Gut Microbiome-Based Metagenomic Signature for Non-Invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease (NAFLD)

Approximately 60-80 million Americans are estimated to have nonalcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of liver disease ranging from benign steatosis, referred to as nonalcoholic fatty liver (NAFL), the non-progressive subtype of NAFLD, to nonalcoholic steatohepatitis (NASH), the progressive subtype of NAFLD, which can progress to cirrhosis, hepatocellular carcinoma and liver-related death.

NASH is now the most prevalent liver disease in the Western World and expected to be the leading indication for liver transplant by 2030. Prior to this study, NAFL and NASH could only be differentiated by a liver biopsy.

NASH is typically associated with steatosis in Zone-3, lobular inflammation, ballooning degeneration with or without peri-sinusoidal fibrosis on liver histology. Due to rising rates of obesity and diabetes, the prevalence of NAFLD and NASH related cirrhosis is expected to rise in the coming decades.

The gut microbiome has been linked to obesity, insulin resistance, diabetes and metabolic syndrome, which are all risk factors for the progressive form of NAFLD, as well as fibrosis progression in patients with NAFLD.

Given that NAFLD affects approximately 80 million adults and children in the USA, it is a major public health problem. Understanding the genomics components of this disease will have tremendous impact on diagnosis and treatment.

This study provides preliminary evidence for a fecal-microbiome-derived metagenomic signature to detect advanced fibrosis in NAFLD. 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.


Cell metabolism. 2017-05-02; 25.5: 1054-1062.e5.
Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease
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
PMID: 28467925
Hepatology (Baltimore, Md.). 2016-11-01; 64.5: 1547-1558.
Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study
Cui J, Chen CH, Lo MT, Schork N, Bettencourt R, Gonzalez MP, Bhatt A, Hooker J, Shaffer K, Nelson KE, Long MT, Brenner DA, Sirlin CB, Loomba R, For The Genetics Of Nafld In Twins Consortium
PMID: 27315352
Gastroenterology. 2015-12-01; 149.7: 1784-93.
Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study
Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D, Genetics of NAFLD in Twins Consortium
PMID: 26299412


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.