Emerging Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease: From Composition to Function

The gut microbiome, a diverse microbial community in the gastrointestinal tract, plays a pivotal role in the maintenance of health. The gut microbiome metabolizes dietary and host-derived molecules to produce bioactive metabolites, which have a wide array of effects on host metabolism and immunity. 'Dysbiosis' of the gut microbiome, commonly considered as perturbation of microbiome diversity and composition, has been associated with intestinal and extra-intestinal diseases, including nonalcoholic fatty liver disease (NAFLD). A number of endogenous and exogenous factors, such as nutritional intake and xenobiotic exposure, can alter the gut microbiome. We will review the evolving methods for studying the gut microbiome and how these profiling techniques have been utilized to further our understanding of the gut microbial community composition and functional potential in the clinical spectrum of NAFLD. We will highlight microbiome-host interactions that may contribute to the pathogenesis of NAFLD, with a primary focus on mechanisms related to the metabolic output of the gut microbiome. Finally, we will discuss potential therapeutic implications of the gut microbiome in NAFLD. The gut microbiome, a diverse microbial community in the gastrointestinal tract, plays a pivotal role in the maintenance of health. The gut microbiome metabolizes dietary and host-derived molecules to produce bioactive metabolites, which have a wide array of effects on host metabolism and immunity. 'Dysbiosis' of the gut microbiome, commonly considered as perturbation of microbiome diversity and composition, has been associated with intestinal and extra-intestinal diseases, including nonalcoholic fatty liver disease (NAFLD). A number of endogenous and exogenous factors, such as nutritional intake and xenobiotic exposure, can alter the gut microbiome. We will review the evolving methods for studying the gut microbiome and how these profiling techniques have been utilized to further our understanding of the gut microbial community composition and functional potential in the clinical spectrum of NAFLD. We will highlight microbiome-host interactions that may contribute to the pathogenesis of NAFLD, with a primary focus on mechanisms related to the metabolic output of the gut microbiome. Finally, we will discuss potential therapeutic implications of the gut microbiome in NAFLD. The gut microbiota is a diverse microbial community comprised of bacteria, fungi, viruses, and archaea that encodes several orders of magnitude more functional genes than the human genome.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar The collective genetic material of the microbiota is often referred to as the "gut microbiome" and encodes pathways that produce a wide array of bioactive small molecules that are derived from dietary or metabolic precursors and may alter human health.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Although under normal circumstances the relationship between the human host and gut microbiome is mutually beneficial, perturbations of the gut microbiome, often referred to as "dysbiosis," have been associated with several chronic diseases, including obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD).1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Preclinical studies have provided the strongest evidence for a causal role of the gut microbiome in NAFLD. Several pivotal studies established that mice lacking gut microbiota are resistant to the development of diet-induced hepatic steatosis and that hepatic steatosis is transmissible via fecal microbiota transplantation (FMT) and ameliorated by probiotics and antibiotics in murine models.2Schnabl B. Brenner D.A. Interactions between the intestinal microbiome and liver diseases.Gastroenterology. 2014; 146: 1513-1524Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar More recent studies suggest that the manipulation of the gut microbiome, either with antibiotics or FMT, also suppresses liver tumorigenesis and reduces portal hypertension in murine models.3Yu L.X. Schwabe R.F. The gut microbiome and liver cancer: mechanisms and clinical translation.Nat Rev Gastroenterol Hepatol. 2017; 14: 527-539Crossref PubMed Scopus (287) Google Scholar, 4García-Lezana T. Raurell I. Bravo M. et al.Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis.Hepatology. 2018; 67: 1485-1498Crossref PubMed Scopus (68) Google Scholar Given this compelling preclinical evidence, the gut-liver axis is a rapidly developing area of investigation and new insights are emerging from a growing number of human studies. This review highlights current methods for studying the microbiome and human gut microbial profiles associated with the clinical spectrum of NAFLD, stratified by community composition and function. We also review postulated mechanisms linking the gut microbiome to the pathogenesis of NAFLD. Finally, we discuss potential therapeutic implications of the gut microbiome in NAFLD. Advances in profiling and analytic techniques are transforming microbiome research and have been recently reviewed elsewhere,5Gilbert J.A. Blaser M.J. Caporaso J.G. et al.Current understanding of the human microbiome.Nat Med. 2018; 24: 392-400Crossref PubMed Scopus (965) Google Scholar, 6Knight R. Vrbanac A. Taylor B.C. et al.Best practices for analysing microbiomes.Nat Rev Microbiol. 2018; 16: 410-422Crossref PubMed Scopus (734) Google Scholar so we limit our discussion to an overview of methods that have been used in human studies in NAFLD (Figure 1). To date, most studies have used culture-independent, biomarker-based profiling techniques. This method involves sequencing a ubiquitous gene, which is represented by the 16S ribosomal RNA (16S rRNA) gene in bacteria. Biomarker-based profiling techniques provide a relatively accurate fingerprint of microbial community composition (ie, taxonomic relative abundance); however, little can be learned about the microbial community's functional properties.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Although inferential algorithms based on reference genome databases enable predictions of functional capacities from 16S rRNA sequences, there are limitations to functional predictions.