Clinical research progress on drugs for non-alcoholic steatohepatitis treatment / 药学学报

Nonalcoholic steatohepatitis (NASH) is the leading chronic liver disease worldwide. NASH is commonly associated with metabolic risk factors, including obesity, hypertension, and diabetes. Hepatic glucose and lipid metabolism disorder, bile acid toxicity, oxidative stress, inflammation, fibrosis, intestinal dysbacteriosis, and susceptibility gene variation are involved in the pathogenesis of NASH. Drug development for NASH has been slow, this article focuses on the clinical research and development of several promising NASH drugs and their mechanisms, such as drugs targeting gut-liver axis, improving metabolism, inhibiting inflammation and fibrosis.

Research progress on the relationship between gut-liver axis disorder and sepsis / 中华危重病急救医学

Sepsis is a life-threatening organ dysfunction caused by an uncontrolled host response to infection. The mechanism of sepsis is extremely complicated and the mortality is still high. Persistent researches provide an important way to break through the "bottleneck" of clinical diagnosis and treatment of sepsis. In recent years, more and more studies have shown that gut-liver axis disorders, especially those caused by intestinal dysbiosis, intestinal barrier dysfunction, abnormal liver immune function, and bile acid metabolism disorders, play an important role in the occurrence and development of sepsis. This review describes the research progress of gut-liver axis disorders in the pathogenesis of sepsis for providing new ideas for clinical treatment.

Research progress of traditional Chinese medicine formulas and active compounds in the treatment of non-alcoholic fatty liver disease by regulating gut microbiota / 药学学报

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. However, due to its complex pathogenesis, there are no officially approved drugs for NAFLD treatment currently. Therefore, it is extremely urgent to find safe and effective anti-NAFLD drugs. Nowadays, lipid-lowering drugs are the main option for NAFLD therapy, but the clinical efficacy of chemical drugs is also very limited, as well as the frequent side effects or adverse reactions. Traditional Chinese medicine (TCM) has attracted more and more attention in the treatment of NAFLD due to its unique advantages through multiple targets and pathways with few side effects. In recent years, numerous studies have demonstrated that the imbalance of gut microbiota plays an important role in the occurrence and development of NAFLD. This review systematically summarizes the experimental and clinical evidences of TCM active compounds and TCM prescription involved in the regulation of intestinal flora in the treatment of NAFLD in recent years, so as to provide a reference for further exploring the pathogenesis of NAFLD and exploring TCM treatment methods.

Progress on the composition of intestinal mucosal barrier and its relationship with liver injury / 国际儿科学杂志

The complete mucosal barrier of the healthy intestine is the line of defense to prevent the translocation of substances.Many animal models and human pathological studies have proved that the changes of intestinal mucosal barrier function are closely related to the occurrence and treatment of liver disease.This review summarizes the composition of intestinal mucosal barrier, its interaction with liver injury and potential therapeutic targets.

The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut-liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.

Mechanism of gut-microbiota-liver axis in the pathogenesis of intestinal failure-associated liver disease / 中华胃肠外科杂志

Intestinal failure (IF) is defined as the critical reduction of functional intestines below the minimum needed to absorb nutrients and fluids, so that intravenous supplementation with parenteral nutrition (PN) is required to maintain health and/or growth. Although the benefits are evident, patients receiving PN can suffer from serious cholestasis due to lack of enteral feeding and small intestinal bacterial overgrowth (SIBO). One such complication that may arise is intestinal failure-associated liver disease (IFALD). Evidences from recent studies suggest that alterations in the intestinal microbiota, as well as intraluminal bile acid driven signaling, may play a critical role in both hepatic and intestinal injury. Since Marshall first proposed the concept of the gut-liver axis in 1998, the role of gut-liver axis disorders in the development of IFALD has received considerable attention. The conversation between gut and liver is the key to maintain liver metabolism and intestinal homeostasis, which influences each other and is reciprocal causation. However, as a "forgotten organ" , intestinal microbiota on the pathogenesis of IFALD has not been well reflected. As such, we propose, for the first time, the concept of gut-microbiota-liver axis to emphasize the importance of intestinal microbiota in the interaction of gut-liver axis. Analysis and research on gut-microbiota-liver axis will be of great significance for understanding the pathogenesis of IFALD and improving the prevention and treatment measures.

