scholarly journals Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis

2021 ◽  
Vol 22 (13) ◽  
pp. 6921
Author(s):  
Norihisa Nishimura ◽  
Kosuke Kaji ◽  
Koh Kitagawa ◽  
Yasuhiko Sawada ◽  
Masanori Furukawa ◽  
...  
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Intestinal Permeability ◽  
Proinflammatory Cytokines ◽  
Liver Diseases ◽  
Pathogenic Bacteria ◽  
Necrosis Factor Alpha ◽  
Cytokines And Chemokines ◽  
Liver Disease Progression ◽  
Cirrhotic Patients

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.

scholarly journals Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?

Diseases ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 58 ◽  
Author(s):  
Hiroshi Fukui
Keyword(s):  
Gut Microbiota ◽  
Fatty Liver ◽  
Liver Diseases ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Early Death ◽  
Barrier Dysfunction ◽  
Nonalcoholic Fatty Liver ◽  
Gut Dysbiosis ◽  
Cirrhotic Patients

Accumulating evidence supports that gut dysbiosis may relate to various liver diseases. Alcoholics with high intestinal permeability had a decrease in the abundance of Ruminnococcus. Intestinal dysmotility, increased gastric pH, and altered immune responses in addition to environmental and genetic factors are likely to cause alcohol-associated gut microbial changes. Alcohol-induced dysbiosis may be associated with gut barrier dysfunction, as microbiota and their products modulate barrier function by affecting epithelial pro-inflammatory responses and mucosal repair functions. High levels of plasma endotoxin are detected in alcoholics, in moderate fatty liver to advanced cirrhosis. Decreased abundance of Faecalibacterium prausnitzii, an anti-inflammatory commensal, stimulating IL-10 secretion and inhibiting IL-12 and interferon-γ expression. Proteobacteria, Enterobacteriaceae, and Escherichia were reported to be increased in NAFLD (nonalcoholic fatty liver disease) patients. Increased abundance of fecal Escherichia to elevated blood alcohol levels in these patients and gut microbiota enriched in alcohol-producing bacteria produce more alcohol (alcohol hypothesis). Some undetermined pathological sequences related to gut dysbiosis may facilitate energy-producing and proinflammatory conditions for the progression of NAFLD. A shortage of autochthonous non-pathogenic bacteria and an overgrowth of potentially pathogenic bacteria are common findings in cirrhotic patients. The ratio of the amounts of beneficial autochthonous taxa (Lachnospiraceae + Ruminococaceae + Veillonellaceae + Clostridiales Incertae Sedis XIV) to those of potentially pathogenic taxa (Enterobacteriaceae + Bacteroidaceae) was low in those with early death and organ failure. Cirrhotic patients with decreased microbial diversity before liver transplantation were more likely to develop post-transplant infections and cognitive impairment related to residual dysbiosis. Patients with PSC had marked reduction of bacterial diversity. Enterococcus and Lactobacillus were increased in PSC patients (without liver cirrhosis.) Treatment-naive PBC patients were associated with altered composition and function of gut microbiota, as well as a lower level of diversity. As serum anti-gp210 antibody has been considered as an index of disease progression, relatively lower species richness and lower abundance of Faecalibacterium spp. in gp210-positive patients are interesting. The dysbiosis-induced altered bacterial metabolites such as a hepatocarcinogenesis promotor DCA, together with a leaky gut and bacterial translocation. Gut protective Akkermansia and butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early hepatocellular carcinoma (HCC) patients.

scholarly journals The Role of the Gut Microbiome in Liver Cirrhosis Treatment

2020 ◽  
Vol 22 (1) ◽  
pp. 199
Author(s):  
Na Young Lee ◽  
Ki Tae Suk
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Chronic Liver ◽  
Chronic Liver Diseases

Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease of other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver fibrosis.

scholarly journals Extracellular Vesicles in NAFLD/ALD: From Pathobiology to Therapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 817 ◽  
Author(s):  
Alejandra Hernández ◽  
Juan Pablo Arab ◽  
Daniela Reyes ◽  
Ainhoa Lapitz ◽  
Han Moshage ◽  
...  
Keyword(s):  
Liver Disease ◽  
Extracellular Vesicles ◽  
Liver Diseases ◽  
Experimental Studies ◽  
Cell Communication ◽  
Cell Types ◽  
Bioactive Molecules ◽  
Therapeutic Implications ◽  
Isolation And Characterization ◽  
Liver Disease Progression

In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.

scholarly journals Pseudomonas aeruginosa Exoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines

2000 ◽  
Vol 68 (8) ◽  
pp. 4811-4814 ◽  
Author(s):  
Slava Epelman ◽  
Tony F. Bruno ◽  
Graham G. Neely ◽  
Donald E. Woods ◽  
Christopher H. Mody
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Proinflammatory Cytokines ◽  
Pulmonary Inflammation ◽  
Lung Damage ◽  
Gene Probe ◽  
Necrosis Factor Alpha ◽  
Exoenzyme S ◽  
Cytokines And Chemokines ◽  
Immunoregulatory Cytokines

