functions,including involvement in metabolic and...The gut microbiota is of growing interest to clinicians and researchers.This is because there is a growing understanding that the gut microbiota performs many different functions,including involvement in metabolic and immune processes that are systemic in nature.The liver,with its important role in detoxifying and metabolizing products from the gut,is at the forefront of interactions with the gut microbiota.Many details of these interactions are not yet known to clinicians and researchers,but there is growing evidence that normal gut microbiota function is important for liver health.At the same time,factors affecting the gut microbiota,including nutrition or medications,may also have an effect through the gut-liver axis.展开更多
Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investig...Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.展开更多
With the rising prevalence of chronic liver diseases worldwide,there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease.Currently,the most c...With the rising prevalence of chronic liver diseases worldwide,there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease.Currently,the most common causes of liver disease are non-alcoholic fatty liver disease,hepatitis,and alcoholic liver disease.Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis.In this review,we analyse the relationship between the gut and liver and their significance in liver disease.This two-way relationship has interesting effects on each other in liver diseases.The gut microbiota,through its metabolites,influences the metabolism in numerous ways.Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases.Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.展开更多
Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and...Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. Data sources: Recently there have been several innovative studies investigating gut microbial dysbiosismediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the Pub Med database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. Results: Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. Conclusions: Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.展开更多
Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstric...Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.展开更多
A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels ...A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.展开更多
Aflatoxin B_1(AFB_1)is a common contaminant in cereals of global concern,and long-term low-dose exposure can adversely affect human health.Here,we showed that populations with dietary patterns characterized by high-fa...Aflatoxin B_1(AFB_1)is a common contaminant in cereals of global concern,and long-term low-dose exposure can adversely affect human health.Here,we showed that populations with dietary patterns characterized by high-fat diet(HFD)might have an increased risk of exposure to high levels of AFB_1.Our data indicated that chronic exposure of AFB_1 induced“gut-liver axis”injury in mice under HFD and normal diet(ND)patterns.AFB_1 further aggravated hepatic and intestinal injury,and intestinal microbiota disruption in HFD mice.Bifidobacterium breve BAA-2849 intervention analysis showed that liver injury and lipid disorders caused by AFB_1 exposure were alleviated by regulating the proportions of different gut microbes.We demonstrated through a mice model that the populations with a dietary pattern of HFD might be more susceptible to AFB_1 exposure and adverse effects on the gut-liver axis,and the toxicity of AFB_1 exposure can be alleviated by regulating the gut microbiota.展开更多
Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induc...Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induced MASLD through the gut-liver axis.Methods:The TM6SF2 gut-specific knockout(TM6SF2 GKO)mouse was constructed using CRISPR/Cas9 technology.TM6SF2 GKO and wild-type(CON)mice were fed either a HFD or a control diet for 16 weeks to induce MASLD.Blood,liver,and intestinal lipid content,as well as gut microbiota and serum metabolites,were then analyzed.Results:TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice.The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice.The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase,alanineaminotransferase,and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice,while triglyceride levels were lower.Serum metabolite analysis revealed that HFDfed TM6SF2 GKO mice had an increase in the expression of 17 metabolites(e.g.,LPC[18:0/0-0])and a decrease in 22 metabolites(e.g.,benzene sulfate).The differential metabolites of LPC(18:0/0-0)may serve as HFD-fed TM6SF2 serum biomarkers,leading to MASLD exacerbation in GKO mice.Conclusions:TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice.TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.展开更多