Progress in understanding hepatic fibrosis and renal fibrosis based on the gut-liver-kidney axis / 药学学报

Fibrosis is a pathological process of abnormal hyperplasia and excessive deposition of extracellular matrix during the process of repair after tissue and organ damage. Injury/inflammation caused by variously chronic diseases is a major trigger for fibrogenesis. Fibrosis of the liver and kidney is a common organ fibrosis. Recently, the intestinal microbiota has been shown to be extensively involved in the development of liver and kidney diseases, which may follow from changes in the intestinal microbial composition and intestinal integrity. This promotes the development of liver and/or kidney fibrosis through endocrine, cell signaling and other pathways. This paper reviews the research progress in understanding liver fibrosis and kidney fibrosis based on the gut-liver-kidney axis, which may be helpful for providing new strategies and theoretical basis for the diagnosis and treatment of hepatic and renal fibrosis.

The effects and mechanisms of chronic stress on intestinal and liver injuries in rats / 中华行为医学与脑科学杂志

Objective:To investigate the effects and its mechanism of chronic unpredictable stress on intestine and liver injuries in rats, and explore the possibility of the existence of brain-gut-liver axis.Methods:Twenty male SD rats were randomly divided into control group and stress group (with 10 in each group). The rats in the stress group were stimulated by chronic unpredictable stress for 4 weeks to prepare the chronic stress model. The rats in the control group were fed normally without stress stimulation. After modeling, ten rats in the control group and seven rats in the stress group were included. The depressive behavior of the two groups was evaluated by sugar water preference experiment. Then the rats were sacrificed. The diversity of gut flora in intestinal feces was analyzed by 16S rRNA sequencing analysis. The pathological injuries of ileum and liver were detected by HE staining. The expressions of occludin in ileum and Toll-like receptor 4 (TLR4) in liver were detected by immunohistochemistry. The expression of TLR4 protein in liver tissue was detected by Western blot. The level of lipopolysaccharide (LPS) in rat portal vein serum was detected by AZO chromogenic limulus test and blood biochemical method was used to detect liver function.Statistical analysis was performed using SPSS 25.0 software, and t-test or Mann-Whitney U test was used for comparison between the two groups. Using STAMP software, Wilcoxon rank sum test was used to analyze the difference in bacterial abundance between the two groups. Results:The consumption of sugar water ((7.86±0.90)ml) and the preference rate of sugar water ((43.06±5.65)%) in the stress group were lower than those in the control group ((15.10±1.51)ml, (76.81±6.44)%), and the difference were statistically significant ( t=11.33, 11.16, both P<0.01). Chronic stress caused pathological damage to rat ileum tissue. Compared with the control group, the ileum villi of rats in the chronic stress group were longer ((448.93±12.71)μm, (497.12±16.72)μm, t=-5.88, P<0.01) and thicker ((81.99±16.54)μm, (133.93±6.78)μm, t=-7.12, P<0.01), and the expression of occludin was significantly down-regulated ((0.236±0.011), (0.130±0.026), t=9.12 , P<0.01), the LPS level increased significantly ((18.83±2.62)EU/L, (38.64±2.51)EU/L, t=-5.79, P<0.01). The Beta diversity of rat intestinal flora changed under chronic stress, and the abundance of WPS-2 phylum in intestinal tract of rats in stress group was higher than that in control group ( t=2.76, P<0.05). Chronic stress caused pathological damage to the liver tissue of rats. Compared with the control group, the expression of TLR4 protein in the liver tissue of the chronic stress group increased ((0.169±0.014), (0.475±0.034), Z=-2.37, P<0.05). Compared with the control group, the ALT ((39.7±6.2)U/L, (82.9±43.1)U/L, Z=-2.35, P<0.05) and AST((130.9±28.9)U/L, (472.7±263.3)U/L, Z=-2.64, P<0.05) levels of the chronic stress group increased, especially in AST. Conclusion:Chronic stress cause synchronous damage to the intestine and liver in rats. The mechanism may be related to the results caused by chronic stress such as the changes of the diversity of intestinal flora, the increasing of intestinal permeability, the action of LPS translocated through portal vein blood on TLR4 in liver.

Explore Effect of Jieyu Qutan Huazhuo Prescription on Gut-liver Axis of Rats with High-fat Diet Based on 16S rDNA Sequencing / 中国实验方剂学杂志

