Gut microbiota and the liver. Federico Alessandro,Dallio Marcello,Caprio Giuseppe G,Ormando Vittorio M,Loguercio Carmela Minerva gastroenterologica e dietologica Nowadays liver diseases represent one of major healthy problems in the world in terms of morbidity and mortality. The high prevalence of liver pathologies represents the key point to understand the necessity to identify the pathogenetic mechanisms that support these disorders in order to nurse them. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Gut microbiota is considered both as a promoting factor and as a potential therapeutic target of a large number of liver pathologies due to the connection between intestine and liver: the gut-liver axis. This connection influences absorption and deposition of nutrients into the liver, but also induces the activation of toll-like receptors due to the passage of pathogen-associated molecular patterns in the portal blood and therefore may start both the development of liver damage and its consequent progression to more advanced stages, including cirrhosis and hepatocarcinoma. The gut liver axis also includes the intestinal permeability (IP) degree. It is very variable and interconnected to several factors, most of them dependent from gut microbiota, that is the "lead" in the control of IP. This revue is aimed to report the more recent knowledges about gut microbiota and chronic liver disease, from liver steatosis to cirrhosis and its complications, including hepatocellular carcinoma. For these reasons, it could be useful to intervene, through suitable therapeutic approaches, on the interruption of mechanisms that underlie dysbiosis, IP increase, activation of liver inflammasome, hepatic stellate cells and hepatocarcinogenic processes in order to reduce the liver damage. 10.23736/S1121-421X.17.02375-3
    Small intestinal bacterial overgrowth and nonalcoholic fatty liver disease. Augustyn Monika,Grys Iwon,Kukla Michał Clinical and experimental hepatology The gut microbiota has recently been recognized as a major environmental factor in the pathophysiology of several human diseases. The anatomical and functional association existing between the gut and the liver provides the theoretical basis to assume that the liver is a major target for gut microbes. In the last decades, many studies have reported an altered composition of gut microbiota in patients with chronic liver diseases and liver cirrhosis, suggesting a progressively marked dysbiosis to be related to worsening of the liver disease. Modifications of microbiota result in alteration in providing signals through the intestine and bacterial products, as well as hormones produced in the bowel that affect metabolism at different levels including the liver. There is increasing evidence for a correlation between intestinal microbiota, bacterial translocation and hepatic steatosis. Intestinal microbiota affects nutrient absorption and energy homeostasis. Altered intestinal permeability may favor the passage of bacteria derived compounds into the systemic circulation, causing a systemic inflammatory state, characteristic of the metabolic syndrome. At present, an increasing number of studies indicate a close relationship between dysbiosis, defined as abnormal composition and the amount of intestinal bacteria (gut microbiota), intestinal permeability and some metabolic, inflammatory, degenerative and even psychiatric diseases. Microbiota pharmacological modulation seems to be a promising tool for a new therapeutic approach to non-alcoholic fatty liver disease and in prevention of cirrhosis. The following study aims to briefly discuss the role of microbiota disorder (dysbiosis), and in particular small intestinal bacterial overgrowth (SIBO), in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). 10.5114/ceh.2019.83151
    [Influence of nonsteroidal antiinflammatory drugs in gastrointestinal bleeding due to gastroduodenal ulcers or erosions in patients with liver cirrhosis]. Castro-Fernández M,Sánchez-Muñoz D,Galán-Jurado M V,Larraona J L,Suárez E,Lamas E,Rodríguez-Hornillo M C,Pabón M Gastroenterologia y hepatologia INTRODUCTION:Peptic ulcer disease, with or without complications, is more common in patients with liver cirrhosis than in the general population. Factors associated with portal hypertension are involved in its pathogenesis. The prevalence of Helicobacter pylori infection in patients with liver cirrhosis and the general population is similar. The aim of the present study was to determine the influence of nonsteroidal antiinflammatory drugs (NSAIDs) in the etiology of bleeding peptic ulcer disease in patients with liver cirrhosis. PATIENTS AND METHODS:We studied 35 patients with liver cirrhosis and gastrointestinal bleeding due to gastroduodenal ulcers or erosions (group A), 125 noncirrhotic patients with gastrointestinal bleeding due to gastroduodenal ulcers or erosions (group B), and 70 patients with liver cirrhosis who were admitted to hospital without gastrointestinal bleeding (group C). All patients were questioned about NSAID consumption, including aspirin, during the week prior to hospital admission. RESULTS:NSAID consumption was reported by 15 patients (42.8%) in group A, 102 patients (58.2%) in group B, and 6 patients (8.5%) in group C. Statistically significant differences were obtained when the results for group A were compared with those for group C. CONCLUSIONS:NSAID consumption in patients with liver cirrhosis without gastrointestinal bleeding was low (8.5%) and was much lower than that observed in patients with cirrhosis admitted to hospital for bleeding due to gastroduodenal ulcers or erosions (42.8%). As occurs in the general population, NSAIDs play a significant role in the pathogenesis of bleeding due to peptic ulcer disease in patients with liver cirrhosis and portal hypertension. 10.1157/13083251
    Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut. Ridlon Jason M,Kang Dae-Joong,Hylemon Phillip B,Bajaj Jasmohan S Digestive diseases (Basel, Switzerland) The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid, and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in the intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic, and disease progression in cirrhosis, metabolic syndrome, and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal, and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa, and increasing production of deoxycholic acid. Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis, and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis of inflammation in humans. 10.1159/000371678
    A story of liver and gut microbes: how does the intestinal flora affect liver disease? A review of the literature. Giuffrè Mauro,Campigotto Michele,Campisciano Giuseppina,Comar Manola,Crocè Lory Saveria American journal of physiology. Gastrointestinal and liver physiology Each individual is endowed with a unique gut microbiota (GM) footprint that mediates numerous host-related physiological functions, such as nutrient metabolism, maintenance of the structural integrity of the gut mucosal barrier, immunomodulation, and protection against microbial pathogens. Because of increased scientific interest in the GM, its central role in the pathophysiology of many intestinal and extraintestinal conditions has been recognized. Given the close relationship between the gastrointestinal tract and the liver, many pathological processes have been investigated in the light of a microbial-centered hypothesis of hepatic damage. In this review we introduce to neophytes the vast world of gut microbes, including prevalent bacterial distribution in healthy individuals, how the microbiota is commonly analyzed, and the current knowledge of the role of GM in liver disease pathophysiology. Also, we highlight the potentials and downsides of GM-based therapy. 10.1152/ajpgi.00161.2019
    Pathophysiology, prevention, treatment, and outcomes of intestinal failure-associated liver disease. Al-Shahwani Noora H,Sigalet David L Pediatric surgery international BACKGROUND:Intestinal failure-associated liver disease (IFALD) remains a serious problem in the treatment of infants with nutritional problems and short bowel syndrome. METHODS:A review of the recent literature from 2010 to 2016, concentrating on articles related to the pathophysiology of IFALD and to outcomes of novel nutritional and pharmacological therapies for neonatal cholestasis in the post-surgical neonate. RESULTS:The pathophysiology of IFALD relates to an increase sensitivity of the neonatal liver to cholestasis in the non-fed state; prolonged cholestasis almost inevitably results in liver damage which will progress from fibrosis to cirrhosis. Clinically discerned risk factors include premature birth, inflammation, sepsis, disruption of the enterohepatic circulation by creation of a proximal stoma, and the duration and type of parenteral nutritional support. Within the hepatocyte, the regulatory enzyme farsanoid receptor X (FXR) appears to play a pivotal role in the development of cholestasis. Recent studies have shown that its activity is suppressed by sepsis, and by plant phytosterols found in soy-based lipid preparations. This paradigm is reflected in the emerging consensus for the care of post-surgical neonates, which is based around a multi-disciplinary team approach. Using an algorithm-driven approach, an appropriate balance between caloric support and prevention of IFALD can be achieved. CONCLUSIONS:Further prospective studies are required to further refine the optimal sequence of use of these therapies and the long-term effects on neurological development and hepatic function. However, with optimal care, the number of IF patients progressing to end-stage liver disease because of IFALD should be very low. 10.1007/s00383-016-4042-7