ABSTRACT Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orchestrated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeruginosamitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1α [IL-1α], IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, MCP-1, RANTES, and I-309), modest transcription of immunoregulatory cytokines (IL-10 and IL-12p40), and weak transcription of Th1 cytokines (IL-2 and gamma interferon). The response occurred early and subsided without evolving over time. These data suggest that cells responding to exoenzyme S would rapidly express proinflammatory cytokines and chemokines that may contribute to pulmonary inflammation in cystic fibrosis.

scholarly journals Differential Gene Expression during Meningeal-Meningococcal Interaction: Evidence for Self-Defense and Early Release of Cytokines and Chemokines

2001 ◽  
Vol 69 (4) ◽  
pp. 2718-2722 ◽  
Author(s):  
Damien B. Wells ◽  
Patrick J. Tighe ◽  
Karl G. Wooldridge ◽  
Karen Robinson ◽  
Dlawer A. A. Ala' Aldeen
Keyword(s):  
Pathogenic Bacteria ◽  
Necrosis Factor Alpha ◽  
Cytokines And Chemokines ◽  
Self Defense ◽  
Meningeal Cells ◽  
Differential Gene ◽  
Factor Alpha ◽  
Apoptotic Genes ◽  
Necrosis Factor ◽  
Early Source

ABSTRACT Using microarray technology, we studied the early differential expression of 3,528 genes in human meningothelial cells in response to meningococcal challenge. Thirty-two genes were up-regulated, and four were down-regulated. Those up-regulated included the tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-8 (but not IL-1β) genes, suggesting that meningeal cells may be a local and early source of these cytokines. Also, a trend in up-regulation of anti-apoptotic genes and down-regulation of pro-apoptotic genes was observed. This is the first evidence that meningothelial cells may mount cytoprotective responses to pathogenic bacteria.

scholarly journals Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

2017 ◽  
Vol 242 (16) ◽  
pp. 1605-1616 ◽  
Author(s):  
Alejandro Soto-Gutierrez ◽  
Albert Gough ◽  
Lawrence A Vernetti ◽  
DL Taylor ◽  
Satdarshan P Monga
Keyword(s):  
Gene Expression ◽  
Liver Disease ◽  
Disease Progression ◽  
Liver Diseases ◽  
Human Liver ◽  
Liver Zonation ◽  
Metabolic Zonation ◽  
Liver Disease Progression ◽  
And Function

The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of β-catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/β-catenin signaling within a lobule and determine gene expression and function in other hepatic zones. Currently, the molecular basis of metabolic zonation in the liver appears to be a ‘push and pull’ between signaling pathways. Such compartmentalization not only provides an efficient assembly line for hepatocyte functions but also can account for restricting the initial hepatic damage and pathology from some hepatotoxic drugs to specific zones, possibly enabling effective regeneration and restitution responses from unaffected cells. Careful analysis and experimentation have also revealed that many pathological conditions in the liver lobule are spatially heterogeneous. We will review current research efforts that have focused on examination of the role and regulation of such mechanisms of hepatocyte adaptation and repair. We will discuss how the pathological organ-specific microenvironment affects cell signaling and metabolic liver zonation, especially in steatosis, viral hepatitis, and hepatocellular carcinoma. We will discuss how the use of new human microphysiological platforms will lead to a better understanding of liver disease progression, diagnosis, and therapies. In conclusion, we aim to provide insights into the role and regulation of metabolic zonation and function using traditional and innovative approaches. Impact statement Liver zonation of oxygen tension along the liver sinusoids has been identified as a critical liver microenvironment that impacts specific liver functions such as intermediary metabolism of amino acids, lipids, and carbohydrates, detoxification of xenobiotics and as sites for initiation of liver diseases. To date, most information on the role of zonation in liver disease including, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC) have been obtained from animal models. It is now possible to complement animal studies with human liver, microphysiology systems (MPS) containing induced pluripotent stem cells engineered to create disease models where it is also possible to control the in vitro liver oxygen microenvironment to define the role of zonation on the mechanism(s) of disease progression. The field now has the tools to investigate human liver disease progression, diagnosis, and therapeutic development.

The Human Gut Microbiome in Liver Diseases

2017 ◽  
Vol 37 (02) ◽  
pp. 128-140 ◽  
Author(s):  
Brian Davis ◽  
Jasmohan Bajaj
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Alcoholic Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Nonalcoholic Fatty Liver

AbstractRecent advances in culture-independent laboratory techniques and bioinformatics have contributed to enriched characterizations of the gut microbiota and microbiome in chronic liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cholangitis, and cirrhosis. In this review, the authors focus on studies characterizing and modulating the gut microbiota and microbiome in humans. The majority of studies that characterized microbiota involved a small number of patients using 16S ribosomal RNA genetic sequencing. Few studies applied whole-genome shotgun sequencing and metagenomics analyses. The majority of clinical trials on modulating the microbiome have focused on probiotics or antibiotics in small groups of patients with cirrhosis versus healthy controls. Several trials are underway using fecal microbial transplantation in alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, and cirrhosis. Future research is needed on understanding the viral and fungal microbiome and developing user-friendly microbiome tools.

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