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Moreover, this sequencing approach lacks the resolution needed to identify bacteria on a species or strain level, and different strains of the same bacterial species can exert different effects on the human host.5Gilbert J.A. Blaser M.J. Caporaso J.G. et al.Current understanding of the human microbiome.Nat Med. 2018; 24: 392-400Crossref PubMed Scopus (965) Google Scholar Recent advances in computational biology have improved the feasibility of systems-level "omics" approaches, which allow for microbial community characterization beyond compositional states.5Gilbert J.A. Blaser M.J. Caporaso J.G. et al.Current understanding of the human microbiome.Nat Med. 2018; 24: 392-400Crossref PubMed Scopus (965) Google Scholar, 6Knight R. Vrbanac A. Taylor B.C. et al.Best practices for analysing microbiomes.Nat Rev Microbiol. 2018; 16: 410-422Crossref PubMed Scopus (734) Google Scholar These approaches include next-generation sequencing approaches to determine the functional genes encoded (metagenomics) or expressed (metatranscriptomics) by a microbial community, and mass spectrometry platforms to identify proteins (metaproteomics) and bioactive small molecules (metabolomics) collectively produced by a microbial community.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Shotgun metagenomic sequencing characterizes the DNA library from a microbial community to obtain the entire gene complement ("metagenome"), although this method cannot assess the activity of microbial gene expression, which is regulated at the transcriptional and translational level.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Even with metagenomic sequencing data, predicted function should be interpreted with caution because pathway presence does not reveal information about activity or directionality. Nevertheless, when compared with biomarker-based sequencing, metagenomics allows for more accurate characterization of microbial functional properties, in addition to taxonomical resolution to the species level.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar Metabolomics facilitates the identification and quantification of small molecule metabolic products ("metabolome") through use of complementary analytical chemistry techniques and can include targeted and untargeted approaches.1Lynch S.V. Pedersen O. The human intestinal microbiome in health and disease.N Engl J Med. 2016; 375: 2369-2379Crossref PubMed Scopus (1673) Google Scholar For the purpose of this review, we use the term "functional potential" to represent the gene content and/or metabolic output of the gut microbiome, as measured by 1 or more "omic" approaches. Numerous human studies have demonstrated an association between gut dysbiosis and the spectrum of NAFLD in children7Zhu L. Baker S.S. Gill C. et al.Characterization of gut microbiomes in nonalcoholic steatohepatitis patients: a connection between endogenous alcohol and NASH.Hepatology. 2013; 57: 601-609Crossref PubMed Scopus (1023) Google Scholar, 8Michail S. Lin M. Frey M.R. et al.Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease.FEMS microbiology ecology. 2015; 91: 1-9Crossref PubMed Google Scholar, 9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar, 10Nobili V. Putignani L. Mosca A. et al.Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players?.Arch Med Sci. 2018; 14: 81-87Crossref PubMed Scopus (59) Google Scholar and adults.11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 12Wong V.W.-S. Tse C.-H. Lam T.T.-Y. et al.Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis: a longitudinal study.PloS One. 2013; 8: e62885Crossref PubMed Scopus (233) Google Scholar, 13Mouzaki M. Wang A.Y. Bandsma R. et al.Bile acids and dysbiosis in non-alcoholic fatty liver disease.PloS One. 2016; 11: e0151829Crossref PubMed Scopus (216) Google Scholar, 14Boursier J. Mueller O. Barret M. et al.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: 764-775Crossref PubMed Scopus (739) Google Scholar, 15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar, 16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar, 17Loomba R. Seguritan V. Li W. et al.Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease.Cell Metab. 2017; 25: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar, 19Duarte S.M.B. Stefano J.T. Miele L. et al.Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: a prospective pilot study.Nutr Metab Cardiovasc Dis. 2018; 28: 369-384Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 20Ponziani F.R. Bhoori S. Castelli C. et al.Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in non-alcoholic fatty liver disease.Hepatology. 2018; ([Epub ahead of print])Crossref PubMed Scopus (274) Google Scholar, 21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar, 22Caussy C. Hsu C. Lo M.-T. et al.Novel link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD.Hepatology. 2018; ([Epub ahead of print])Crossref Scopus (98) Google Scholar, 23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar All except 1 of these studies were cross-sectional,12Wong V.W.-S. Tse C.-H. Lam T.T.-Y. et al.Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis: a longitudinal study.PloS One. 2013; 8: e62885Crossref PubMed Scopus (233) Google Scholar and most used biomarker-based sequencing to profile the gut microbiome. We review gut microbiome profiles, with a focus on genus-level differences, in the following clinical phenotypes: nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), NAFLD-related advanced fibrosis, and NAFLD-related hepatocellular carcinoma (HCC) (Table 1).Table 1Characterization of the Gut Microbiome in Clinical Phenotypes of NAFLD, stratified by Genus-Level Taxonomic Composition and "Functional Potential"Clinical phenotypes of NAFLDCommunity compositionaComparison groups differed among studies. In NAFL, comparison groups included healthy control subjects8–11,15,16,18,23 and obese control subjects.21 In NASH, comparison groups included healthy control subjects,9,10,12,13,18,19 obese control subjects,7 and NAFL.24,16 In NAFLD-associated advanced fibrosis, comparison groups included healthy control subjects20 and NAFLD without advanced fibrosis (stage <2).16,17,22,24 In NAFLD-related HCC, the comparison group included NAFLD-related cirrhosis without HCC.20Functional potentialbThe fecal and serum metabolites listed are postulated to be derived from the gut microbiome.PhylumGenusFecal metabolitesSerum metabolitesNAFLcTwo studies enrolled only nonobese subjects, to examine compositional changes in nonobese ("lean") NAFL15 and NASH.19Firmicutes↑Blautia16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar↑Dorea11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar↓↑Roseburia11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar↓↑Lactobacillus10Nobili V. Putignani L. Mosca A. et al.Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players?.Arch Med Sci. 2018; 14: 81-87Crossref PubMed Scopus (59) Google Scholar, 11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar, 18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar, 23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↑Streptococcus23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↑Clostridium23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↓Oscillospira9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar↓Coprococcus15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar, 18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar, 21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar↓Faecalibacterium18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↓Moryella15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar↓Flavonifractor19Duarte S.M.B. Stefano J.T. Miele L. et al.Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: a prospective pilot study.Nutr Metab Cardiovasc Dis. 2018; 28: 369-384Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar↓↑Oscillobacter11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar, 21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar, 23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↓↑Ruminococcus9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar, 15Wang B. Jiang X. Cao M. et al.Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease.Sci Rep. 2016; 6: 32002Crossref PubMed Scopus (190) Google Scholar, 16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar, 18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↑Butanoic acid11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar↑Propanoic acid11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar↑Acetic acid11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar↑Isobutyric acid18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↑Propionate18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↑Unconjugated cholic acid13Mouzaki M. Wang A.Y. Bandsma R. et al.Bile acids and dysbiosis in non-alcoholic fatty liver disease.PloS One. 2016; 11: e0151829Crossref PubMed Scopus (216) Google Scholar↑Ethanol8Michail S. Lin M. Frey M.R. et al.Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease.FEMS microbiology ecology. 2015; 91: 1-9Crossref PubMed Google Scholar↓2-butanone11Raman M. Ahmed I. Gillevet P.M. et al.Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol. 2013; 11: 868-875Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar↑2-butanone9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar↑1-pentanol9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar↑2-hydroxy-butyrate18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↑L-lactic acid18Da Silva H.E. Teterina A. Comelli E.M. et al.Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance.Sci Rep. 2018; 8: 1466Crossref PubMed Scopus (144) Google Scholar↑Phenylacetic acid21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar↑Valine21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar↑Leucine21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar↑Isoleucine21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google ScholarBacteroidetes↓↑Prevotella8Michail S. Lin M. Frey M.R. et al.Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease.FEMS microbiology ecology. 2015; 91: 1-9Crossref PubMed Google Scholar, 16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar, 23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↓Odoribacter23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google Scholar↓Alistipes23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google ScholarProteobacteria↑Escherichia16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar, 21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google Scholar, 23Jiang W. Wu N. Wang X. et al.Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease.Sci Rep. 2015; 5: 8096Crossref PubMed Scopus (373) Google ScholarActinobacteria↓↑Bifidobacterium10Nobili V. Putignani L. Mosca A. et al.Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players?.Arch Med Sci. 2018; 14: 81-87Crossref PubMed Scopus (59) Google Scholar, 21Hoyles L. Fernandez-Real J.M. Federici M. et al.Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women.Nat Med. 2018; 24: 1070-1080Crossref PubMed Scopus (326) Google ScholarNASHcTwo studies enrolled only nonobese subjects, to examine compositional changes in nonobese ("lean") NAFL15 and NASH.19Firmicutes↑Blautia9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar, 16Shen F. Zheng R.D. Sun X.Q. et al.Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.Hepatobiliary Pancreat Dis Int. 2017; 16: 375-381Crossref PubMed Scopus (264) Google Scholar↑Dorea9Del Chierico F. Nobili V. Vernocchi P. et al.Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.Hepatology. 2017; 65: 451-464Crossref PubMed Scopus (397) Google Scholar↑Lactobacillus10Nobili V. Putignani L. Mosca A. et al.Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players?.Arch Med Sci. 2018; 14: 81-87Crossref PubMed Scopus (59) Google Scholar, 19Duarte S.M.B. Stefano J.T. Miele L. et al.Gut microbiome composition in lean patients with NASH is associated with liver damage independent of caloric intake: a prospective pilot study.Nutr Metab Cardiovasc Dis. 2018; 28: 369-384Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar↑Clostridium13Mouzaki M. Wang A.Y. Bandsma R. et al.Bile acids and dysbiosis in non-alcoholic fatty liver disease.PloS One. 2016; 11: e0151829Crossref PubMed Scopus (216) Google Scholar↑Allisonella12Wong V.W.-S. Tse C.-H