    A correlation between gastrointestinal dysfunction and cirrhosis severity. Wang Ping,Zhang Ying-Jian,Li Yi-Ran,Liu Xiao-Min,Lv Shu-Yan,Xia Xiao-Yan Medicine This study aims to investigate the relationship between gastrointestinal dysfunction (GD) and cirrhosis severity in cirrhotic patients, to provide evidences for the prevention and treatment of GD in cirrhotic patients.A total of 95 cirrhotic inpatients and outpatients, who were treated in the Department of Gastroenterology of Xinqu Hospital of the First Affiliated Hospital of Henan University of Science and Technology, were enrolled in the present study, and assigned as the experimental group (cirrhosis group). According to Child-Pugh classification, these patients were divided into 3 groups: group A (n = 45), group B (n = 23), and group C (n = 27). Forty healthy adults who received health check-ups during the same period served as the control group. The gastrointestinal (GI) symptoms of cirrhotic patients were scored, and the fasting serum gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) levels were measured in all subjects.The potential correlations of GI symptom scores of patients in these cirrhosis groups with GI hormone levels and cirrhosis severity were analyzed. In cirrhotic patients, the GI symptom scores significantly increased. Furthermore, the symptom scores gradually increased along with the aggravation of liver damage. Moreover, serum GAS and VIP levels were significantly higher in the cirrhosis groups than in the control group, whereas MTL levels were significantly lower. These changes were significantly correlated with cirrhosis severity. The linear correlation analysis revealed that the GI symptom score was positively correlated with GAS and VIP levels, and negatively correlated with MTL level. In addition, the linear correlation analysis revealed that GI symptom score and GAS and VIP levels were positively correlated with cirrhosis severity, whereas MTL level was negatively correlated with cirrhosis severity.Cirrhotic patients have more obvious GI symptoms and higher GI hormone levels, which are closely correlated with the progression of liver cirrhosis and the degree of liver function damage. 10.1097/MD.0000000000012070
    Gut microbiome and liver diseases. Tilg Herbert,Cani Patrice D,Mayer Emeran A Gut The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies. 10.1136/gutjnl-2016-312729
    Interactions between the intestinal microbiome and liver diseases. Schnabl Bernd,Brenner David A Gastroenterology The human intestine harbors a diverse community of microbes that promote metabolism and digestion in their symbiotic relationship with the host. Disturbance of its homeostasis can result in disease. We review factors that disrupt intestinal homeostasis and contribute to nonalcoholic fatty liver disease, steatohepatitis, alcoholic liver disease, and cirrhosis. Liver disease has long been associated with qualitative and quantitative (overgrowth) dysbiotic changes in the intestinal microbiota. Extrinsic factors, such as the Western diet and alcohol, contribute to these changes. Dysbiosis results in intestinal inflammation, a breakdown of the intestinal barrier, and translocation of microbial products in animal models. However, the contribution of the intestinal microbiome to liver disease goes beyond simple translocation of bacterial products that promote hepatic injury and inflammation. Microbial metabolites produced in a dysbiotic intestinal environment and host factors are equally important in the pathogenesis of liver disease. We review how the combination of liver insult and disruptions in intestinal homeostasis contribute to liver disease. 10.1053/j.gastro.2014.01.020
    Antimicrobial proteins: intestinal guards to protect against liver disease. Hendrikx Tim,Schnabl Bernd Journal of gastroenterology Alterations of gut microbes play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative and quantitative changes in gut microbiota have been associated with liver disease. Intestinal dysbiosis can disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In order to sustain symbiosis and protect from pathological bacterial translocation, antimicrobial proteins (AMPs) such as a-defensins and C-type lectins are expressed in the gastrointestinal tract. In this review, we provide an overview of the role of AMPs in different chronic liver disease such as alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cirrhosis. In addition, potential approaches to modulate the function of AMPs and prevent bacterial translocation are discussed. 10.1007/s00535-018-1521-8
    Disorganized Gut Microbiome Contributed to Liver Cirrhosis Progression: A Meta-Omics-Based Study. Shao Li,Ling Zongxin,Chen Deying,Liu Yufeng,Yang Fengling,Li Lanjuan Frontiers in microbiology Early detection and effective interventions for liver cirrhosis (LC) remain an urgent unmet clinical need. Inspired from intestinal disorders in LC patients, we investigated the associations between gut microbiome and disease progression based on a raw metagenomic dataset of 47 healthy controls, 49 compensated, and 46 decompensated LC patients from our previous study, and a metabolomic dataset of urine samples from the same controls/patients using ultra-performance liquid chromatography/mass spectrophotometry system. It was found that the combination and relative abundance of gut microbiome, the inter-microbiome regulatory networks, and the microbiome-host correlation patterns varied during disease progression. The significant reduction of bacteria involved in fermentation of plant cell wall polysaccharides and resistant starch (such as sp. , ) contributed to the reduced supply of energy sources, the disorganized self-feeding and cross-feeding networks and the thriving of some opportunistic pathogens in genus . The marked decrease of butyrate-producing bacteria and increase of implicated in degradation of elements from the mucus layer provided an explanation for the impaired intestinal barrier function and systematic inflammation in LC patients. Our results pave the way for further developments in early detection and intervention of LC targeting on gut microbiome. 10.3389/fmicb.2018.03166
