Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 Many of the effects of gut microbiome on the liver seem mediated by metabolites produced by commensal bacteria utilizing dietary nutrients as precursors, which does not seem to depend on particular species but rather on microbial metabolic pathways. + 1174 word(s) 1174 2020-05-15 05:25:10 |
2 format change + 2 word(s) 1176 2020-10-30 04:43:19 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Iruzubieta, P.; Medina, J.M.; Fernández-López, R.; Crespo, J.; De La Cruz, F. The Gut Microbiome in NAFLD. Encyclopedia. Available online: (accessed on 14 April 2024).
Iruzubieta P, Medina JM, Fernández-López R, Crespo J, De La Cruz F. The Gut Microbiome in NAFLD. Encyclopedia. Available at: Accessed April 14, 2024.
Iruzubieta, Paula, Juan M. Medina, Raúl Fernández-López, Javier Crespo, Fernando De La Cruz. "The Gut Microbiome in NAFLD" Encyclopedia, (accessed April 14, 2024).
Iruzubieta, P., Medina, J.M., Fernández-López, R., Crespo, J., & De La Cruz, F. (2020, May 15). The Gut Microbiome in NAFLD. In Encyclopedia.
Iruzubieta, Paula, et al. "The Gut Microbiome in NAFLD." Encyclopedia. Web. 15 May, 2020.
The Gut Microbiome in NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. 

NAFLD gut microbiome microbial metabolic pathway microbiome-based signature fecal microbiota transplantation

1. Introduction

GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.

2. The Gut Microbiome in Non-Alcoholic Fatty Liver Disease (NAFLD) 

Accumulated evidence indicates that the GM interacts with the liver via the so-called the “liver–gut axis”[1][2][3]. Dysfunction of this axis, including gut microbial imbalances and mucosa permeability alterations, leads to the passage of metabolic byproducts of bacterial metabolism as well as microbial components to the portal system reaching the liver. The microbial components, called pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide and peptidoglycan, are capable of inducing inflammatory responses mediated by the activation of pattern recognition receptors (PRRs), like Toll-like receptor (TLR), in Kupffer cells and hepatic stellate cells, leading to liver injury and fibrosis[4][5][6]. Besides, some metabolic byproducts of bacterial metabolism may interfere with glucose and lipid metabolism, as discussed below, contributing to the exacerbation of liver disease[7][8]. On the other hand, it is well known that GM and bile acids (BAs) closely interact and modulate each other; BAs prevent intestinal bacterial overgrowth and subsequent gut barrier dysfunction, and the GM regulates bile acid composition[9]. Given that BAs modulate host metabolism and immunity, through farnesoid X receptor (FXR) and membrane-associated G protein-coupled receptor (TGR5) signaling, an imbalance in gut bacteria and BAs may trigger metabolic diseases, such as NAFLD[10] (Figure 1).

Jcm 09 01369 g001 550

Figure 1. The effect of gut microbial unbalance in NAFLD. Different factors affect the gut microbiome. Gut microbial unbalance causes an increase in secondary BAs, which modulates FXR and FGR5 signaling, affecting the glucose and lipid metabolism and anti-inflammatory immune response. Besides, the increase in certain microbial metabolites mediates weakening of intestinal tight junction, enabling passage to the systemic circulation of PAMPs and microbial metabolites (such as ethanol) that reach the liver inducing inflammatory responses, liver injury and fibrosis. BAs, bile acids; FXR, farnesoid X receptor; PAMPs, pathogen associated molecular patterns; SCFAs, short-chain fatty acids; TGR5, membrane-associated G protein-coupled receptor; TMA, trimethylamine; TMAO, trimethylamine N-oxide; VLDL, very low-density lipoprotein.

Specific GM alterations have been correlated with the development and progression of NAFLD, both in human and in experimental animal models[11][7][12][13][14]. NAFLD patients exhibit more Gram-negative and fewer Gram-positive bacteria compared to healthy subjects, and disease progression correlates with phylum-level changes, such as an increase in Proteobacteria and a decrease in Firmicutes[15]. At the genus level, a significant increase in the abundance of Bacteroides and a decrease in Prevotella was observed in NASH patients, when compared to NAFLD patients without NASH[16]. Increased abundance of Ruminococcus in patients with fibrosis was also reported, as well as a relative increase in Streptococcus in obese patients with NAFLD[17]. These alterations are specifically linked to hepatic conditions, and are not the byproduct of insulin resistance, as demonstrated by Da Silva et al.[18]. However, although results point to a correlation between the GM and liver condition, the particular bacterial species involved are largely discordant across individual studies. These inconsistent results may be attributed to the lack of control and regularization for factors known to severely impact the GM, such as weight, diet, and drug intake[19][20]. Additionally, restricting the analysis to changes in diversity indices or comparisons at the phylum and other high-rank taxonomic levels is unlikely to yield insight into the molecular mechanisms involved. For these reasons, we are in need of approaches able to infer causal links, rather than mere statistical associations between specific bacterial species and liver conditions. The different methods for characterization of the GM are shown in Figure 2.

