Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2017 May 4

PMID 28467925

Citations 455

Authors

Rohit Loomba

Victor Seguritan

Weizhong Li

Tao Long

Niels Klitgord

Archana Bhatt

Parambir Singh Dulai

Cyrielle Caussy

Richele Bettencourt

Sarah K Highlander

Marcus B Jones

Claude B Sirlin

Bernd Schnabl

Lauren Brinkac

Nicholas Schork

Chi-Hua Chen

David A Brenner

William Biggs

Shibu Yooseph

J Craig Venter

Karen E Nelson

Affiliations

Soon will be listed here.

Abstract

The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota-derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, of which 72 had mild/moderate (stage 0-2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of 40 features (p < 0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD.

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References

Loomba R, Schork N, Chen C, Bettencourt R, Bhatt A, Ang B . Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology. 2015; 149(7):1784-93. PMC: 4663110. DOI: 10.1053/j.gastro.2015.08.011. View

Seki E, De Minicis S, Osterreicher C, Kluwe J, Osawa Y, Brenner D . TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007; 13(11):1324-32. DOI: 10.1038/nm1663. View

Liu H, Pathak P, Boehme S, Chiang J . Cholesterol 7α-hydroxylase protects the liver from inflammation and fibrosis by maintaining cholesterol homeostasis. J Lipid Res. 2016; 57(10):1831-1844. PMC: 5036364. DOI: 10.1194/jlr.M069807. View

Loomba R, Sanyal A . The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013; 10(11):686-90. DOI: 10.1038/nrgastro.2013.171. View

Lelouvier B, Servant F, Paisse S, Brunet A, Benyahya S, Serino M . Changes in blood microbiota profiles associated with liver fibrosis in obese patients: A pilot analysis. Hepatology. 2016; 64(6):2015-2027. DOI: 10.1002/hep.28829. View

Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal W, Strowig T . Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012; 482(7384):179-85. PMC: 3276682. DOI: 10.1038/nature10809. View

Affo S, Morales-Ibanez O, Rodrigo-Torres D, Altamirano J, Blaya D, Dapito D . CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut. 2014; 63(11):1782-92. PMC: 4092046. DOI: 10.1136/gutjnl-2013-306098. View

Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S . Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015; 528(7581):262-266. PMC: 4681099. DOI: 10.1038/nature15766. View

Bajaj J, Heuman D, Hylemon P, Sanyal A, White M, Monteith P . Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2013; 60(5):940-7. PMC: 3995845. DOI: 10.1016/j.jhep.2013.12.019. View

10.

Guo L, Milburn M, Ryals J, Lonergan S, Mitchell M, Wulff J . Plasma metabolomic profiles enhance precision medicine for volunteers of normal health. Proc Natl Acad Sci U S A. 2015; 112(35):E4901-10. PMC: 4568216. DOI: 10.1073/pnas.1508425112. View

11.

Cui J, Chen C, Lo M, Schork N, Bettencourt R, Gonzalez M . Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study. Hepatology. 2016; 64(5):1547-1558. PMC: 5090982. DOI: 10.1002/hep.28674. View

12.

De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L . Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2013; 59(5):1738-49. DOI: 10.1002/hep.26695. View

13.

Dulai P, Singh S, Patel J, Soni M, Prokop L, Younossi Z . Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017; 65(5):1557-1565. PMC: 5397356. DOI: 10.1002/hep.29085. View

14.

Betrapally N, Gillevet P, Bajaj J . Changes in the Intestinal Microbiome and Alcoholic and Nonalcoholic Liver Diseases: Causes or Effects?. Gastroenterology. 2016; 150(8):1745-1755.e3. PMC: 5026236. DOI: 10.1053/j.gastro.2016.02.073. View

15.

Chen Y, Liu Y, Zhou R, Chen X, Wang C, Tan X . Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep. 2016; 6:19076. PMC: 4705470. DOI: 10.1038/srep19076. View

16.

Dulai P, Sirlin C, Loomba R . MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol. 2016; 65(5):1006-1016. PMC: 5124376. DOI: 10.1016/j.jhep.2016.06.005. View

17.

Bhala N, Angulo P, van der Poorten D, Lee E, Hui J, Saracco G . The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011; 54(4):1208-16. PMC: 3238674. DOI: 10.1002/hep.24491. View

18.

Bai L, Kong M, Zheng Q, Zhang X, Liu X, Zu K . Inhibition of the translocation and extracellular release of high-mobility group box 1 alleviates liver damage in fibrotic mice in response to D-galactosamine/lipopolysaccharide challenge. Mol Med Rep. 2016; 13(5):3835-41. PMC: 4838152. DOI: 10.3892/mmr.2016.5003. View

19.

Gill S, Pop M, DeBoy R, Eckburg P, Turnbaugh P, Samuel B . Metagenomic analysis of the human distal gut microbiome. Science. 2006; 312(5778):1355-9. PMC: 3027896. DOI: 10.1126/science.1124234. View

20.

Zhu L, Baker S, Gill C, Liu W, Alkhouri R, Baker R . Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2012; 57(2):601-9. DOI: 10.1002/hep.26093. View