    Microbial Profiles of Cirrhosis in the Human Small Intestine. Dong Tien S,Jacobs Jonathan P,Hussain Shehnaz K Current gastroenterology reports PURPOSE OF REVIEW:The aim of this review is to summarize the recent literature on associations of small intestinal microbial and bile acid profiles with liver cirrhosis and its complications. RECENT FINDINGS:Recent studies into the duodenal microbiome of patients with cirrhosis have linked the microbiome to certain etiologies of chronic liver disease as well as complications of cirrhosis. In particular, microbial differences in the duodenum of patients with cirrhosis have been linked to the presence of hepatic encephalopathy and varices. While the fecal microbiome of patients with liver cirrhosis is well characterized, the small intestinal microbiome of cirrhotic patients is an active area of research. This review focuses on the current understanding of the small intestinal microbiome in human cirrhosis as well as future directions of the field. 10.1007/s11894-019-0717-2
    Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Pande C,Kumar A,Sarin S K Alimentary pharmacology & therapeutics BACKGROUND:Small-intestinal bacterial overgrowth (SIBO) is known to be present in patients with cirrhosis, predisposing to various complications. AIM:To determine the frequency of SIBO in cirrhotics and correlate with severity of cirrhosis. METHODS:Small-intestinal bacterial overgrowth was determined by glucose-hydrogen breath test (GHBT). A basal breath-hydrogen >20 ppm or a rise by > or = 12 ppm above baseline following glucose administration was taken as positive test. Prevalence of SIBO in cirrhotics was compared with healthy controls and correlated with severity of cirrhosis. RESULTS:Of the 53 cirrhotics, 26 (49%) had SIBO, compared to one (8%) control (P = 0.010). The prevalence of SIBO increased with severity of cirrhosis (Child-Pugh A 20%, B 52% and C 73%; P = 0.013). On multivariate analysis, SIBO was independently associated with serum bilirubin and ascites. The best cut-off of serum bilirubin was >/=2 mg/dL [AUROC 0.77 (95% CI 0.64-0.90)] predicting SIBO with sensitivity 65%, specificity 81%, positive predictive value 77%, negative predictive value 71% and accuracy 74%. Patients having combination of ascites and serum bilirubin > or = 2 mg/dL had 82% chance, while patients having neither had only 10% chance of having SIBO. CONCLUSIONS:Small-intestinal bacterial overgrowth was prevalent in about half of cirrhotics. Its frequency increased with increase in severity of cirrhosis. Ascites and raised serum bilirubin reliably predicted presence of SIBO. 10.1111/j.1365-2036.2009.03994.x
    Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. Bajaj Jasmohan S,Khoruts Alexander Journal of hepatology Patients with chronic liver disease and cirrhosis demonstrate a global mucosal immune impairment, which is associated with altered gut microbiota composition and functionality. These changes progress along with the advancing degree of cirrhosis and can be linked with hepatic encephalopathy, infections and even prognostication independent of clinical biomarkers. Along with compositional changes, functional alterations to the microbiota, related to short-chain fatty acids, bioenergetics and bile acid metabolism, are also associated with cirrhosis progression and outcomes. Altering the functional and structural profile of the microbiota is partly achieved by medications used in patients with cirrhosis such as rifaximin, lactulose, proton pump inhibitors and other antibiotics. However, the role of faecal or intestinal microbiota transplantation is increasingly being recognised. Herein, we review the challenges, opportunities and road ahead for the appropriate and safe use of intestinal microbiota transplantation in liver disease. 10.1016/j.jhep.2020.01.017
    Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Gunnarsdottir Steingerdur Anna,Sadik Riadh,Shev Steven,Simrén Magnus,Sjövall Henrik,Stotzer Per Ove,Abrahamsson Hasse,Olsson Rolf,Björnsson Einar S The American journal of gastroenterology OBJECTIVE:Altered small bowel motility and a high prevalence of small intestinal bacterial overgrowth (SIBO) has been observed in patients with liver cirrhosis. Our aim was to explore the relationship between motility abnormalities, portal hypertension, and SIBO. METHODS:Twenty-four patients with liver cirrhosis were included. Twelve had portal hypertension (PH) and 12 had liver cirrhosis (LC) alone. Child-Pugh score was the same in the groups. Antroduodenojejunal pressure recordings were performed, and noninvasive variceal pressure