Link between gut‐microbiome derived metabolite and shared gene‐effects with hepatic steatosis and fibrosis in NAFLD
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Previous studies have shown that gut‐microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut‐microbiome, have a shared gene‐effect with hepatic steatosis and fibrosis. This is a cross‐sectional analysis of a prospective discovery cohort including 156 well‐characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic‐resonance‐imaging proton‐density‐fat‐fraction (MRI‐PDFF) and fibrosis using MR‐elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene‐effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy‐proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene‐effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3‐(4‐hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold‐change of higher‐MRE versus lower‐MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3‐(4‐hydroxyphenyl)lactate with hepatic steatosis was R G :0.57,95%CI:0.27‐0.80, P < 0.001 and with fibrosis was R G :0.54,95%CI:0.036‐1, P = 0.036. Pathway reconstruction linked 3‐(4‐hydroxyphenyl)lactate to several human gut‐microbiome species. In the validation cohort, 3‐(4‐hydroxyphenyl)lactate was significantly correlated with the abundance of several gut‐microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion : This proof of concept study provides evidence of a link between the gut‐microbiome and 3‐(4‐hydroxyphenyl)lactate that shares gene‐effect with hepatic steatosis and fibrosis. (H epatology 2018).
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Specific microbiome signatures can distinguish human MASH from MASLD.
“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 [199]
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- Authors
- Caussy, C., Hsu, C., Lo, M., Liu, A., Bettencourt, R., Ajmera, V. H., Bassirian, S., Hooker, J., Sy, E., Richards, L., Schork, N., Schnabl, B., Brenner, D. A., Sirlin, C. B., Chen, C., Loomba, R., & Genetics of NAFLD in Twins Consortium
- Affiliations
- Lyon 1 Université (FR)
- NAFLD Research Center,Department of Medicine,La Jolla,California
- University of California San Diego (US)
- J. Craig Venter Institute (US)
- Corresponding author
- Loomba, Rohit
- ORCID
- Venue
- Hepatology
- Published
- 2018-05-20
- Volume
- 68
- Issue
- 3
- Pages
- 918-932
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6151296
- OpenAlex
- W2793865429
- Cited by
- 205
- References
- 46
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 26 · 2023: 33 · 2022: 24 · 2021: 29 · 2020: 39 · 2019: 13 · 2018: 11
- FWCI
- 17.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Fulbright Program
- John A. Hartford Foundation
- Hartford Foundation for Public Giving
- American Gastroenterological Association (R01‐DK106419, K23DK090303)
- Philippe Foundation
- Société Francophone du Diabète
- National Institutes of Health (UL1TR001442)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106419, K23DK090303)
- National Institute of Environmental Health Sciences (P42ES010337)
- National Center for Research Resources (KL2RR031978)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- non-alcoholic fatty liver disease, gut microbiota, microbial metabolites, hepatic steatosis, liver fibrosis, serum metabolites, twin studies, magnetic resonance elastography, proton density fat fraction, Firmicutes, Bacteroidetes, metabolic pathway reconstruction
- MeSH terms
- Gastrointestinal Microbiome, Proof of Concept Study, Adult, Aged, Cross-Sectional Studies, Female, Humans, Liver Cirrhosis, Male, Metformin, Middle Aged, Phenylpropionates, Non-alcoholic Fatty Liver Disease
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