Meta-taxonomical approaches, if merely understood as the analysis of 16S sequences, are probably insufficient to unravel the causal links between GM composition and diseased states. Bacterial species contain pleomorphic genomes, with a conserved genetic core conserved among all members of a species, but also an accessory part that is highly variable among individual clones. The accessory part of the genome is often encoded in plasmids and other mobile genetic elements, thus subject to frequent change[21]. Due to this intrinsic genomic plasticity, strains of the same species frequently display significant phenotypic differences. Alternate metabolic profiles and even distinct virulence levels are common among strains of the same species, as exemplified by pathogenic and commensal E.coli [22][23][24]. As a consequence, meta-taxonomy alone may be unable to discriminate between strains that promote hepatic damage from those that do not. Similarly, if hepatic damage is the by-product of bacterial metabolism, it is likely that strains from different species produce similar hepatotoxic compounds as, in many species, non-essential, adaptive metabolic pathways are often encoded in mobile genetic elements[25][26].

Although the specific bacterial strains and species involved in NAFLD are still unknown, there is ample evidence that GM perturbations have a causal role in the development of the disease, rather than being a mere consequence of it. In animal models, it was shown that introducing a conventional GM in axenic mice increased monosaccharide absorption and triggered liver lipogenesis[27]. Similarly, faecal transplants from human donors with hepatic steatosis triggered a rapid development of hepatic steatosis in mice[28]. These phenomena suggest that GM does affect the host energy metabolism and fat storage. It may be thus key in the systemic inflammation associated with obesity, which leads to insulin resistance and hepatic steatosis. The molecular mechanisms by which GM alterations translate into hepatic damage are uncertain. However, several studies identified microbial metabolites associated with NAFLD, suggesting a role of certain gut-microbiome-derived metabolites in the pathogenesis and progression of NAFLD[28][29][30][31].

Jcm 09 01369 g002 550

Figure 2. Methods for characterizing gut microbiota. 16S rRNA is highly conserved among bacterial species, except that it contains hypervariable regions that confer phylogenetic association; thus, 16S rRNA gene sequencing is widely used for phylogenetic reconstruction and quantification of microbial diversity. However, this technique does not make it possible to decipher functional changes in the microbiome or to find out the true impact of gut microbes on disease states. For this reason, several -omics approaches were put forward. These methods dig into genes for genetic information storage, transcription for gene expression, proteins for structural and metabolic activities, and metabolites for end products of metabolism. cDNA, complementary DNA; ITS2, internal transcribed spacer 2; rRNA, ribosomal RNA.