Objective:To study the effect of Jieyu Qutan Huazhuo prescription（JQHP） on the gut microbiota of rats with high-fat diet，and to explore the effect of Chinese medicine on the regulation of gut microflora and the restoration of gut-liver axis balance. Method:Seventy male SPF Wistar rats were randomly divided into a normal group of 10 and a model group of 60. Mice in the normal group were fed with normal diet and mice in the model group were fed high-fat diet. After 12 weeks，the model group was randomly divided into 6 groups with 10 animals in each group，namely the model group，Xuezhikang group，Liputuo group，and low，medium and high-dose groups of JQHP. The JQHP low-dose，medium-dose and high-dose rats were intragastrically daministered with 0.4，0.8，1.6 g·kg^-1，respectively， rats in Liputuo group with Liputuo 2 mg·kg^-1，rats in Xuezhikang group with Xuezhikang 0.1 g·kg^-1. The rats in the normal group and the model group were intragastrically administered with the same amount of distilled water. Stool were collected after continuous gavaging for 8 weeks，16S rRNA gene sequencing was performed，blood was collected from the abdominal aorta to detect blood lipids，and the liver tissue and ileum tissue were collected for hematoxylin and eosin （HE） staining for pathomorphological observation. Result:Compared with the normal group，the total cholesterol （TC），triglyceride （TG），and low-density lipoprotein （LDL-C） in the model group were significantly increased，while the high-density lipoprotein （HDL-C） was decreased （<italic>P</italic><0.01）. Compared with the model group，TC and TG values were decreased significantly in Xuezhikang group （<italic>P</italic><0.01），HDL-C value was increased （<italic>P</italic><0.05），and in the Liputuo group TC and TG were decreased significantly （<italic>P</italic><0.01）. Compared with the model group，the middle-dose group of JQHP had a certain alleviating effect on liver steatosis and could reduce the infiltration of inflammatory cells. The JQHP could improve the proliferation of lymphoid tissues in the ileal structure，and the middle-dose group has the most significant effect. The results of Shannon curve showed that compared with the normal group，the middle-dose group of JQHP increased significantly （<italic>P</italic><0.01）. Compared with the model group，the middle and high-dose group of JQHP increased （<italic>P</italic><0.05，<italic>P</italic><0.01）. Compared with the middle-dose group of JQHP，the other drug group decreased （<italic>P</italic><0.05，<italic>P</italic><0.01）. Principal component diversity analysis（PCA） showed that the diversity and abundance in the middle-dose JQHP group were higher than those in other drug groups. In linear discriminant analysis（LDA），compared with the normal group，Bacteroidia，Ruminococcaceae，<italic>Bacteroides </italic>S24-7，and <italic>Rumenococcus </italic>UCG-005 were down-regulated in the model group（<italic>P</italic><0.01），while the orders of Desulfovibrionales，Erysipelotrichales and<italic> </italic>Lachnospiraceae were up-regulated in the model group （<italic>P</italic><0.05，<italic>P</italic><0.01）. Compared with the model group，the Bacteroidia，Ruminococcaceae，<italic>Bacteroides</italic> S24-7，and <italic>Rumencoccus</italic> UCG-005 in the middle-dose JQHP group were increased （<italic>P</italic><0.05，<italic>P</italic><0.01），and the orders of Erysipelotrichales were decreased （<italic>P</italic><0.01）. Compared with the middle-dose JQHP group，Bacteroidia，Ruminococcaceae，<italic>Bacteroides</italic> S24-7，and <italic>Rumencoccus</italic> UCG-005 in other drug groups were reduced（<italic>P</italic><0.05，<italic>P</italic><0.01），and the order of Erysipelotrichales and Lachnospiraceae were increased （<italic>P</italic><0.05，<italic>P</italic><0.01）. Conclusion:JQHP can regulate the abundance and diversity of the gut microbiota，improve the state of liver tissue and ileum mucosa，regulate blood lipid levels，and restore the normal intestinal ecological environment. It may be related to the regulation of inflammation-related gut microbiota in order to restore the balance of the gut-liver axis，and the middle-dose JQHP group has the best effect.

The role of gut microbiota in the pathogenesis of portal hypertension / 临床肝胆病杂志

Gut microbiota is the largest collection of commensal micro-organisms in the human body. Since the liver has unique anatomical location and vascular system, it is easily exposed to gut microbiota and their metabolites. Under normal conditions, the barrier function of the intestinal epithelium and the cleaning and detoxification function of the liver can prevent microorganisms or their products from entering the liver and systemic circulation. However, when the intestinal barrier function is damaged, a large number of bacterial products may enter the liver and systemic circulation and stimulate the body’s immune and inflammatory responses, and such perturbations become prominent in liver cirrhosis and may increase the risk of clinically significant portal hypertension. This article summarizes the role of gut microbiota in the pathogenesis of portal hypertension and provides ideas for clinical treatment.

