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Link between gut‐microbiome derived metabolite and shared gene‐effects with hepatic steatosis and fibrosis in NAFLD
Author(s) -
Caussy Cyrielle,
Hsu Cynthia,
Lo MinTzu,
Liu Amy,
Bettencourt Ricki,
Ajmera Veeral H.,
Bassirian Shirin,
Hooker Jonathan,
Sy Ethan,
Richards Lisa,
Schork Nicholas,
Schnabl Bernd,
Brenner David A.,
Sirlin Claude B.,
Chen ChiHua,
Loomba Rohit
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29892
Subject(s) - steatosis , medicine , metabolome , nonalcoholic fatty liver disease , cohort , hepatic fibrosis , gastroenterology , microbiome , fibrosis , prospective cohort study , fatty liver , metabolite , biology , bioinformatics , disease
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).