measurements were undertaken. Thirty-two healthy volunteers served as a reference group. Bacterial cultures were obtained from jejunal aspirates. RESULTS:The PH group had a higher proportion of individual pressure waves that were retrograde in the proximal duodenum during phase II (52% vs 13% vs 8% of propagated contractions; p < 0.001) as well as postprandially (49% vs 18% vs 13%; p < 0.01) compared with LC and controls, respectively. Long clusters were more common in PH than in controls (9.1 +/- 2.1 vs 4.9 +/- 0.8; p < 0.05), and a higher motility index in phase III in the proximal and distal duodenum was seen in the PH as compared with the other groups. The mean variceal pressure was 21 +/- 1 mm Hg. Motor abnormalities were not correlated to the level of variceal pressure. Thirty-three percent of the patients in the PH group but none in the LC group had SIBO. CONCLUSIONS:Abnormal small bowel motility and SIBO is common in patients with liver cirrhosis with concomitant portal hypertension. Portal hypertension per se might be significantly related to small bowel abnormalities observed in patients with liver cirrhosis. 10.1111/j.1572-0241.2003.07475.x
    Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Chen Yanfei,Ji Feng,Guo Jing,Shi Ding,Fang Daiqiong,Li Lanjuan Scientific reports Cirrhosis-associated duodenal dysbiosis is not yet clearly defined. In this research, duodenal mucosal microbiota was analyzed in 30 cirrhotic patients and 28 healthy controls using 16S rRNA gene pyrosequencing methods. The principal coordinate analysis revealed that cirrhotic patients were colonized by remarkable different duodenal mucosal microbiota in comparison with controls. At the genus level, Veillonella, Megasphaera, Dialister, Atopobium, and Prevotella were found overrepresented in cirrhotic duodenum. And the duodenal microbiota of healthy controls was enriched with Neisseria, Haemophilus, and SR1 genera incertae sedis. On the other hand, based on predicted metagenomes analyzed, gene pathways related to nutrient absorption (e.g. sugar and amino acid metabolism) were highly abundant in cirrhosis duodenal microbiota, and functional modules involved in bacterial proliferation and colonization (e.g. bacterial motility proteins and secretion system) were overrepresented in controls. When considering the etiology of cirrhosis, two operational taxonomic units (OTUs), OTU-23 (Neisseria) and OTU-36 (Gemella), were found discriminative between hepatitis-B-virus related cirrhosis and primary biliary cirrhosis. The results suggest that the structure of duodenal mucosa microbiota in cirrhotic patients is dramatically different from healthy controls. The duodenum dysbiosis might be related to alterations of oral microbiota and changes in duodenal micro-environment. 10.1038/srep34055
    [Hepatic encephalopathy and colon pathology in liver cirrhosis]. Safonova M V,Kozlova I V,Ovsiannikova V V,Kvetnoĭ I M Eksperimental'naia i klinicheskaia gastroenterologiia = Experimental & clinical gastroenterology RESEARCH OBJECTIVE:to define a role of structural and functional changes of a colon, expression indicators of epithelial cells of mucous coat of colon that produce serotonin and hromogranin-A at in encephalopathy development at liver cirrhoses. We have examined 146 patients with liver cirrhosis of various classes using the clinical, endoscopic, morphologic and immunohistochemical methods. It is established that with increase of a class of a cirrhosis frequency of revealing of a hepatic encephalopathy, structural changes, degree dysbacteriosis of a colon. Progressing of a hepatic encephalopathy at liver cirrhoses associates with development destructive and atrophic changes of a mucous membrane of a colon and a dysbacteriosis. The increase in the morphometric rates of epithelial cells of mucous coat of colon that produce serotonin and hromogranin-A at liver cirrhoses plays a part in development of a manifesting of a hepatic encephalopathy.
    [Chronic liver disease increases with damage to intestinal barrier function]. Liang F F,Wang J,Li L,Yuan Y,Xie W R,Wu L H,He X X Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology To probe into the correlation between chronic liver disease and intestinal barrier function. 1 491 cases of hospitalized patients were enrolled, of which 741 cases were of chronic liver diseases, including 397 cases of fatty liver diseases, 230 cases of chronic hepatitis, 114 cases of liver cirrhosis, and 750 cases of non-hepatic diseases. All admitted patients' intestinal barrier function like diamine oxidase (DAO), D-lactate, lipopolysaccharide, and biochemical indicators of liver functions were tested. According to different data, statistical analysis was done using -test, ANOVA, Dunnett's test, (2) test of fourfold table, Pearson's correlation, and binary logistic regression. The intestinal barrier dysfunction was more likely to occur in the chronic liver disease group than that of non-hepatic disease group [54.15% (379/741) vs. 18.53% (139/750), (2) = 193.58, < 0.001]. The correlation analysis between biochemical indicators of liver function and intestinal barrier function in chronic liver disease group showed that alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and total bilirubin levels were more susceptible to intestinal barrier dysfunction than those with normal indexes ( < 0.05 ). GGT had stimulated DAO ( < 0.05, > 1), D-lactate ( < 0.05, > 1), lipopolysaccharide ( < 0.05, > 1), ALT and AST. Chronic liver disease increases with damage to intestinal barrier function. 10.3760/cma.j.issn.1007-3418.2018.08.010