Gut-derived metabolites are essential for liver fibrogenesis.The aim of this study was to determine the alteration of indole-3-propionic acid(IPA),a crucial tryptophan metabolite,in liver fibrosis and delineate the ro...Gut-derived metabolites are essential for liver fibrogenesis.The aim of this study was to determine the alteration of indole-3-propionic acid(IPA),a crucial tryptophan metabolite,in liver fibrosis and delineate the roles of enterogenic IPA in fibrogenesis.In the present study,metabolomics assays focused on tryptophan metabolism were applied to explore the decreased levels of IPA in the feces and serum of cirrhotic patients,as well as in the feces and portal vein serum of fibrotic mice.Oral IPA administration exerted strong antifibrotic effects with favorable biosafety in three fibrotic models via multicellular modulation.Multiplex immunohistochemical staining and DAOSLIMIT imaging demonstrated that gut-derived IPA was directly captured by hepatic macrophages.Macrophage-specific AhR knockout blocked the antifibrotic effect of IPA,while the therapeutic efficacy was maintained in mice with HSC-or hepatocyte-specific AhR depletion.Furthermore,IPA governed macrophage recruitment,S100A8/A9+phenotype transformation and profibrotic and proinflammatory functions,resulting in amelioration of hepatic fibrogenesis.Mechanistically,IPA targeted the AhR/NF-κB/S100A8/A9 axis and AhR/SPHK2/S1P signaling to inhibit the profibrotic biological characteristics of macrophages and subsequently interrupted the profibrogenic crosstalk between macrophages and hepatic stellate cells(HSCs)in coculture systems and 3D liver spheroid models.These findings increase the understanding of the effects of enterogenic tryptophan metabolites on liver fibrogenesis via the gut-liver axis and support the translational potential of IPA.By targeting profibrogenic macrophages,IPA could serve as a promising candidate for the clinical management of liver fibrosis.展开更多
基金supported by the National Natural Science Foundation of China(32372894)Key Project of Science and Technology Research Program of Chongqing Municipal Education Commission(KJZD-K202300209)+1 种基金Fundamental Research Funds for National Key R&D Program of China(SQ2022YFD1300007)Innovation Research 2035 Pilot Program of Southwest University(SWU-XDPY22005).
文摘Background Oxidative stress can impair intestinal barrier function and cause liver damage,resulting in reduced animal productivity.Paraquat(PQ)induces significant oxidative stress in weaned piglets.The antioxidant,anti-inflammatory,and metabolic regulatory functions of taurine(Tau),a free amino acid that is widely distributed in the body,have been extensively studied.However,the mechanisms by which dietary Tau alleviates oxidative stress and gut-liver axis damage in weaned piglets remain unclear.Methods Forty weaned piglets(20 males and 20 females;6.41±0.11 kg;25 days old;Duroc×Landrace×Yorkshire)were used in a 2×2 factorial design to investigate the mechanism by which dietary Tau(0%or 0.4%)alleviates PQ-induced oxidative stress and gut-liver axis damage.We analyzed key biomarkers related to gut barrier function,mucosal damage repair,liver damage,gut-liver immunity,antioxidant capacity,systemic immune homeostasis,antioxidant levels,and gut microbiota diversity in piglets under normal and acute oxidative stress.In particular,we evaluated the coordinated regulation of gut-liver axis function mediated by Tau through the Nrf2/Keap1(antioxidant)and TLR4/NF-κB(immune modulation)signaling pathways.Partial least squares path modeling and molecular docking were used to explore the intrinsic relationship between PQ,Tau,and the gut-liver axis.Results PQ exposure impaired gut barrier function,increased the liver fibrosis area,and markedly affected gut microbial diversity(P<0.05).Tau effectively alleviated PQ-induced oxidative stress by activating the Nrf2/Keap1 pathway and inhibiting the TLR4/NF-κB pathway.This enhanced gut barrier function,promoted mucosal repair,and significantly suppressed the concentration and circulation of lipopolysaccharides in the blood,consequently reducing liver damage(P<0.05).This further facilitated the optimization of gut microbiota composition,thereby supporting the positive regulation of the gut-liver axis and improving systemic immune and antioxidant functions.Conclusions Tau improved the health status of weaned piglets under both normal and stressed conditions by modulating the Nrf2/Keap1 and TLR4/NF-κB pathways,offering a potential new nutritional strategy for alleviating gut-liver damage.
