Discovery of Robust and Highly Specific Microbiome Signatures of Non-alcoholic Fatty Liver Disease

Overview

Journal Microbiome

Publisher Biomed Central

Date 2025 Jan 14

PMID 39810263

Authors

Emmanouil Nychas

Andrea Marfil-Sanchez

Xiuqiang Chen

Mohammad Mirhakkak

Huating Li

Weiping Jia

Aimin Xu

Henrik Bjorn Nielsen

Max Nieuwdorp

Rohit Loomba

Yueqiong Ni

Gianni Panagiotou

Affiliations

Soon will be listed here.

Abstract

Background: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) with a global prevalence of 30% is multifactorial and the involvement of gut bacteria has been recently proposed. However, finding robust bacterial signatures of NAFLD has been a great challenge, mainly due to its co-occurrence with other metabolic diseases.

Results: Here, we collected public metagenomic data and integrated the taxonomy profiles with in silico generated community metabolic outputs, and detailed clinical data, of 1206 Chinese subjects w/wo metabolic diseases, including NAFLD (obese and lean), obesity, T2D, hypertension, and atherosclerosis. We identified highly specific microbiome signatures through building accurate machine learning models (accuracy = 0.845-0.917) for NAFLD with high portability (generalizable) and low prediction rate (specific) when applied to other metabolic diseases, as well as through a community approach involving differential co-abundance ecological networks. Moreover, using these signatures coupled with further mediation analysis and metabolic dependency modeling, we propose synergistic defined microbial consortia associated with NAFLD phenotype in overweight and lean individuals, respectively.

Conclusion: Our study reveals robust and highly specific NAFLD signatures and offers a more realistic microbiome-therapeutics approach over individual species for this complex disease. Video Abstract.

References

Goffredo M, Santoro N, Trico D, Giannini C, DAdamo E, Zhao H . A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients. 2017; 9(7). PMC: 5537762. DOI: 10.3390/nu9070642. View

Loomba R, Sanyal A . The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013; 10(11):686-90. DOI: 10.1038/nrgastro.2013.171. View

Machado D, Andrejev S, Tramontano M, Patil K . Fast automated reconstruction of genome-scale metabolic models for microbial species and communities. Nucleic Acids Res. 2018; 46(15):7542-7553. PMC: 6125623. DOI: 10.1093/nar/gky537. View

Priya S, Burns M, Ward T, Mars R, Adamowicz B, Lock E . Identification of shared and disease-specific host gene-microbiome associations across human diseases using multi-omic integration. Nat Microbiol. 2022; 7(6):780-795. PMC: 9159953. DOI: 10.1038/s41564-022-01121-z. View

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A . Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017; 25(5):1054-1062.e5. PMC: 5502730. DOI: 10.1016/j.cmet.2017.04.001. View

Brocker C, Velenosi T, Flaten H, McWilliams G, McDaniel K, Shelton S . Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites. Hum Genomics. 2020; 14(1):10. PMC: 7066769. DOI: 10.1186/s40246-020-00260-w. View

Huang Z, Chen M, Guo W, Li T, Liu B, Bai W . Monascus purpureus-fermented common buckwheat protects against dyslipidemia and non-alcoholic fatty liver disease through the regulation of liver metabolome and intestinal microbiome. Food Res Int. 2020; 136:109511. DOI: 10.1016/j.foodres.2020.109511. View

Clarke E, Taylor L, Zhao C, Connell A, Lee J, Fett B . Sunbeam: an extensible pipeline for analyzing metagenomic sequencing experiments. Microbiome. 2019; 7(1):46. PMC: 6429786. DOI: 10.1186/s40168-019-0658-x. View

Moore G, Howell S, Brady M, Xu X, McNeil K . Anomalous collapses of Nares Strait ice arches leads to enhanced export of Arctic sea ice. Nat Commun. 2021; 12(1):1. PMC: 7782487. DOI: 10.1038/s41467-020-20314-w. View

Xu T, Zhou J, Zhu J, Zhang S, Zhang N, Zhao Y . Carnosic acid protects non-alcoholic fatty liver-induced dopaminergic neuron injury in rats. Metab Brain Dis. 2016; 32(2):483-491. DOI: 10.1007/s11011-016-9941-8. View

10.

de Mello V, Sehgal R, Mannisto V, Klavus A, Nilsson E, Perfilyev A . Serum aromatic and branched-chain amino acids associated with NASH demonstrate divergent associations with serum lipids. Liver Int. 2020; 41(4):754-763. PMC: 8048463. DOI: 10.1111/liv.14743. View

11.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

12.

Pasolli E, Schiffer L, Manghi P, Renson A, Obenchain V, Truong D . Accessible, curated metagenomic data through ExperimentHub. Nat Methods. 2017; 14(11):1023-1024. PMC: 5862039. DOI: 10.1038/nmeth.4468. View

13.

Magnusdottir S, Heinken A, Kutt L, Ravcheev D, Bauer E, Noronha A . Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota. Nat Biotechnol. 2016; 35(1):81-89. DOI: 10.1038/nbt.3703. View

14.

Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S . Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019; 25(7):1096-1103. PMC: 6699990. DOI: 10.1038/s41591-019-0495-2. View

15.

Le Bastard Q, Al-Ghalith G, Gregoire M, Chapelet G, Javaudin F, Dailly E . Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Aliment Pharmacol Ther. 2017; 47(3):332-345. DOI: 10.1111/apt.14451. View

16.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

17.

Ni Y, Qian L, Siliceo S, Long X, Nychas E, Liu Y . Resistant starch decreases intrahepatic triglycerides in patients with NAFLD via gut microbiome alterations. Cell Metab. 2023; 35(9):1530-1547.e8. DOI: 10.1016/j.cmet.2023.08.002. View

18.

Zelezniak A, Andrejev S, Ponomarova O, Mende D, Bork P, Patil K . Metabolic dependencies drive species co-occurrence in diverse microbial communities. Proc Natl Acad Sci U S A. 2015; 112(20):6449-54. PMC: 4443341. DOI: 10.1073/pnas.1421834112. View

19.

Samara J, Moossavi S, Alshaikh B, Ortega V, Pettersen V, Ferdous T . Supplementation with a probiotic mixture accelerates gut microbiome maturation and reduces intestinal inflammation in extremely preterm infants. Cell Host Microbe. 2022; 30(5):696-711.e5. DOI: 10.1016/j.chom.2022.04.005. View