Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease

被引：134

作者：

Lang, Sonja ^{[1
,2
,3
]}

Demir, Muenevver ^{[4
]}

Martin, Anna ^{[2
,3
]}

Jiang, Lu ^{[1
,5
]}

Zhang, Xinlian ^{[6
]}

Duan, Yi ^{[1
,5
]}

Gao, Bei ^{[1
]}

Wisplinghoff, Hilmar ^{[7
,8
,9
]}

Kasper, Philipp ^{[2
,3
]}

Roderburg, Christoph ^{[4
]}

Tacke, Frank ^{[4
]}

Steffen, Hans-Michael ^{[2
,3
]}

Goeser, Tobias ^{[2
,3
]}

Abraldes, Juan G. ^{[10
]}

Tu, Xin M. ^{[6
]}

Loomba, Rohit ^{[1
]}

Starkel, Peter ^{[11
]}

Pride, David ^{[1
,12
,13
]}

Fouts, Derrick E. ^{[14
]}

Schnabl, Bernd ^{[1
,5
,13
]}

机构：

[1] Univ Calif San Diego, Dept Med, MC0063,9500 Gilman Dr, La Jolla, CA 92093 USA

[2] Univ Cologne, Fac Med, Cologne, Germany

[3] Univ Cologne, Univ Hosp Cologne, Dept Gastroenterol & Hepatol, Cologne, Germany

[4] Charite, Dept Hepatol & Gastroenterol, Campus Virchow Clin, Berlin, Germany

[5] Vet Affairs San Diego Healthcare Syst, Dept Med, San Diego, CA USA

[6] Univ Calif San Diego, Dept Family Med & Publ Hlth, Div Biostat & Bioinformat, La Jolla, CA 92093 USA

[7] Wisplinghoff Labs, Cologne, Germany

[8] Univ Witten Herdecke, Inst Virol & Med Microbiol, Witten, Germany

[9] Univ Cologne, Univ Hosp Cologne, Fac Med, Inst Med Microbiol Immunol & Hyg, Cologne, Germany

[10] Univ Alberta, Liver Unit, Div Gastroenterol, Dept Med, Edmonton, AB, Canada

[11] Catholic Univ Louvain, St Luc Univ Hosp, Brussels, Belgium

[12] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

[13] Univ Calif San Diego, Ctr Innovat Phage Applicat & Therapeut, La Jolla, CA 92093 USA

[14] J Craig Venter Inst, Rockville, MD USA

来源：

GASTROENTEROLOGY | 2020年 / 159卷 / 05期

基金：

美国国家卫生研究院;

关键词：

Microbiota; Biomarker; Prognostic Factor; Progression; HUMAN GUT; MICROBIOTA; FIBROSIS; PREDICTION; MORTALITY; BACTERIA; NAFLD;

D O I：

10.1053/j.gastro.2020.07.005

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. METHODS: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary chol-angitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. RESULTS: Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5- 8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. CONCLUSIONS: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data.

引用

页码：1839 / 1852

页数：14

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[1] Nonalcoholic Fatty Liver Disease Activity Score and Mortality: Imperfect But Not Insignificant [J].