Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats

Brunella Posteraro, Francesco Paroni Sterbini, Valentina Petito, Stefano Rocca, Tiziana Cubeddu, Cristina Graziani, Vincenzo Arena, Gabriele A. Vassallo, Carolina Mosoni, Loris Lopetuso, Irene Lorrai, Paola Maccioni, Luca Masucci, Cecilia Martini, Antonio Gasbarrini, Maurizio Sanguinetti, Giancarlo Colombo, Giovanni Addolorato

Research output: Contribution to journalArticle

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Abstract

Background: There is strong evidence that alcoholism leads to dysbiosis in both humans and animals. However, it is unclear how changes in the intestinal microbiota (IM) relate to ethanol (EtOH)-induced disruption of gut–liver homeostasis. We investigated this issue using selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive EtOH consumption. Methods: Independent groups of male adult sP rats were exposed to the standard, home-cage 2-bottle “EtOH (10% v/v) versus water” choice regimen with unlimited access for 24 h/d (Group Et) for 3 (T1), 6 (T2), and 12 (T3) consecutive months. Control groups (Group Ct) were composed of matched-age EtOH-naïve sP rats. We obtained samples from each rat at the end of each experimental time, and we used blood and colon tissues for intestinal barrier integrity and/or liver pathology assessments and used stool samples for IM analysis with 16S ribosomal RNA gene sequencing. Results: Rats in Group Et developed hepatic steatosis and elevated serum transaminases and endotoxin/lipopolysaccharide (LPS) levels but no other liver pathological changes (i.e., necrosis/inflammation) or systemic inflammation. While we did not find any apparent alteration of the intestinal colonic mucosa, we found that rats in Group Et exhibited significant changes in IM composition compared to the rats in Group Ct. These changes were sustained throughout T1, T2, and T3. In particular, Ruminococcus, Coprococcus, and Streptococcus were the differentially abundant microbial genera at T3. The KEGG Ortholog profile revealed that IM functional modules, such as biosynthesis, transport, and export of LPS, were also enriched in Group Et rats at T3. Conclusions: We showed that chronic, voluntary EtOH consumption induced liver injury and endotoxemia together with dysbiotic changes in sP rats. This work sets the stage for improving our knowledge of the prevention and treatment of EtOH-related diseases.

Original languageEnglish
Pages (from-to)2313-2325
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume42
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

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Endotoxemia
Liver
Rats
Alcohols
Wounds and Injuries
Chemical analysis
Lipopolysaccharides
Animals
Ruminococcus
Dysbiosis
16S Ribosomal RNA
Inflammation
RNA Sequence Analysis
Gastrointestinal Microbiome
Biosynthesis
Bottles
Pathology
Intestinal Mucosa
Transaminases
Streptococcus

Keywords

  • Alcohol Use Disorder
  • Biological Markers
  • Blood Endotoxin Level
  • Sardinian Alcohol-Preferring Rats
  • Stool Microbiota

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats. / Posteraro, Brunella; Paroni Sterbini, Francesco; Petito, Valentina; Rocca, Stefano; Cubeddu, Tiziana; Graziani, Cristina; Arena, Vincenzo; Vassallo, Gabriele A.; Mosoni, Carolina; Lopetuso, Loris; Lorrai, Irene; Maccioni, Paola; Masucci, Luca; Martini, Cecilia; Gasbarrini, Antonio; Sanguinetti, Maurizio; Colombo, Giancarlo; Addolorato, Giovanni.

In: Alcoholism: Clinical and Experimental Research, Vol. 42, No. 12, 01.12.2018, p. 2313-2325.

Research output: Contribution to journalArticle

Posteraro, B, Paroni Sterbini, F, Petito, V, Rocca, S, Cubeddu, T, Graziani, C, Arena, V, Vassallo, GA, Mosoni, C, Lopetuso, L, Lorrai, I, Maccioni, P, Masucci, L, Martini, C, Gasbarrini, A, Sanguinetti, M, Colombo, G & Addolorato, G 2018, 'Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats', Alcoholism: Clinical and Experimental Research, vol. 42, no. 12, pp. 2313-2325. https://doi.org/10.1111/acer.13900
Posteraro, Brunella ; Paroni Sterbini, Francesco ; Petito, Valentina ; Rocca, Stefano ; Cubeddu, Tiziana ; Graziani, Cristina ; Arena, Vincenzo ; Vassallo, Gabriele A. ; Mosoni, Carolina ; Lopetuso, Loris ; Lorrai, Irene ; Maccioni, Paola ; Masucci, Luca ; Martini, Cecilia ; Gasbarrini, Antonio ; Sanguinetti, Maurizio ; Colombo, Giancarlo ; Addolorato, Giovanni. / Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats. In: Alcoholism: Clinical and Experimental Research. 2018 ; Vol. 42, No. 12. pp. 2313-2325.
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T1 - Liver Injury, Endotoxemia, and Their Relationship to Intestinal Microbiota Composition in Alcohol-Preferring Rats

AU - Posteraro, Brunella

AU - Paroni Sterbini, Francesco

AU - Petito, Valentina

AU - Rocca, Stefano

AU - Cubeddu, Tiziana

AU - Graziani, Cristina

AU - Arena, Vincenzo

AU - Vassallo, Gabriele A.

AU - Mosoni, Carolina

AU - Lopetuso, Loris

AU - Lorrai, Irene

AU - Maccioni, Paola

AU - Masucci, Luca

AU - Martini, Cecilia

AU - Gasbarrini, Antonio

AU - Sanguinetti, Maurizio

AU - Colombo, Giancarlo

AU - Addolorato, Giovanni

PY - 2018/12/1

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N2 - Background: There is strong evidence that alcoholism leads to dysbiosis in both humans and animals. However, it is unclear how changes in the intestinal microbiota (IM) relate to ethanol (EtOH)-induced disruption of gut–liver homeostasis. We investigated this issue using selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive EtOH consumption. Methods: Independent groups of male adult sP rats were exposed to the standard, home-cage 2-bottle “EtOH (10% v/v) versus water” choice regimen with unlimited access for 24 h/d (Group Et) for 3 (T1), 6 (T2), and 12 (T3) consecutive months. Control groups (Group Ct) were composed of matched-age EtOH-naïve sP rats. We obtained samples from each rat at the end of each experimental time, and we used blood and colon tissues for intestinal barrier integrity and/or liver pathology assessments and used stool samples for IM analysis with 16S ribosomal RNA gene sequencing. Results: Rats in Group Et developed hepatic steatosis and elevated serum transaminases and endotoxin/lipopolysaccharide (LPS) levels but no other liver pathological changes (i.e., necrosis/inflammation) or systemic inflammation. While we did not find any apparent alteration of the intestinal colonic mucosa, we found that rats in Group Et exhibited significant changes in IM composition compared to the rats in Group Ct. These changes were sustained throughout T1, T2, and T3. In particular, Ruminococcus, Coprococcus, and Streptococcus were the differentially abundant microbial genera at T3. The KEGG Ortholog profile revealed that IM functional modules, such as biosynthesis, transport, and export of LPS, were also enriched in Group Et rats at T3. Conclusions: We showed that chronic, voluntary EtOH consumption induced liver injury and endotoxemia together with dysbiotic changes in sP rats. This work sets the stage for improving our knowledge of the prevention and treatment of EtOH-related diseases.

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