In the past decade, an exciting realization has been that diverse liver diseases — ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma — fall along a spectrum. Work on the biology of the gut–liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut–liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work 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’ could be especially useful for guiding new microbiome-based or microbiome-informed therapies.
The liver and intestine communicate extensively through the biliary tract, portal vein and systemic mediators.
Liver products primarily influence the gut microbiota composition and gut barrier integrity, whereas intestinal factors regulate bile acid synthesis, glucose and lipid metabolism in the liver.
Diverse liver diseases (including nonalcoholic fatty liver disease and alcoholic liver disease) are not unrelated but converge along a common path of progression; pro-inflammatory changes in the liver and intestine mediate development of fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma.
Alcoholic and nonalcoholic fatty liver diseases share key characteristics, such as intestinal dysbiosis, gut permeability and shifts in levels of bile acids, ethanol and choline metabolites.
Precise contributions of the microbiome to liver diseases could differ based on aetiology; improvements in experimental design and development of animal models are rapidly elucidating causal mechanisms.
Advances in understanding the gut–liver axis could encourage research into microbiome-based, diagnostic, prognostic and therapeutic modalities to improve management of liver diseases.
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The authors thank D. McDonald, T. Kosciółek, Z. Xu and A. Plymoth for their helpful discussions. M.K. is supported by NIH grants R01 AI043477 and R01 CA118165. R.L. is supported in part by grant R01-DK106419-03. Research reported in this publication was supported in part by the National Institute of Environmental Health Sciences of the NIH under award number P42ES010337. B.S. is supported by NIH grants R01 AA020703, U01 AA021856 and U01AA24726 and by award number I01BX002213 from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development. J.D. is supported by the Robert Wood Johnson Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The authors declare no competing interests.
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