title: Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach.
abstract: There is evidence that nonalcoholic fatty liver disease (NAFLD) is affected by gut microbiota. Therefore, we investigated its modifications in pediatric NAFLD patients using targeted metagenomics and metabolomics. Stools were collected from 61 consecutive patients diagnosed with nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), or obesity and 54 healthy controls (CTRLs), matched in a case-control fashion. Operational taxonomic units were pyrosequenced targeting 16S ribosomal RNA and volatile organic compounds determined by solid-phase microextraction gas chromatography-mass spectrometry. The α-diversity was highest in CTRLs, followed by obese, NASH, and NAFL patients; and β-diversity distinguished between patients and CTRLs but not NAFL and NASH. Compared to CTRLs, in NAFLD patients Actinobacteria were significantly increased and Bacteroidetes reduced. There were no significant differences among the NAFL, NASH, and obese groups. Overall NAFLD patients had increased levels of Bradyrhizobium, Anaerococcus, Peptoniphilus, Propionibacterium acnes, Dorea, and Ruminococcus and reduced proportions of Oscillospira and Rikenellaceae compared to CTRLs. After reducing metagenomics and metabolomics data dimensionality, multivariate analyses indicated a decrease of Oscillospira in NAFL and NASH groups and increases of Ruminococcus, Blautia, and Dorea in NASH patients compared to CTRLs. Of the 292 volatile organic compounds, 26 were up-regulated and 2 down-regulated in NAFLD patients. Multivariate analyses found that combination of Oscillospira, Rickenellaceae, Parabacteroides, Bacteroides fragilis, Sutterella, Lachnospiraceae, 4-methyl-2-pentanone, 1-butanol, and 2-butanone could discriminate NAFLD patients from CTRLs. Univariate analyses found significantly lower levels of Oscillospira and higher levels of 1-pentanol and 2-butanone in NAFL patients compared to CTRLs. In NASH, lower levels of Oscillospira were associated with higher abundance of Dorea and Ruminococcus and higher levels of 2-butanone and 4-methyl-2-pentanone compared to CTRLs.
  
  
  
  An Oscillospira decrease coupled to a 2-butanone up-regulation and increases in Ruminococcus and Dorea were identified as gut microbiota signatures of NAFL onset and NAFL-NASH progression, respectively. (Hepatology 2017;65:451-464).
authors.affiliation: Human Microbiome Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Del Chierico
authors.affiliation: Hepato-Metabolic Disease Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.|Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.affiliation: Human Microbiome Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Vernocchi
authors.affiliation: Human Microbiome Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Russo
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: De Stefanis
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gnani
authors.affiliation: Predictive Models for Biomedicine and Environment Unit, Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Furlanello
authors.affiliation: Predictive Models for Biomedicine and Environment Unit, Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zandonà
authors.affiliation: Institute for Systems Analysis and Computer Science "Antonio Ruberti", National Research Council, 00185, Rome, Italy.|SysBio Centre for Systems Biology, 00185, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Paci
authors.affiliation: Department of Chemistry, Sapienza University of Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Capuani
authors.affiliation: Scientific Directorate, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Department of Chemistry, Sapienza University of Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Miccheli
authors.affiliation: Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.affiliation: Human Microbiome Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.|Parasitology Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Putignani
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D016022:Case-Control Studies; D002648:Child; D005234:Fatty Liver / Q000382:microbiology / Q000503:physiopathology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease / Q000382:microbiology* / Q000503:physiopathology; D009765:Obesity / Q000382:microbiology* / Q000503:physiopathology; D010372:Pediatrics; D000071696:Proteogenomics / Q000379:methods; D012016:Reference Values; D012680:Sensitivity and Specificity