文摘The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this axis,mediated by gut microbiota dysbiosis,impaired intestinal barrier function,and pro-inflammatory signaling,contributes significantly to insulin resistance,hepatic steatosis,and systemic metabolic dysfunction.This review explores the underlying mechanisms by which microbial alterations,increased gut permeability,and inflammatory pathways influence hepatic insulin resistance and glucose metabolism.In addition to established mechanisms,emerging pathways involving neuroendocrine circuits,microbial metabolites,and immune mediators are discussed,offering deeper insight into gut-liver interactions in metabolic disease.The review also outlines therapeutic strategies targeting the gut-liver axis,including microbiota modulation,barrier function enhancement,and anti-inflammatory interventions,emphasizing their potential in advancing diabetes management.A conceptual framework is proposed to integrate these components into a precision medicine approach for metabolic regulation.Key challenges in clinical translation,including patient heterogeneity and the absence of reliable biomarkers to guide treatment decisions are also discussed to inform future research.By linking mechanistic understanding with therapeutic innovation,the review highlights the gut-liver axis as a promising target for personalized diabetes care.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,No.RS-2023-00237287.
文摘Autoimmune liver disease overlap syndrome(OS)is a rare and clinically significant condition that has received limited attention in microbiome research.In their recent study,Wang et al combined 16S rRNA sequencing with untargeted metabolomics to characterize the gut-liver axis in OS,identifying shared features of dysbiosis in autoimmune hepatitis(AIH)and primary biliary cholangitis(PBC),and unique signatures,including enrichment of Klebsiella and Escherichia and depletion of aromatic amino acids.In this letter,we critically appraise these findings,emphasizing that OS should be considered a distinct immunometabolic phenotype rather than a simple mixture of AIH and PBC.We discuss the potential mechanistic relevance of the Fusicatenibacter-tyrosine relationship,highlight the clinical implications of integrating microbiota-metabolite analyses,and outline the limitations that future studies must address.
基金supported by the Incubation Fund of Zhongshan Hospital,Fudan University(Xiamen Branch)(2020ZSXMYS24).
文摘Recent research has indicated that sialic acid,such as free sialic acid(N-acetylneuraminic acid,Neu5Ac)and bound sialic acid(3ʹ-sialyllactose,3ʹ-SL),can ameliorate disorders associated with glycolipid metabolism,although the underlying mechanisms have yet to be determined.We examined the effects of 3ʹ-SL on glycolipid metabolism in mice fed a high-fat diet.Male C57BL/6J mice were divided into 6 groups:2 model control groups(normal and high-fat diets)and 4 intervention groups(Neu5Ac,and low,moderate,and high-dose 3ʹ-SL).After 8 weeks of continuous gavage intervention,mice in the 3ʹ-SL intervention groups had lower body weight and total fat content;reduced fasting blood glucose,triglycerides,low-density lipoproteins and oxidized-low-density lipoproteins;and increased high-density lipoproteins,but no dosage-dependent of 3ʹ-SL intervention was found,moderate-dose 3ʹ-SL intervention as optimal for further exploration.3ʹ-SL intervention could increase respiratory exchange ratio,energy expenditure,and amount of exercise performed.3ʹ-SL increased the colonic abundances of Akkermansia,Lactobacillus,and Bacteroides,and reduced those of Erysipelatoclostridium,Faecalibaculum,and Aldercreutzia.Changes were also observed in colonic metabolites,and liver gene transcript and metabolites,which were mainly enriched in bile secretion,taurine and hypotaurine metabolism,and insulin resistance.Additionally,3ʹ-SL was observed to regulate genes associated with physiological rhythms,including Clock,Per2,Cry1,and Bhihe41.Collectively,our findings indicate that 3ʹ-SL can contribute to the prevention and control of disorders associated with glucose and lipid metabolism caused by high-fat diets.Compared with Neu5Ac,3ʹ-SL intervention can more effectively ameliorate intestinal flora disorders,enhance bile acid circulation,increase tissue energy expenditure,and reduce lipid synthesis,thereby promoting lipid-lowering effects mediated via the gut-liver axis,and can also enhance energy metabolism and alleviate disorders of glucolipid metabolism by altering physiological rhythms in high fat-diet mice.
