FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis

Sorribas, Marcel; Jakob, Manuel O.; Yılmaz, Bahtiyar; Li, Hai; Stutz, David; Noser, Yannik; Gottardi, Andrea De; Moghadamrad, Sheida; Hassan, Moshin; Albillos, Agustı́n; Francés, Rubén; Juanola, Oriol; Spadoni, Ilaria; Rescigno, María; Wiest, Reiner

doi:10.1016/j.jhep.2019.06.017

Cited by 179 publications

(140 citation statements)

References 61 publications

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“…Although gut barrier disruption has not been reported to be a pre requisite for nonalcoholic steatohepatitis (NASH) development and belongs to the 'multiple hit' pathogenesis of disease progression [60], more recent observations in preclinical models have shown that disruption of epithelial and vascular barriers in the intestine were early events reported in NASH [61]. Gut-liver axis deterioration has also been described in patients with chronic liver diseases who develop sepsis and multiorgan failure [62,63]. Zhou et al in their recent retrospective cohort study of 191 patients reported that more than half of hospitalized patients developed sepsis as a common complication of SARS-CoV-2 infection [18].…”

Section: Discussionmentioning

confidence: 99%

COVID-19, MERS and SARS with Concomitant Liver Injury—Systematic Review of the Existing Literature

Kukla

Skonieczna-Żydecka

Kotfis

et al. 2020

JCM

103

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The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection has been predominantly linked to respiratory distress syndrome, but gastrointestinal symptoms and hepatic injury have also been reported. The mechanism of liver injury is poorly understood and may result as a consequence of viral hepatitis, systemic inflammatory response, gut barrier and microbiome alterations, intensive care treatment or drug toxicity. The incidence of hepatopathy among patients with coronavirus disease 2019 (COVID-19) is unclear, but studies have reported liver injury in patients with SARS and Middle East respiratory syndrome (MERS). We aimed to systematically review data on the prevalence of hepatic impairments and their clinical course in SARS and MERS Coronaviridae infections. A systematic literature search (PubMed/Embase/Cinahl/Web of Science) according to preferred reporting items for systematic review and meta-analysis protocols (PRISMA) was conducted from database inception until 17/03/2020 for studies that evaluated the incidence of hepatic abnormalities in SARS CoV-1, SARS CoV-2 and MERS infected patients with reported liver-related parameters. A total of forty-three studies were included. Liver anomalies were predominantly mild to moderately elevated transaminases, hypoalbuminemia and prolongation of prothrombin time. Histopathology varied between non-specific inflammation, mild steatosis, congestion and massive necrosis. More studies to elucidate the mechanism and importance of liver injury on the clinical course and prognosis in patients with novel SARS-CoV-2 infection are warranted.

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Section: Discussionmentioning

confidence: 99%

COVID-19, MERS and SARS with Concomitant Liver Injury—Systematic Review of the Existing Literature

Kukla

Skonieczna-Żydecka

Kotfis

et al. 2020

JCM

103

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“…103,118,119 Recent evidence indicates that in cirrhosis the lymphatic route of translocation coexists with the portalvenous passage to the liver of bacteria and bacterial products due to disruption of the GVB. 120 Vascular hyperpermeability is independent of the lymphatic route as well as of portal hypertension, since it is only present in models incorporating liver insufficiency. Interestingly, obeticholic acid was able to restore reduced ileum FXR signalling, improve the mucus machinery and stabilise the GVB in rats with cirrhosis, which supports the notion that the nuclear receptor FXR partly modulates mucus-and GVB in cirrhosis.…”

Section: Gut Microbiomementioning

confidence: 99%

“…Interestingly, obeticholic acid was able to restore reduced ileum FXR signalling, improve the mucus machinery and stabilise the GVB in rats with cirrhosis, which supports the notion that the nuclear receptor FXR partly modulates mucus-and GVB in cirrhosis. 120 Additionally, obeticholic acid and other FXR-agonists reconstitute microbiota composition, improve intestinal innate defence mechanisms, reduce intestinal inflammation and decrease bacterial translocation and endotoxemia in experimental cirrhosis. 108,[120][121][122] In fact, reduced ileal FXR signalling has been described in experimental cirrhosis as a likely consequence of a reduction in primary bile acids and an increase in secondary bile acids in the lumen, as well as of intestinal inflammation.…”

Section: Gut Microbiomementioning

confidence: 99%

“…120 Additionally, obeticholic acid and other FXR-agonists reconstitute microbiota composition, improve intestinal innate defence mechanisms, reduce intestinal inflammation and decrease bacterial translocation and endotoxemia in experimental cirrhosis. 108,[120][121][122] In fact, reduced ileal FXR signalling has been described in experimental cirrhosis as a likely consequence of a reduction in primary bile acids and an increase in secondary bile acids in the lumen, as well as of intestinal inflammation. 108,120,123 The aforementioned abnormalities in intestinal barrier function in cirrhosis have been linked to structural changes in the intestine, including submucosal oedema, minimal infiltration by immune system cells, and disorganisation of interepithelial tight junction proteins in humans and experimental models of cirrhosis.…”

Section: Gut Microbiomementioning

confidence: 99%

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The gut-liver axis in liver disease: Pathophysiological basis for therapy

Albillos

Gottardi

Rescigno

2020

Journal of Hepatology

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1,253

881

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The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.

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“…Indeed, on the one hand, BAs shape the intestinal microbiome through direct antimicrobial effects and FXR‐induced production of antimicrobial peptides; and on the other hand, gut microbiota modify the BA pool composition through defined enzymatic activities (such as deconjugation, dihydroxylation, oxidation, and epimerization, among others) . Additionally, FXR modulates the gut–vascular barrier by regulating the entry sites for bacterial translocation . In the setting of NAFLD and ALD, both altered BA metabolism and changes in microbiota composition have been found, which potentially promotes disease development .…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

Arab

Arrese

Shah

2020

Hepatology Research

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The term, gut-liver axis, is used to highlight the close anatomical and functional relationship between the intestine and the liver. It has been increasingly recognized that the gut-liver axis plays an essential role in the development and progression of liver disease. In particular, in non-alcoholic fatty liver disease and alcohol-related liver disease, the two most common causes of chronic liver disease, a dysbiotic gut microbiota can influence intestinal permeability, allowing some pathogens or bacteriaderived factors from the gut reaching the liver through the enterohepatic circulation contributing to liver injury, steatohepatitis, and fibrosis progression. Pathways involved are multiple, including changes in bile acid metabolism, intestinal ethanol production, generation of short-chain fatty acids, and other by-products. Bile acids act through dedicated bile acid receptors, farnesoid X receptor and TGR5, in both the ileum and the liver, influencing lipid metabolism, inflammation, and fibrogenesis. Currently, both non-alcoholic fatty liver disease and alcohol-related liver disease lack effective therapies, and therapeutic targeting of gut microbiota and bile acids enterohepatic circulation holds promise. In this review, we summarize current knowledge about the role of gut microbiota in the pathogenesis of non-alcoholic fatty liver disease and alcohol-related liver disease, as well as the relevance of microbiota or bile acid-based approaches in the management of those liver diseases.

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FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis

Cited by 179 publications

References 61 publications

COVID-19, MERS and SARS with Concomitant Liver Injury—Systematic Review of the Existing Literature

COVID-19, MERS and SARS with Concomitant Liver Injury—Systematic Review of the Existing Literature

The gut-liver axis in liver disease: Pathophysiological basis for therapy

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

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