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

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

doi:10.1016/j.cmet.2017.04.001

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

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 VenterKaren E. Nelson

^*Corresponding author for this work

Medicine, Gastroenterology Division

Research output: Contribution to journal › Article › peer-review

769 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1054-1062.e5
Journal	Cell Metabolism
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2017.04.001
State	Published - May 2 2017

Funding

The authors are grateful to Alan Hofmann, MD for his insightful comments and suggestions. The study was conducted at the Clinical and Translational Research Institute, University of California at San Diego. R.L. is supported in part by the American Gastroenterological Association (AGA) Foundation – Sucampo – ASP Designated Research Award in Geriatric Gastroenterology and by a T. Franklin Williams Scholarship Award. P.S.D. is supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) training grant 5T32DK007202. Funding provided by Atlantic Philanthropies, the John A. Hartford Foundation, OM, the Association of Specialty Professors, and the American Gastroenterological Association, grant K23-DK090303. The microbiome sequencing was performed and funded by Human Longevity. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the NIH under award number P42ES010337. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding agencies did not have any role in the design and conduct of the study, collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript. The genomic sequencing data underlying this manuscript were generated solely with private funding.

Keywords

NASH
biomarker
cirrhosis
fatty liver
fibrosis
hepatic steatosis
hepatitis
liver disease
microbiome
non-invasive

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2017.04.001

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Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., Dulai, P. S., Caussy, C., Bettencourt, R., Highlander, S. K., Jones, M. B., Sirlin, C. B., Schnabl, B., Brinkac, L., Schork, N., Chen, C. H., Brenner, D. A., Biggs, W., Yooseph, S., ... Nelson, K. E. (2017). Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metabolism, 25(5), 1054-1062.e5. https://doi.org/10.1016/j.cmet.2017.04.001

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

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.",

keywords = "NASH, biomarker, cirrhosis, fatty liver, fibrosis, hepatic steatosis, hepatitis, liver disease, microbiome, non-invasive",

author = "Rohit Loomba and Victor Seguritan and Weizhong Li and Tao Long and Niels Klitgord and Archana Bhatt and Dulai, {Parambir Singh} and Cyrielle Caussy and Richele Bettencourt and Highlander, {Sarah K.} and Jones, {Marcus B.} and Sirlin, {Claude B.} and Bernd Schnabl and Lauren Brinkac and Nicholas Schork and Chen, {Chi Hua} and Brenner, {David A.} and William Biggs and Shibu Yooseph and Venter, {J. Craig} and Nelson, {Karen E.}",

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Loomba, R, Seguritan, V, Li, W, Long, T, Klitgord, N, Bhatt, A, Dulai, PS, Caussy, C, Bettencourt, R, Highlander, SK, Jones, MB, Sirlin, CB, Schnabl, B, Brinkac, L, Schork, N, Chen, CH, Brenner, DA, Biggs, W, Yooseph, S, Venter, JC & Nelson, KE 2017, 'Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease', Cell Metabolism, vol. 25, no. 5, pp. 1054-1062.e5. https://doi.org/10.1016/j.cmet.2017.04.001

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T1 - Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

AU - Loomba, Rohit

AU - Seguritan, Victor

AU - Li, Weizhong

AU - Long, Tao

AU - Klitgord, Niels

AU - Bhatt, Archana

AU - Dulai, Parambir Singh

AU - Caussy, Cyrielle

AU - Bettencourt, Richele

AU - Highlander, Sarah K.

AU - Jones, Marcus B.

AU - Sirlin, Claude B.

AU - Schnabl, Bernd

AU - Brinkac, Lauren

AU - Schork, Nicholas

AU - Chen, Chi Hua

AU - Brenner, David A.

AU - Biggs, William

AU - Yooseph, Shibu

AU - Venter, J. Craig

AU - Nelson, Karen E.

PY - 2017/5/2

Y1 - 2017/5/2

N2 - 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.

AB - 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.

KW - NASH

KW - biomarker

KW - cirrhosis

KW - fatty liver

KW - fibrosis

KW - hepatic steatosis

KW - hepatitis

KW - liver disease

KW - microbiome

KW - non-invasive

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M3 - Article

C2 - 28467925

AN - SCOPUS:85018954191

SN - 1550-4131

VL - 25

SP - 1054-1062.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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