文摘Targeting the gut-liver axis has emerged as a promising strategy in the treatment of metabolic dysfunction-associated steatotic liver disease(MASLD),a condition that currently represents the most common cause of chronic liver disease worldwide.Within this axis,the duodenum serves not only as a site of nutrient absorption but also as a metabolic sensor capable of influencing systemic and hepatic homeostasis.We have read with great interest the recent study by Yu et al,investigating the effects of duodenal mucosal ablation(DMA)by irreversible electroporation in a rat model of MASLD.The authors reported remarkable reductions in hepatic lipid content,improvements in serum lipid profiles,and both structural and functional changes in the intestinal mucosa,including alterations in enteroendocrine signaling.These results corroborate the pivotal role of the gut-liver axis in the pathogenesis of MASLD and highlight the potential of minimally invasive approaches targeting the proximal intestine.In this letter,we discuss the broader implications of these findings,emphasizing the translational relevance of intestinal modulation strategies in the comprehensive treatment of MASLD.
基金Supported by(in part)FARB-ex 60%2012 of the University of Salerno grant to Vajro P
文摘The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a “low bacterial richness” may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier (“leaky gut”), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy.
基金Scientific Research(KAKENHI)(C),No.25460958Japan Society for the Promotion of Science,No.20K11513and Adaptable and Seamless Technology Transfer Program through target driven R&D from the Japan Agency for Medical Research and Development.
文摘BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modulating gut microbiota.Partially hydrolyzed guar gum(PHGG),a water-soluble dietary fiber,has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes.However,its effects on NAFLD remain to be fully elucidated.To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODS Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic(Ath)diet(a mouse model of NAFLD)for 8 wk,with or without 5%PHGG.Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium.Body weight,liver weight,macroscopic findings in the liver,blood biochemistry[aspartate aminotransferase(AST)and alanine aminotransferase(ALT),total cholesterol,triglyceride,free fatty acids,and glucose levels],liver histology,myeloperoxidase activity in liver tissue,mRNA expression in the liver and intestine,serum endotoxin levels in the portal vein,intestinal permeability,and microbiota and short-chain fatty acid(SCFA)profiles in the cecal samples were investigated.RESULTS Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels,liver fat accumulation,liver inflammatory(tumor necrosis factor-αand monocyte chemotactic protein-1)and fibrogenic(collagen 1a1 andαsmooth muscle actin)marker levels,and liver myeloperoxidase activity,which were significantly attenuated by PHGG treatment.Furthermore,the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor(TLR)4 and TLR9 expression,confirming that intestinal permeability was significantly elevated,as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran.PHGG treatment did not affect fatty acid metabolism in the liver.However,it decreased lipopolysaccharide signaling through the gut-liver axis.In addition,it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa.Treatment with PHGG markedly increased the levels of SCFAs,particularly,butyric acid,acetic acid,propionic acid,and formic acid,in the cecal samples.CONCLUSION PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
基金This study was supported by the National Natural Science Foundation of China(31672430)the National Key Research and Development Program of China(2017YFD0500502)the Natural Science Foundation of Zhejiang Province(Z19C170001).
