The Role of Intestinal C‐type Regenerating Islet Derived‐3 Lectins for Nonalcoholic Steatohepatitis

Bluemel, Sena; Martino, Cameron; Lee, Suhan; Wang, Yanhan; Williams, Brandon; Horvath, Angela; Stadlbauer, Vanessa; Zengler, Karsten; Schnabl, Bernd

doi:10.1002/hep4.1165

Cited by 38 publications

(27 citation statements)

References 49 publications

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“…Unlike in the case of ALD, loss of intestinal Reg3 lectins is insufficient to aggravate diet-induced obesity and NASH. 81 Bacterial products and metabolites Changes in the functional capacity of the gut microbiome are probably more relevant than changes in its composition. Bacterial components (PAMPs) and metabolites derived from the actions of the gut microbiome on exogenous (from diet and environmental exposure) and endogenous (bile acids and amino acids) substrates can reach the liver through the portal vein and promote inflammation.…”

Section: Gut Microbiomementioning

confidence: 99%

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

Albillos

Gottardi

Rescigno

2020

Journal of Hepatology

1,155

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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Section: Gut Microbiomementioning

confidence: 99%

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

Albillos

Gottardi

Rescigno

2020

Journal of Hepatology

1,155

881

View full text Add to dashboard Cite

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“…Patients with NAFL or NASH are believed to have gut barrier dysfunction, with increased translocation of microbial products to the liver. Although there have been many reports of increased intestinal permeability in mice with fatty liver following an HFD or steatohepatitis following a Western-like diet,11 37 these results were not confirmed in all studies 38. Intestinal permeability has been most frequently evaluated by measuring translocated microbial products in the systemic circulation of rodents.…”

Section: Gut Barrier Dysfunction In Patients With Nafldmentioning

confidence: 99%

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Chu

Duan

Yang

et al. 2018

Gut

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257

217

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The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.

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“…Although REG3G is important for protection from alcohol-related liver disease, it is dispensable for the development of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. 37 Deficiency of Mucin-2 (Muc2), the most abundantly secreted mucin in the small and large intestine, leads to a compensatory increase in antimicrobial lectins, such as REG3B and REG3G, and is protective against ethanol-induced liver damage. 51 An additional layer of protection is the innate and adaptive immune system in the subepithelial space.…”

Section: Mechanistic Contribution Of the Gut Microbiota To Alcohol-rementioning

confidence: 99%

Microbiome as a therapeutic target in alcohol-related liver disease

Sarin

Pande

Schnabl

2019

Journal of Hepatology

Self Cite

188

154

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Alcohol-related liver disease is associated with significant changes in gut microbial composition. The transmissibility of ethanol-induced liver disease has been demonstrated using faecal microbiota transfer in preclinical models. This technique has also led to improved survival in patients with severe alcoholic hepatitis, suggesting that changes in the composition and function of the gut microbiota are causatively linked to alcohol-related liver disease. A major mechanism by which gut microbiota influence the development of alcohol-related liver disease is through a leaky intestinal barrier. This permits translocation of viable bacteria and microbial products to the liver, where they induce and promote inflammation, as well as contribute to hepatocyte death and the fibrotic response. In addition, gut dysbiosis is associated with changes in the metabolic function of the intestinal microbiota, bile acid composition and circulation, immune dysregulation during onset and progression of alcohol-related liver disease. Findings from preclinical and human studies will be used to demonstrate how alcohol causes intestinal pathology and contributes to alcohol-related liver disease and how the latter is self-perpetuating. Additionally, we summarise the effects of untargeted treatment approaches on the gut microbiota, such as diet, probiotics, antibiotics and faecal microbial transplantation in alcohol-related liver disease. We further discuss how targeted approaches can restore intestinal homeostasis and improve alcohol-related liver disease. These approaches are likely to add to the therapeutic options for alcohol-related liver disease independently or in conjunction with steroids. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.Gut microbiota contributes to the development of alcohol-related liver disease via different mechanisms. The altered gut bacteria in alcoholic hepatitis lead to suppression of the immune system, increase in hepatic inflammation and changes in microbial metabolites.

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The Role of Intestinal C‐type Regenerating Islet Derived‐3 Lectins for Nonalcoholic Steatohepatitis

Cited by 38 publications

References 49 publications

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

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

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

Microbiome as a therapeutic target in alcohol-related liver disease

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