Gut microbiota-an important contributor to liver diseases / 南方医科大学学报

Gut microbiota constitute a complicated but manifold ecosystem, in which specific symbiotic relationships are formed among various bacteria. To maintain a steady state, the gastrointestinal tract and the liver form a close anatomical and functional two-way, interconnected network through the portal circulation. "Gut-liver axis" plays a key role in the pathogenesis of liver diseases. Accumulating evidence indicates that gut microbiota can influence the liver pathophysiology directly or indirectly via a variety of signal pathways. In a pathological state where an ecological imbalance occurs at the compositional and functional levels, gut microbes would interact with the host immune system and other type of cells to cause liver steatosis, inflammation and fibrosis, which in turn give rise to the development of such liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, and acute liver failure, to name a few. Studies have shown that microorganisms, such as prebiotics and probiotics, can improve the prognosis of certain diseases, which open a new era of treating liver diseases with bacteria. There are many unknowns and hidden values in the gut microbiome. To explore the pathophysiological mechanism of various complex diseases and develop scientific and effective clinical treatment strategies, efforts should be made to obtain insights into how certain intestinal microbiota participates in the occurrence and progression of liver diseases. As the connection between gut microbiota and liver diseases at both the acute and chronic phases was not elaborated in previously published review articles, herein we discuss the association between gut microbiota and both acute and chronic liver injury. The anatomical structure of the liver enables it to form a close network with the gut microbiota, which is an important mediator in the regulation of the hepatic physiological and pathological functions.

Association between nonalcoholic fatty liver disease and gut microbiota based on the theory of gut-liver axis / 临床肝胆病杂志

Nonalcoholic fatty liver disease (NAFLD) has become the most important chronic liver disease and is recognized as the hepatic manifestation of metabolic syndrome, which may progress to liver fibrosis, liver cirrhosis, and even hepatocellular carcinoma in the advanced stage. Gut microbiota, as important symbiotic organisms in the human body, affects metabolic function and may be closely associated with NAFLD, and the theory of gut-liver axis provides a theoretical basis for understanding that intestinal dysbacteriosis may cause liver pathological changes. This article explores the association between NAFLD and gut microbiota, so as to lay a theoretical foundation for the future research on the therapy for NAFLD targeting gut microbiota.

Influence of Intestinal Mucosal Barrier Dysfunction on Non-alcoholic Fatty Liver Disease / 胃肠病学

Nowadays, non-alcoholic fatty liver disease (NAFLD) is prevalent all over the world, and its incidence has been increasing year by year in China. The four aspects of intestinal mucosal barrier, including mechanical barrier, chemical barrier, biological barrier and immunological barrier are interrelated closely and related to NAFLD. This article reviewed the influence of intestinal mucosal barrier dysfunction on NAFLD.

New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.

Prospects of germ-free animals in the study of gut?liver axis / 中国实验动物学报

Intestine and liver have very closely relationship due to the gut-liver axis, intestinal disease can affect the liver function, and the liver disease may also induce intestinal disorders. The germ?free animals have no living bacteria, fungi, viruses and parasites. The appearance of germ?free animals provides a powerful experimental tool for studying the in?teraction between the host and the intestinal microorganisms. At the same time, due to the characteristics of lacking normal intestinal flora, germ?free animals play a great role in promoting the study of gut?liver axis. In this paper, we will briefly re?view the application prospects of germ?free animals in the research of gut?liver axis.

Advances in Study on Intestinal Apical Sodium-dependent Bile Acid Transporter and Related Diseases / 胃肠病学

Bile acids play critical roles in the solubilization and absorption of lipids. The ileal apical sodium-dependent bile acid transporter( ASBT)located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently,great success has been made in understanding the relationship between ASBT and intestinal inflammation,tumorigenesis,secretion,motility,sensation,gut microbiota,and gut-liver axis in addition to its expression regulation,which implicates ASBT as a contributor of some gastrointestinal diseases and a promising new therapeutic target for these diseases. In this review article,the advances in study on above-mentioned issues were summarized.

The role of gut microbiota in the pathogenesis of portal hypertension / 临床肝胆病杂志

Gut microbiota is the largest collection of commensal micro-organisms in the human body. Since the liver has unique anatomical location and vascular system, it is easily exposed to gut microbiota and their metabolites. Under normal conditions, the barrier function of the intestinal epithelium and the cleaning and detoxification function of the liver can prevent microorganisms or their products from entering the liver and systemic circulation. However, when the intestinal barrier function is damaged, a large number of bacterial products may enter the liver and systemic circulation and stimulate the body’s immune and inflammatory responses, and such perturbations become prominent in liver cirrhosis and may increase the risk of clinically significant portal hypertension. This article summarizes the role of gut microbiota in the pathogenesis of portal hypertension and provides ideas for clinical treatment.