Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure

Abstract

The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.

Key points

  • The gut microbiome is altered during development of liver cirrhosis, and these changes are associated with decompensation and development of acute-on-chronic liver failure (ACLF).

  • Progression of liver cirrhosis towards decompensation and ACLF is mainly driven by the extent of systemic inflammation and associated with high short-term mortality.

  • The gut microbiota can contribute to systemic inflammation and, thereby, to progression of cirrhosis towards decompensation and ACLF, directly via translocation or indirectly via their metabolites.

  • Gut microbiota members or pathobionts might be helpful biomarkers to predict the presence and development of decompensation and ACLF, but the signatures are not consistent and more research is needed.

  • Gut microbiome targeted therapies are promising strategies to improve the outcome of decompensated cirrhosis and ACLF, but better stratification for the existing drugs and novel, more effective strategies are needed.

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Fig. 1: Currently known and suggested microbiota–gut–liver interactions in cirrhosis.
Fig. 2: Transition of liver cirrhosis to ACLF.
Fig. 3: Strategies to target the gut microbiome in cirrhosis.

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Acknowledgements

The MICROB-PREDICT project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 825694. This Review reflects only the authors’ view, and the European Commission is not responsible for any use that may be made of the information it contains. The authors have been supported in addition by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18, CRC 1382 to A09), European Union’s Horizon 2020 research and innovation programme (Galaxy, No. 668031; MICROB-PREDICT, No. 825694; DECISION, No. 847949), Eurostars (DeFiber, E!12350), IK and Societal Challenges — Health, Demographic Change and Wellbeing (No. 731875). Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre, based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation (grant No. NNF18CC0034900).

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Trebicka, J., Bork, P., Krag, A. et al. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00376-3

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