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Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders

Abstract

Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.

Key points

  • Whereas animal studies have demonstrated a potential causal role of gut microbiota in non-alcoholic fatty liver disease (NAFLD), human studies have only just started to describe microbiome signatures in NAFLD.

  • Proteobacteria are consistently enriched in steatosis and non-alcoholic steatohepatitis.

  • The invasion of oral bacteria (such as Prevotella or Veillonella) into the distal intestine is observed in cirrhosis.

  • Faecalibacterium prausnitzii abundance is reduced in cirrhosis and other diseases, including diabetes, obesity and irritable bowel syndrome.

  • Bacterial signatures (Clostridium and Lactobacillus) overlap between NAFLD and metabolic diseases (type 2 diabetes mellitus).

  • Discrepant microbiome signatures across studies could be linked to the heterogeneity of geographical regions, ethnicity, population characteristics, microbiome sequencing tools, NAFLD diagnostic tools, disease spectrum, drug consumption and circadian rhythm.

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Fig. 1: Overlapping microbiota species and genera signatures in NAFLD, diabetes and obesity.
Fig. 2: Microbiota species and genera signatures in non-alcoholic steatohepatitis-related fibrosis, cirrhosis, diabetes and obesity.
Fig. 3: Gut-derived metabolites and factors that could drive progression of NAFLD.

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Acknowledgements

The authors wish to thank funding support for research activities in metagenomics in metabolic disorders (including liver diseases); the European Union support via H2020 EPoS (H2020-PHC-2014-634413 to K.C. and C.V.), the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777377 to M.N. and K.C.). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. J.A.-W. and K.C. thank FP7 Metacardis (grant agreement HEALTH-F4-2012-305312) as well as National support from French Investment for the Future (National Agency of Research; F-CRIN FORCE, Metagenopolis and ICAN). J.A.-W. received a grant from Bettencourt Schueller Fondation. M.N. is supported by a personal ZONMW-VIDI grant 2013 [016.146.327]. A.G.H. is supported by the Amsterdam UMC Fellowship grant, a Health Holland TKI-PPP grant and by the Gilead Research scholarship grant. The authors thank T. Swartz for language editing and E. Prifti for critical reading.

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J.A.-W. contributed to the research, discussion of content, writing and editing of this manuscript. C.V., J.W., P. L., A.G.H. and J.V. contributed to the research, discussion of content, writing of this manuscript. M.N. and K.C. initiated the project and contributed to the discussion of content as well as writing and reviewing/editing the manuscript.

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Correspondence to Karine Clément.

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M.N. is in the Scientific Advisory Board of Caelus Pharmaceuticals, the Netherlands. K.C. is on the Scientific Advisory Board of LNC therapeutics and CONFO therapeutics and has contract consultancy and contract collaboration with Danone Research. None of these are directly relevant to the current paper. There are no patents, products in development or marketed products to declare. The other authors declare no competing financial interests.

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Nature Reviews Gastroenterology & Hepatology thanks A. Alisi, A. Mardinoglu, R. Reimer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Shotgun sequencing

Involves randomly breaking up DNA sequences into lots of small segments, which are further sequenced to obtain reads; computational programmes then reassemble the sequence by looking for regions of overlap.

Faecal microbiota transplantation

(FMT). Transfer of faeces from a donor to a receiver to obtain a beneficial clinical outcome by modifying the recipient’s gut microbiota.

Non-alcoholic fatty liver disease

(NAFLD). A liver disease characterized by pathological hepatic fat accumulation from simple steatosis to non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis

(NASH). A severe stage of NAFLD characterized by steatosis, hepatocyte ballooning (that is, cell injury) and inflammation, which can be associated with and/or evolve to fibrosis, cirrhosis and hepatocellular carcinoma.

Steatosis

Corresponds to intrahepatic fat of at least 5% of liver weight, which can be reversible upon lifestyle modifications.

Liver fibrosis

The excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most chronic liver aetiologies.

Cirrhosis

Corresponds to the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury.

Compensated cirrhosis

Occurs when the liver is at the stage of severe fibrosis yet can still perform its basic functions; thus, compensated cirrhosis is not associated with specific clinical symptoms.

Decompensated cirrhosis

Occurs when the liver is at the stage of severe fibrosis and liver dysfunction, leading to clinical symptoms such as internal bleeding, ascites and hepatic encephalopathy.

Gynoid distribution

Refers to the body fat that is preferentially placed around the hip.

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Aron-Wisnewsky, J., Vigliotti, C., Witjes, J. et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 17, 279–297 (2020). https://doi.org/10.1038/s41575-020-0269-9

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