文摘Background:This study investigated the protective effects of L.reuteri ZJ617 on intestinal and liver injury and the underlying mechanisms in modulating inflammatory,autophagy,and apoptosis signaling pathways in a piglet challenged with lipopolysaccharide(LPS).Methods:Duroc×Landrace×Large White piglets were assigned to 3 groups(n=6/group):control(CON)and LPS groups received oral phosphate-buffered saline for 2 weeks before intraperitoneal injection(i.p.)of physiological saline or LPS(25μg/kg body weight),respectively,while the ZJ617+LPS group was orally inoculated with ZJ617 for 2 weeks before i.p.of LPS.Piglets were sacrificed 4 h after LPS injection to determine intestinal integrity,serum biochemical parameters,inflammatory signaling involved in molecular and liver injury pathways.Results:Compared with controls,LPS stimulation significantly increased intestinal phosphorylated-p38 MAPK,phosphorylated-ERK and JNK protein levels and decreased IκBαprotein expression,while serum LPS,TNF-α,and IL-6 concentrations(P<0.05)increased.ZJ617 pretreatment significantly countered the effects induced by LPS alone,with the exception of p-JNK protein levels.Compared with controls,LPS stimulation significantly increased LC3,Atg5,and Beclin-1 protein expression(P<0.05)but decreased ZO-1,claudin-3,and occludin protein expression(P<0.05)and increased serum DAO and D-xylose levels,effects that were all countered by ZJ617 pretreatment.LPS induced significantly higher hepatic LC3,Atg5,Beclin-1,SOD-2,and Bax protein expression(P<0.05)and lower hepatic total bile acid(TBA)levels(P<0.05)compared with controls.ZJ617 pretreatment significantly decreased hepatic Beclin-1,SOD2,and Bax protein expression(P<0.05)and showed a tendency to decrease hepatic TBA(P=0.0743)induced by LPS treatment.Pretreatment of ZJ617 before LPS injection induced the production of 5 significant metabolites in the intestinal contents:capric acid,isoleucine 1TMS,glycerol-1-phosphate byproduct,linoleic acid,alanine-alanine(P<0.05).Conclusions:These results demonstrated that ZJ617 pretreatment alleviated LPS-induced intestinal tight junction protein destruction,and intestinal and hepatic inflammatory and autophagy signal activation in the piglets.
文摘Viral B and C hepatitis are a major current health issue,both diseases having a chronic damaging effect on the liver and its functions.Chronic liver disease can lead to even more severe and life-threatening conditions,such as liver cirrhosis and hepatocellular carcinoma.Recent years have uncovered an important interplay between the liver and the gut microbiome:the gut-liver axis.Hepatitis B and C infections often cause alterations in the gut microbiota by lowering the levels of‘protective’gut microorganisms and,by doing so,hinder the microbiota ability to boost the immune response.Treatments aimed at restoring the gut microbiota balance may provide a valuable addition to current practice therapies and may help limit the chronic changes observed in the liver of hepatitis B and C patients.This review aims to summarize the current knowledge on the anatofunctional axis between the gut and liver and to highlight the influence that hepatitis B and C viruses have on the microbiota balance,as well as the influence of treatments aimed at restoring the gut microbiota on infected livers and disease progression.
基金supported by the National Natural Science Foundation of China (91857101)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000)the National Key Research and Development Program of China (2018YFC2000500)
文摘The gut-liver axis denotes the intricate connection and interaction between gut microbiome and liver, in which compositional and functional shifts in gut microbiome affect host metabolism. Hepatic portal vein of the blood circulation system has been thought to be the major route for metabolite transportation in the gut-liver axis, but the existence and importance of other routes remain elusive. Here, we perform metabolome comparison in blood circulation and mesenteric lymph systems and identify significantly shifted metabolites in serum and mesentery. Using cellular assays, we find that the majority of decreased metabolites in lymph system under high-fat diet are effective in alleviating metabolic disorders, indicating a high potential of lymph system in regulating liver metabolism. Among those, a representative metabolite, L-carnitine, reduces diet-induced obesity in mice. Metabolic tracing analysis identifies that L-carnitine is independently transported by the mesenteric lymph system, serving as an example that lymph circulation comprises a second route in the gut-liver axis to modulate liver metabolism. Our study provides new insights into metabolite transportation via mesenteric lymph system in the gut-liver axis, offers an extended scope for the investigations in host-gut microbiota metabolic interactions and potentially new targets in the treatment of metabolic disorders.
文摘The gut microbiota is of growing interest to clinicians and researchers.This is because there is a growing understanding that the gut microbiota performs many different functions,including involvement in metabolic and immune processes that are systemic in nature.The liver,with its important role in detoxifying and metabolizing products from the gut,is at the forefront of interactions with the gut microbiota.Many details of these interactions are not yet known to clinicians and researchers,but there is growing evidence that normal gut microbiota function is important for liver health.At the same time,factors affecting the gut microbiota,including nutrition or medications,may also have an effect through the gut-liver axis.
