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      The gut–liver axis and the intersection with the microbiome

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          Abstract

          <p class="first" id="P2">In the past decade, an exciting realization has been that diverse liver diseases, ranging from non-alcoholic steatohepatitis, alcoholic steatohepatitis, and cirrhosis, to hepatocellular carcinoma, are not unrelated but fall along a spectrum. Recent work on the biology of the gut-liver communication axis has assisted in understanding the basic biology of both alcoholic and nonalcoholic fatty liver disease. Of immense importance is the massive advancement in understanding of the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that allow the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review the gut-liver communications of these various forms of liver disease, explore the molecular, genetic and microbiome relationships, discuss prospects for exploiting the microbiome to determine the stage of liver disease, and to predict the effects of pharmaceutical, dietary, and other interventions at a population and individual level. We conclude that although much remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These “avatar mice” may be especially useful for guiding new microbiome-based or microbiome-informed therapies. </p>

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          Most cited references160

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.

            Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
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              Mouse model of chronic and binge ethanol feeding (the NIAAA model).

              Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
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                Author and article information

                Journal
                Nature Reviews Gastroenterology & Hepatology
                Nat Rev Gastroenterol Hepatol
                Springer Nature
                1759-5045
                1759-5053
                May 10 2018
                Article
                10.1038/s41575-018-0011-z
                6319369
                29748586
                5fa7c294-0063-466c-951b-861ddc59146c
                © 2018

                http://www.springer.com/tdm

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