    Role of the intestinal microbiome in liver fibrosis development and new treatment strategies. Zhou Rongrong,Fan Xuegong,Schnabl Bernd Translational research : the journal of laboratory and clinical medicine Liver cirrhosis is a major cause of morbidity and mortality worldwide. The most common chronic liver diseases in western countries are alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Although these diseases have different causes, liver fibrosis develops via shared mechanisms. The liver and intestinal microbiome are linked by the portal vein and have bidirectional interactions. Changes in the intestinal microbiome contribute to the pathogenesis and progression of liver diseases including ALD, NAFLD, viral hepatitis and cholestatic disorders, based on studies in patients and animal models. Intestinal microbial dysbiosis has been associated with liver cirrhosis and its complications. We review the mechanisms by which alterations in the microbiome contribute to liver fibrosis and discuss microbiome-based treatment approaches. 10.1016/j.trsl.2019.02.005
    Alterations of the human gut microbiome in liver cirrhosis. Qin Nan,Yang Fengling,Li Ang,Prifti Edi,Chen Yanfei,Shao Li,Guo Jing,Le Chatelier Emmanuelle,Yao Jian,Wu Lingjiao,Zhou Jiawei,Ni Shujun,Liu Lin,Pons Nicolas,Batto Jean Michel,Kennedy Sean P,Leonard Pierre,Yuan Chunhui,Ding Wenchao,Chen Yuanting,Hu Xinjun,Zheng Beiwen,Qian Guirong,Xu Wei,Ehrlich S Dusko,Zheng Shusen,Li Lanjuan Nature Liver cirrhosis occurs as a consequence of many chronic liver diseases that are prevalent worldwide. Here we characterize the gut microbiome in liver cirrhosis by comparing 98 patients and 83 healthy control individuals. We build a reference gene set for the cohort containing 2.69 million genes, 36.1% of which are novel. Quantitative metagenomics reveals 75,245 genes that differ in abundance between the patients and healthy individuals (false discovery rate < 0.0001) and can be grouped into 66 clusters representing cognate bacterial species; 28 are enriched in patients and 38 in control individuals. Most (54%) of the patient-enriched, taxonomically assigned species are of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis. Biomarkers specific to liver cirrhosis at gene and function levels are revealed by a comparison with those for type 2 diabetes and inflammatory bowel disease. On the basis of only 15 biomarkers, a highly accurate patient discrimination index is created and validated on an independent cohort. Thus microbiota-targeted biomarkers may be a powerful tool for diagnosis of different diseases. 10.1038/nature13568
    Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis. Grąt M,Wronka K M,Krasnodębski M,Masior Ł,Lewandowski Z,Kosińska I,Grąt K,Stypułkowski J,Rejowski S,Wasilewicz M,Gałęcka M,Szachta P,Krawczyk M Transplantation proceedings BACKGROUND:Changes within the gut microbiota contribute to the progression of chronic liver diseases. According to the results of several studies performed in animal models, gut dysbiosis plays an important role in hepatocarcinogenesis. The aim of this study was to explore the characteristics of gut microbiota associated with the presence of hepatocellular cancer (HCC) in patients with cirrhosis of the liver undergoing liver transplantation. METHODS:A total of 15 patients with HCC and 15 non-HCC patients matched according to etiology of cirrhosis and Model for End-Stage Liver Disease (MELD) scores who underwent liver transplantations between 2012 and 2014 were included. Analysis of their gut microbial profile was based on prospectively collected stool samples from the pretransplant period. RESULTS:Patients with and without HCC were similar with respect to age (P = .506), sex (P = .700), hepatitis C virus (P > .999) and hepatitis B virus (P = .715) infection status, alcoholic liver disease (P > .999), and MELD score (P = .337). Notably, the presence of HCC was associated with significantly increased fecal counts of Escherichia coli (P = .025). Prediction of HCC presence based on E coli counts was associated with the area under the receiver-operating curve of 0.742 (95% confidence interval, 0.564-0.920), with the optimal cutoff on the level of 17.728 (natural logarithm of colony-forming units per 1 g of feces). Sensitivity and specificity rates for the established cutoff were 66.7% and 73.3%, respectively. CONCLUSIONS:The profile of gut microbiota associated with the presence of HCC in cirrhotic patients is characterized by increased fecal counts of E coli. Therefore, intestinal overgrowth of E coli may contribute to the process of hepatocarcinogenesis. 10.1016/j.transproceed.2016.01.077