基金supported by fund from the National Natural Science Foundation of China (32172322)Shandong Provincial Natural Science Foundation (ZR2023QC291)Shandong Traditional Chinese Medicine Technology Project (Q-2023130)。
文摘Previous studies have shown that trans fatty acids(TFA) are associated with several chronic diseases,the gut microbiota is directly influenced by dietary components and linked to chronic diseases.Our research investigated the effects of elaidic acid(EA),a typical TFA,on the gut microbiota to understand the underlying mechanisms of TFA-related chronic diseases.16S rDNA gene sequencing on faecal samples from Sprague-Dawley rats were performed to explore the composition change of the gut microbiota by EA gavage for 4 weeks.The results showed that the intake of EA increased the abundance of well-documented harmful bacteria,such as Proteobacteria,Anaerotruncus,Oscillibacter and Desulfovibrionaceae.Plus,EA induced translocation of lipopolysaccharides(LPS) and the above pathogenic bacteria,disrupted the intestinal barrier,led to gut-liver axis derangement and TLR4 pathway activation in the liver.Overall,EA induced intestinal barrier damage and regulated TLR4-MyD88-NF-κB/MAPK pathways in the liver of SD rats,leading to the activation of NLRP3 inflammasome and inflammatory liver damage.
文摘With the rising prevalence of chronic liver diseases worldwide,there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease.Currently,the most common causes of liver disease are non-alcoholic fatty liver disease,hepatitis,and alcoholic liver disease.Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis.In this review,we analyse the relationship between the gut and liver and their significance in liver disease.This two-way relationship has interesting effects on each other in liver diseases.The gut microbiota,through its metabolites,influences the metabolism in numerous ways.Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases.Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.
基金supported by grants from the National Natural Science Foundation of China(81672422 and 81600506)Natural Science Foundation of Zhejiang Province(LY15H160033)+4 种基金Zhejiang Province Health Department Program(2014KYB081 and 2017KY322)Open Project in State Key Laboratory for Diagnosis and Treatment of Infectious Disease(2015KF03)Academician JieShou Li Intestinal Mucosal Barrier Fund(201208)Medical S&T Project of Zhejiang Province(201479797)National S&T Major Project of China(2018ZX10301201)
文摘Background: Hepatocellular carcinoma(HCC) is one of the most common malignancies in the world. Gut microbiota has been demonstrated to play a critical role in liver inflammation, chronic fibrosis, liver cirrhosis, and HCC development through the gut-liver axis. Data sources: Recently there have been several innovative studies investigating gut microbial dysbiosismediated enhancement of HCC through the gut-liver axis. Literatures from January 1998 to January 2018 were searched in the Pub Med database using the keywords "gut microbiota" and "hepatocellular carcinoma" or "liver cancer", and the results of experimental and clinical studies were analyzed. Results: Gut microbial dysbiosis accompanies the progression of alcoholic liver disease, non-alcoholic fatty liver disease and liver cirrhosis, and promotes HCC progression in an experimental mouse model. The immune system and key factors such as Toll-like receptor 4 are involved in the process. There is evidence for gut microbial dysbiosis in hepatitis virus-related HCC patients. Conclusions: Gut microbial dysbiosis is closely associated with hepatic inflammation disease and HCC through the gut-liver axis. With the enhanced understanding of the interactions between gut microbiota and liver through the gut-liver axis, new treatment strategies for HCC are being developed.
文摘Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.
文摘A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.
