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Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease
  1. Silvia Sookoian1,2,
  2. Adrian Salatino1,3,
  3. Gustavo Osvaldo Castaño4,
  4. Maria Silvia Landa1,3,
  5. Cinthia Fijalkowky1,3,
  6. Martin Garaycoechea5,
  7. Carlos Jose Pirola1,3
  1. 1 Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, Argentina
  2. 2 Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council, Buenos Aires, Argentina
  3. 3 Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council, Buenos Aires, Argentina
  4. 4 Liver Unit, Medicine and Surgery Department, Hospital General de Agudos Dr Abel Zubizarreta, Buenos Aires, Argentina
  5. 5 Department of Surgery, Hospital El Cruce, Buenos Aires, Argentina
  1. Correspondence to Dr Silvia Sookoian, Institute of Medical Research A Lanari, University of Buenos Aires Faculty of Medicine, Buenos Aires, 10109 CABA, Argentina; ssookoian{at}intramed.net; Dr Carlos Jose Pirola; pirola.carlos{at}conicet.gov.ar

Abstract

Objective We aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features—from moderate to severe obesity—may be associated with significant changes in the microbial DNA profile.

Design and methods Liver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing.

Results Liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)—specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)—were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences.

Conclusion This is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×104 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.

  • nonalcoholic steatohepatitis
  • intestinal microbiology
  • liver biopsy
  • fatty liver
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Footnotes

  • SS and CJP are joint senior authors.

  • Twitter @SSookoian, @cjpirola, @panat

  • Contributors SS: study concept and design; data acquisition; performed liver biopsies and collected biological material; histological evaluation; immunohistochemistry (IHQ); RT-PCR; data analysis and interpretation; general study supervision; manuscript drafting; and securing funding. AS: bioinformatics analysis of sequencing data and data processing and presentation. MSL and CF: sample processing; MG and GOC: performed liver biopsies and collected biological samples. CJP: study concept and design, biological material collection and data acquisition; RT-PCR; data analysis and interpretation; statistical analysis; IHQ; manuscript drafting; and general study supervision and securing funding.

  • Funding This study was partially supported by grants PID-C2012-0061, PICT 2014-0432, PICT 2014-1816, PICT 2015-0551 and PICT 2016-0135 (Agencia Nacional de Promoción Científica y Tecnológica, FONCyT), CONICET Proyectos Unidades Ejecutoras 2017, PUE 0055.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Biological specimens, including blood samples and liver biopsies from all subjects included in this study, were obtained with written, informed consent in accordance with the Institutional Review Board-approved protocols (protocol numbers: 104/HGAZ/09, 89/100 and 1204/2012).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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