  1. Parlesak, A.; Schäfer, C.; Schütz, T.; Bode, J.C.; Bode, C. Increased Intestinal Permeability to Macromolecules and Endotoxemia in Patients with Chronic Alcohol Abuse in Different Stages of Alcohol-Induced Liver Disease. J. Hepatol. 2000, 32, 742–747.
  2. Son, G.; Kremer, M.; Hines, I.N. Contribution of Gut Bacteria to Liver Pathobiology. Gastroenterol. Res. Pract. 2010, 2010, 453563.
  3. Wahlström, A.; Sayin, S.I.; Marschall, H.U.; Bäckhed, F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016, 24, 41–50.
  4. Compare, D.; Coccoli, P.; Rocco, A.; Nardone, O.M.; De Maria, S.; Cartenì, M.; Nardone, G. Gut-Liver Axis: The Impact of Gut Microbiota on Non Alcoholic Fatty Liver Disease. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 471–476.
  5. He, X.; Ji, G.; Jia, W.; Li, H. Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanism and Application of Metabolomics. Int. J. Mol. Sci. 2016, 17, 300.
  6. Seki, E.; Schnabl, B. Role of Innate Immunity and the Microbiota in Liver Fibrosis-Crosstalk between the Liver and Gut. J. Physiol. 2011, 590, 447–458.
  7. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. Characterization of Gut Microbiomes in Nonalcoholic Steatohepatitis (NASH) Patients: A Connection between Endogenous Alcohol and NASH. Hepatology 2013, 57, 601–609.
  8. Filliol, A.; Piquet-Pellorce, C.; Raguénès-Nicol, C.; Dion, S.; Farooq, M.; Lucas-Clerc, C.; Vandenabeele, P.; Bertrand, M.J.M.; Le Seyec, J.; Samson, M. RIPK1 Protects Hepatocytes from Kupffer Cells-Mediated TNF-Induced Apoptosis in Mouse Models of PAMP-Induced Hepatitis. J. Hepatol. 2017, 66, 1205–1213
  9. Davor Slijepcevic; Stan F. J. Van De Graaf; Bile Acid Uptake Transporters as Targets for Therapy. Digestive Diseases 2017, 35, 251-258, 10.1159/000450983.
  10. Jason M. Ridlon; Spencer C. Harris; Shiva Bhowmik; Dae-Joong Kang; Phillip B. Hylemon; Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016, 7, 22-39, 10.1080/19490976.2015.1127483.
  11. Melanie D. Spencer; Timothy J. Hamp; Robert W. Reid; Leslie M. Fischer; Steven H. Zeisel; Anthony A. Fodor; Association Between Composition of the Human Gastrointestinal Microbiome and Development of Fatty Liver With Choline Deficiency. Gastroenterology 2011, 140, 976-986, 10.1053/j.gastro.2010.11.049.
  12. Wong, V.W.-S.; Tse, C.-H.; Lam, T.T.-Y.; Wong, G.L.-H.; Chim, A.M.-L.; Chu, W.C.-W.; Yeung, D.K.-W.; Law, P.T.-W.; Kwan, H.-S.; Yu, J.; et al. Molecular Characterization of the Fecal Microbiota in Patients with Nonalcoholic Steatohepatitis—A Longitudinal Study. PLoS ONE 2013, 8, e62885.
  13. Raman, M.; Ahmed, I.; Gillevet, P.M.; Probert, C.S.; Ratcliffe, N.M.; Smith, S.; Greenwood, R.; Sikaroodi, M.; Lam, V.; Crotty, P.; et al. Fecal Microbiome and Volatile Organic Compound Metabolome in Obese Humans with Nonalcoholic Fatty Liver Disease. Clin. Gastroenterol. Hepatol. 2013, 11, 868–875.
  14. Alisi, A.; Bedogni, G.; Baviera, G.; Giorgio, V.; Porro, E.; Paris, C.; Giammaria, P.; Reali, L.; Anania, F.; Nobili, V. Randomised Clinical Trial: The Beneficial Effects of VSL#3 in Obese Children with Non-Alcoholic Steatohepatitis. Aliment. Pharmacol. Ther. 2014, 39, 1276–1285.
  15. Rohit Loomba; Victor Seguritan; Weizhong Li; Tao Long; Niels Klitgord; Archana Bhatt; Parambir Singh Dulai; Cyrielle Caussy; Richele Bettencourt; Sarah K. Highlander; et al.Marcus B. JonesClaude B. SirlinBernd SchnablLauren BrinkacNicholas SchorkChi-Hua ChenDavid A. BrennerWilliam BiggsShibu YoosephJ. Craig VenterKaren E. Nelson Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metabolism 2017, 25, 1054-1062.e5, 10.1016/j.cmet.2017.04.001.
  16. Jérôme Boursier; Olaf Mueller; Matthieu Barret; Mariana Verdelho Machado; Lionel Fizanne; Felix Araujo-Perez; Cynthia D. Guy; Patrick C. Seed; John F. Rawls; Lawrence A. David; et al.Gilles HunaultFrédéric ObertiPaul CalèsAnna Mae Diehl The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016, 63, 764-775, 10.1002/hep.28356.