基金supported by grants from the National Natural Science Foundation of China(32125031)the Fundamental Research Funds for the Central Universities(JUSRP222001)Collaborative Innovation Center for Food Safety and Quality Control,China。
文摘Aflatoxin B_1(AFB_1)is a common contaminant in cereals of global concern,and long-term low-dose exposure can adversely affect human health.Here,we showed that populations with dietary patterns characterized by high-fat diet(HFD)might have an increased risk of exposure to high levels of AFB_1.Our data indicated that chronic exposure of AFB_1 induced“gut-liver axis”injury in mice under HFD and normal diet(ND)patterns.AFB_1 further aggravated hepatic and intestinal injury,and intestinal microbiota disruption in HFD mice.Bifidobacterium breve BAA-2849 intervention analysis showed that liver injury and lipid disorders caused by AFB_1 exposure were alleviated by regulating the proportions of different gut microbes.We demonstrated through a mice model that the populations with a dietary pattern of HFD might be more susceptible to AFB_1 exposure and adverse effects on the gut-liver axis,and the toxicity of AFB_1 exposure can be alleviated by regulating the gut microbiota.
基金funded by The National Natural Science Foundation of China(NSFC,No.82100618)the China Postdoctoral Science Foundation(No.2021M701820).
文摘Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induced MASLD through the gut-liver axis.Methods:The TM6SF2 gut-specific knockout(TM6SF2 GKO)mouse was constructed using CRISPR/Cas9 technology.TM6SF2 GKO and wild-type(CON)mice were fed either a HFD or a control diet for 16 weeks to induce MASLD.Blood,liver,and intestinal lipid content,as well as gut microbiota and serum metabolites,were then analyzed.Results:TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice.The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice.The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase,alanineaminotransferase,and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice,while triglyceride levels were lower.Serum metabolite analysis revealed that HFDfed TM6SF2 GKO mice had an increase in the expression of 17 metabolites(e.g.,LPC[18:0/0-0])and a decrease in 22 metabolites(e.g.,benzene sulfate).The differential metabolites of LPC(18:0/0-0)may serve as HFD-fed TM6SF2 serum biomarkers,leading to MASLD exacerbation in GKO mice.Conclusions:TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice.TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.
基金supported by the National Key R&D Program of China(2023YFC2507500)the National Natural Science Foundation of China(82470661,82070616,82270636,82100608,82300607)+1 种基金the New Quality Clinical Specialties of High-end Medical Disciplinary Construction in Pudong New Area(2025-PWXZ-04)the Talent Plan of the Shanghai Municipal Health Commission for Academic Leaders(2022XD028).
文摘Gut-derived metabolites are essential for liver fibrogenesis.The aim of this study was to determine the alteration of indole-3-propionic acid(IPA),a crucial tryptophan metabolite,in liver fibrosis and delineate the roles of enterogenic IPA in fibrogenesis.In the present study,metabolomics assays focused on tryptophan metabolism were applied to explore the decreased levels of IPA in the feces and serum of cirrhotic patients,as well as in the feces and portal vein serum of fibrotic mice.Oral IPA administration exerted strong antifibrotic effects with favorable biosafety in three fibrotic models via multicellular modulation.Multiplex immunohistochemical staining and DAOSLIMIT imaging demonstrated that gut-derived IPA was directly captured by hepatic macrophages.Macrophage-specific AhR knockout blocked the antifibrotic effect of IPA,while the therapeutic efficacy was maintained in mice with HSC-or hepatocyte-specific AhR depletion.Furthermore,IPA governed macrophage recruitment,S100A8/A9+phenotype transformation and profibrotic and proinflammatory functions,resulting in amelioration of hepatic fibrogenesis.Mechanistically,IPA targeted the AhR/NF-κB/S100A8/A9 axis and AhR/SPHK2/S1P signaling to inhibit the profibrotic biological characteristics of macrophages and subsequently interrupted the profibrogenic crosstalk between macrophages and hepatic stellate cells(HSCs)in coculture systems and 3D liver spheroid models.These findings increase the understanding of the effects of enterogenic tryptophan metabolites on liver fibrogenesis via the gut-liver axis and support the translational potential of IPA.By targeting profibrogenic macrophages,IPA could serve as a promising candidate for the clinical management of liver fibrosis.
