Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease
Open accessAbstract
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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Succinic acid is significantly increased in feces, serum, and liver tissue from MAFLD patients.
“Alistipes can produce succinic acid (Liu et al., 2016), which is significantly increased in feces, serum, and liver tissue from MAFLD patients (Loomba et al., 2017; Schofield et al., 2017).”
From <i>Akkermansia muciniphila</i> alleviates <scp>high‐fat‐diet</scp> ‐related metabolic‐associated fatty liver disease by modulating gut microbiota and bile acids (2023) · cites this paper as Loomba et al., 2017
The Results section on microbial metabolism reports a higher abundance of enzymes associated with succinate production in advanced-fibrosis NAFLD, but says the enzyme differences were not statistically significant. It does not report a significant increase in succinic acid itself in feces, serum, or liver tissue; searches for succinic acid and succinate did not locate that finding in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measuredA metagenomic-based model distinguished advanced fibrosis in adult patients with NASH based on increased Proteobacteria (mostly E. Coli) levels and a decrease in Firmicutes.
“Similarly, Loomba et al. constructed a metagenomic-based model to distinguish advanced fibrosis in adult patients with NASH based on increased Proteobacteria (mostly E. Coli) levels and a decrease in Firmicutes [232].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [232]
These changes are positively correlated with NASH severity and fibrosis in patient cohorts and experimental NASH models.
“These changes are positively correlated with NASH severity and fibrosis in patient cohorts and experimental NASH models (16, 79–82).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [79]
MASH fibrosis is linked to a unique gut microbiome.
“MASH fibrosis is linked to a unique gut microbiome (193-197), and specific microbiome signatures can distinguish human MASH from MASLD (4, 198, 199).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [196]
Intestinal microbiota alterations are associated with major conditions like obesity, type-2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease, cancer, and the response to antineoplastic therapy.
“Intestinal microbiota alterations are associated with major conditions like obesity, type-2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease, cancer, and the response to antineoplastic therapy [3][4][5][6] .”
From Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice (2019) · cites this paper as [4]
In patients with NAFLD/NASH, there is an increased abundance of Bacteroides.
“As well, in those studies it was shown that NALFD/NASH in patients associated with increased abundance of Bacteroides abundance36,37.”
From Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice (2019) · cites this paper as [36]
Ruminococcaceae have been found to be enriched in samples from fibrotic patients with NAFLD/NASH, supporting their role in the pathogenesis of other chronic liver diseases that also associate with impaired intestinal barrier function.
“Interestingly, Ruminococcaceae have been found to be enriched in samples from fibrotic patients with NAFLD/NASH36,37, supporting their role in the pathogenesis of other chronic liver diseases that also associate with impaired intestinal barrier function.”
From Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice (2019) · cites this paper as [36]
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- Authors
- 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., Venter, J. C., & Nelson, K. E.
- Affiliations
- University of California San Diego (US)
- Human Longevity (United States) (US)
- J. Craig Venter Institute (US)
- Corresponding author
- Loomba, Rohit
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 25
- Issue
- 5
- Pages
- 1054-1062.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5502730
- OpenAlex
- W2611418622
- Cited by
- 1,123
- References
- 46
- Citations by year
- 2026: 91 · 2025: 122 · 2024: 133 · 2023: 172 · 2022: 128 · 2021: 172 · 2020: 124 · 2019: 89 · 2018: 67 · 2017: 22 · 2015: 1
- FWCI
- 33.56
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-09-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Environmental Health Sciences
- John A. Hartford Foundation (K23-DK090303)
- National Institutes of Health (P42ES010337)
- Atlantic Philanthropies
- University of California, San Diego
- American Gastroenterological Association
- National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007202)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- non-alcoholic fatty liver disease, advanced liver fibrosis, gut microbiota, non-invasive diagnosis, fecal microbiota, bacterial species, random forest, diagnostic accuracy
- MeSH terms
- Gastrointestinal Microbiome, Adult, Aged, Bacteria, Feces, Female, Humans, Liver Cirrhosis, Male, Middle Aged, Prognosis, Prospective Studies, Metagenomics, Non-alcoholic Fatty Liver Disease
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