    The role of the gut microbiome in the development and progression of liver cirrhosis and hepatocellular carcinoma. Roderburg Christoph,Luedde Tom Gut microbes Liver cirrhosis and hepatocellular carcinoma (HCC) represent the endstage of most chronic liver diseases and are a major global health burden. It has been consistently shown that both liver cirrhosis and HCC are triggered by inflammatory processes, but the molecular mechanisms linking chronic hepatitis with cirrhosis and HCC are only poorly understood. Recent studies suggested that the intestinal microflora as a main source of portal-vein LPS might play a critical role in this process. Here we summarize the available literature on the role of the gut microbiome in hepatofibrogenesis and -carcinogenesis. Such knowledge might help to develop novel, innovative strategies for the prevention and therapy of liver disease. 10.4161/gmic.29599
    Characteristics of intestinal bacteria with fatty liver diseases and cirrhosis. Guohong-Liu ,Qingxi-Zhao ,Hongyun-Wei Annals of hepatology Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are significant health burdens worldwide with a substantial rise in prevalence. Both can progress to liver cirrhosis. Recent studies have shown that the gut microbiome was associated with NAFLD/AFLD development and progression. The present review focuses on the characteristics of bacteria in NAFLD, AFLD and liver cirrhosis. The similarities and differences of intestinal bacteria are discussed. This study reviews the existing literatures on the microbiota, fatty liver disease, and liver cirrhosis based on Pubmed database. The study showed NAFLD was characterized by increased amounts of Lachnospiraceae from the phylum Firmicutes and Roseburia from the Lachnospiraceae family, and the proportion of Enterobacteria and Proteobacteria was increased after alcohol intake. Reduced Bacteroidetes was observed in cirrhosis. Microbiota can improve or aggravate the above liver diseases through several mechanisms, like increasing liver lipid metabolism, increasing alcohol production, increasing intestinal permeability, bacterial translocation, intestinal bacterial overgrowth, enteric dysbiosis, and impairing bile secretion. Different hepatic diseases owned different intestinal bacterial characters. Microbiota can improve or aggravate three kinds of liver diseases through several mechanisms. However, the depletion of these bacteria is needed to verify their role in liver disease. 10.1016/j.aohep.2019.06.020
    Gastrointestinal dysfunction in liver cirrhosis. Kalaitzakis Evangelos World journal of gastroenterology Patients with liver cirrhosis exhibit several features of gut dysfunction which may contribute to the development of cirrhosis complications as well as have an impact on nutritional status and health-related quality of life. Gastrointestinal symptoms are common in cirrhosis and their pathophysiology probably involves factors related to liver disease severity, psychological distress, and gut dysfunction (e.g., increased gastric sensitivity to distension and delayed gut transit). They may lead to reduced food intake and, thus, may contribute to the nutritional status deterioration in cirrhotic patients. Although tense ascites appears to have a negative impact on meal-induced accommodation of the stomach, published data on gastric accommodation in cirrhotics without significant ascites are not unanimous. Gastric emptying and small bowel transit have generally been shown to be prolonged. This may be related to disturbances in postprandial glucose, insulin, and ghrelin levels, which, in turn, appear to be associated to insulin resistance, a common finding in cirrhosis. Furthermore, small bowel manometry disturbances and delayed gut transit may be associated with the development of small bowel bacterial overgrowth. Finally, several studies have reported intestinal barrier dysfunction in patients with cirrhosis (especially those with portal hypertension), which is related to bacterial translocation and permeation of intestinal bacterial products, e.g., endotoxin and bacterial DNA, thus potentially being involved in the pathogenesis of complications of liver cirrhosis. 10.3748/wjg.v20.i40.14686
    Gut microbiota and host metabolism in liver cirrhosis. Usami Makoto,Miyoshi Makoto,Yamashita Hayato World journal of gastroenterology The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulating the activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probiotics-treated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics, synbiotics, and prebiotics, with sufficient nutrition could aid the development of treatments and prevention for liver cirrhosis patients. 10.3748/wjg.v21.i41.11597
    [Intestinal dysbiosis in liver cirrhosis]. Zhdanov K V,Gusev D A,Zakharenko S M,Kurtukov M V,Sukachev V S Eksperimental'naia i klinicheskaia gastroenterologiia = Experimental & clinical gastroenterology Intestinal dysbiosis is revealed in 28.5% of patients with liver cirrhosis, mainly in classes B and C by Child-Pugh by the results of hydrogen breath test. It is established that revealed intestinal dysbiosis in patients with liver cirrhosis of viral etiology aggravates the course of the disease.
    Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis. Wilde Benjamin,Katsounas Antonios Mediators of inflammation Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports-and is supported by-uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as "leaky gut." Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation. 10.1155/2019/7537649
    Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis. Xia Xiaoxue,Chen Jiang,Xia Jiayun,Wang Bin,Liu Hua,Yang Ling,Wang Ying,Ling Zongxin The Journal of international medical research Objective This study was performed to investigate the role of probiotics ( Clostridium butyricum combined with Bifidobacterium infantis) in the treatment of minimal hepatic encephalopathy (MHE) in patients with hepatitis B virus (HBV)-induced liver cirrhosis. Methods Sixty-seven consecutive patients with HBV-induced cirrhosis without overt hepatic encephalopathy were screened using the number connection test and digit symbol test. The patients were randomized to receive probiotics (n = 30) or no probiotics (n = 37) for 3 months. At the end of the trial, changes in cognition, intestinal microbiota, venous ammonia, and intestinal mucosal barriers were analyzed using recommended systems biology techniques. Results The patients' cognition was significantly improved after probiotic treatment. The predominant bacteria ( Clostridium cluster I and Bifidobacterium) were significantly enriched in the probiotics-treated group, while Enterococcus and Enterobacteriaceae were significantly decreased. Probiotic treatment was also associated with an obvious reduction in venous ammonia. Additionally, the parameters of the intestinal mucosal barrier were obviously improved after probiotic treatment, which might have contributed to the improved cognition and the decreased ammonia levels. Conclusion Treatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis. 10.1177/0300060518776064
    Prevalence, Evolution, and Risk Factors for Advanced Liver Fibrosis in Adults Undergoing Intestinal Transplantation. Huard Geneviève,Fiel M Isabel,Moon Jang,Iyer Kishore,Schiano Thomas D JPEN. Journal of parenteral and enteral nutrition INTRODUCTION:Intestinal failure-associated liver disease (IFALD) occurs commonly in intestinal transplant (ITx) candidates receiving parenteral nutrition (PN). The aim of this study is to establish the prevalence and risk factors for advanced liver fibrosis in adults at the time of ITx. METHODS:Retrospective chart review of all ITx was performed in adults between January 2000 and May 2014. Advanced liver fibrosis was defined as stage 3 or stage 4 fibrosis. RESULTS:Fifty-three patients met the inclusion criteria. The mean age was 50.6 ± 10.9 years, and the majority were female (60.4%) and Caucasian (67.9%). The mean body mass index was 21.7 ± 3.8 kg/m and the median duration of PN was 402 (interquartile range: 529) days. Advanced liver fibrosis at the time of ITx was found in 13 patients (24.5%). The multivariate analysis revealed that female gender and white race were significant predictors of advanced liver fibrosis. A total bilirubin >3.0 mg/dL for > a month prior to ITx was associated with an odds ratio of 8.9 for advanced fibrosis at the time of ITx but did not reach statistical significance (P = 0.055). CONCLUSION:Close to one-quarter of the ITx recipients had advanced liver fibrosis. In the current era of improved PN management, our data suggests that previously reported risk factors for IFALD, such as extreme short gut syndrome and PN duration, may have a lesser impact on development of liver fibrosis. A prolonged duration of bilirubin elevation may be associated with advanced liver fibrosis in patients with IFALD, but this requires validation in a larger cohort. 10.1002/jpen.1148
    Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Pijls Kirsten E,Jonkers Daisy M A E,Elamin Elhaseen E,Masclee Ad A M,Koek Ger H Liver international : official journal of the International Association for the Study of the Liver Recent evidence suggests that translocation of bacteria and bacterial products, such as endotoxin from the intestinal lumen into the systemic circulation is a contributing factor in the pathogenesis of chronic liver diseases and the development of complications in cirrhosis. In addition to alterations in the intestinal microbiota and immune system, dysfunction of the intestinal epithelial barrier may be an important factor facilitating bacterial translocation. This review aims to provide an overview of the current evidence of intestinal epithelial barrier dysfunction in human chronic liver diseases and cirrhosis, and to discuss possible contributing factors and mechanisms. Data suggest the presence of intestinal epithelial barrier dysfunction in patients with chronic liver diseases, but are more convincing in patients with cirrhosis, especially in those with complications. The barrier dysfunction can result from both direct and indirect effects of aetiological factors, such as alcohol and obesity, which can cause chronic liver diseases and ultimately cirrhosis. On the other hand characteristics of cirrhosis itself, including portal hypertension, alterations in the intestinal microbiota, inflammation and oxidative stress can affect barrier function of both small and large intestine and may contribute to the development of complications. In conclusion, there are indications for intestinal epithelial barrier dysfunction in patients with chronic liver diseases and especially in patients with cirrhosis, which can be caused by various factors affecting both the small and large intestine. 10.1111/liv.12271
    [A NEW APPROACH TO TREATMENT LIVER CIRRHOSIS IN CONNECTION WITH INTESTINAL DYSBIOSIS]. Gavrysh I M,Glushko L V Likars'ka sprava In order to increase the effectiveness of treatment of the liver cirrhosis were examined 65 patients, we studied the effect on the features flow of intestine microbiocenosis and were are included to the combined treatment the synbiotic medications "Bifilakt extra". Inclusion to the combined treatment of the examined patients with liver cirrhosis synbiotic medications "Bifilakt extra" probably led to better reduction of subjective and objective signs of cirrhosis and intensity of functional biochemical syndromes, symptoms of hepatic encephalopathy.