  17. Esther Nistal; Luis E. Sáenz De Miera; María Ballesteros Pomar; Sonia Sánchez Campos; María Victoria García Mediavilla; Begoña Álvarez Cuenllas; Pedro Linares; José Luis Olcoz; María Teresa Arias Loste; Juan María García Lobo; et al.Javier CrespoJavier González GallegoFrancisco Jorquera Plaza An altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NAFLD) associated with obesity. Revista Española de Enfermedades Digestivas 2019, 111, 275-282, 10.17235/reed.2019.6068/2018.
  18. Hannah E. Da Silva; Anastasia Teterina; Elena M. Comelli; Amel Taibi; Bianca M. Arendt; Sandra E. Fischer; Wendy Lou; Johane P. Allard; Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Scientific Reports 2018, 8, 1-12, 10.1038/s41598-018-19753-9.
  19. Zmora, N.; Suez, J.; Elinav, E. You Are What You Eat: Diet, Health and the Gut Microbiota. Nat. Rev. Gastroenterol. Hepatol. 2019, 35–56.
  20. Vich Vila, A.; Collij, V.; Sanna, S.; Sinha, T.; Imhann, F.; Bourgonje, A.R.; Mujagic, Z.; Jonkers, D.M.A.E.; Masclee, A.A.M.; Fu, J.; et al. Impact of Commonly Used Drugs on the Composition and Metabolic Function of the Gut Microbiota. Nat. Commun. 2020, 11, 362.
  21. Fernando De La Cruz; Julian Davies; Horizontal gene transfer and the origin of species: lessons from bacteria. Trends in Microbiology 2000, 8, 128-133, 10.1016/s0966-842x(00)01703-0.
  22. Rasko, D.A.; Rosovitz, M.J.; Myers, G.S.A.; Mongodin, E.F.; Fricke, W.F.; Gajer, P.; Crabtree, J.; Sebaihia, M.; Thomson, N.R.; Chaudhuri, R.; et al. The Pangenome Structure of Escherichia Coli: Comparative Genomic Analysis of E. Coli Commensal and Pathogenic Isolates. J. Bacteriol. 2008, 190, 6881–6893.
  23. Gonzalez-Alba, J.M.; Baquero, F.; Cantón, R.; Galán, J.C. Stratified Reconstruction of Ancestral Escherichia Coli Diversification. BMC Genom. 2019, 20, 936.
  24. Touchon, M.; Hoede, C.; Tenaillon, O.; Barbe, V.; Baeriswyl, S.; Bidet, P.; Bingen, E.; Bonacorsi, S.; Bouchier, C.; Bouvet, O.; et al. Organised Genome Dynamics in the Escherichia Coli Species Results in Highly Diverse Adaptive Paths. PLoS Genet. 2009, 5, e1000344.
  25. Bonham, K.S.; Wolfe, B.E.; Dutton, R.J. Extensive Horizontal Gene Transfer in Cheese-Associated Bacteria. Elife 2017, 6, e22144.
  26. Sayler, G.S.; Hooper, S.W.; Layton, A.C.; King, J.M. Catabolic Plasmids of Environmental and Ecological Significance. Microb. Ecol. 1990, 19, 1–20.
  27. Fredrik Bäckhed; Hao Ding; Ting Wang; Lora V. Hooper; Gou Young Koh; Andras Nagy; Clay F. Semenkovich; Jeffrey I. Gordon; The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences 2004, 101, 15718-15723, 10.1073/pnas.0407076101.
  28. Lesley Hoyles; José-Manuel Fernández-Real; Massimo Federici; Matteo Serino; James Abbott; Julie Charpentier; Christophe Heymes; Jèssica Latorre Luque; Elodie Anthony; Richard H. Barton; et al.Julien ChillouxAntonis MyridakisLaura Martinez-GiliJosé Maria Moreno-NavarreteFadila BenhamedVincent AzalbertVincent Blasco-BaqueJosep PuigGemma XifraWifredo RicartChristopher TomlinsonMark WoodbridgeMarina CardelliniFrancesca DavatoIris CardoliniOttavia PorzioPaolo GentilieschiFrédéric LopezFabienne FoufelleSarah A. ButcherElaine HolmesJeremy K. NicholsonCatherine PosticRémy BurcelinMarc-Emmanuel Dumas Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nature Medicine 2018, 24, 1070-1080, 10.1038/s41591-018-0061-3.
  29. Pedersen, H.K.; Gudmundsdottir, V.; Nielsen, H.B.; Hyotylainen, T.; Nielsen, T.; Jensen, B.A.H.; Forslund, K.; Hildebrand, F.; Prifti, E.; Falony, G.; et al. Human Gut Microbes Impact Host Serum Metabolome and Insulin Sensitivity. Nature 2016, 535, 376–381.
  30. Caussy, C.; Hsu, C.; Lo, M.-T.; Liu, A.; Bettencourt, R.; Ajmera, V.H.; Bassirian, S.; Hooker, J.; Sy, E.; Richards, L.; et al. Link between Gut-Microbiome Derived Metabolite and Shared Gene-Effects with Hepatic Steatosis and Fibrosis in NAFLD. Hepatology 2018, 68, 918–932.
  31. Chen, Y.; Liu, Y.; Zhou, R.; Chen, X.; Wang, C.; Tan, X.; Wang, L.; Zheng, R.; Zhang, H.; Ling, W.; et al. Associations of Gut-Flora-Dependent Metabolite Trimethylamine-N-Oxide, Betaine and Choline with Non-Alcoholic Fatty Liver Disease in Adults. Sci. Rep. 2016, 6, 19076.
Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , ,
View Times: 1.0K
Revisions: 2 times (View History)
Update Date: 30 Oct 2020