Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

ATP Binding Cassette Transporter, Subfamily B / genetics Animals Carcinoma, Hepatocellular / complications Disease Models, Animal Dysbiosis / complications Gastrointestinal Microbiome / physiology Inflammation / complications Liver Neoplasms / complications Mice Time ATP-Binding Cassette Sub-Family B Member 4
Cirrhosis Dysbiosis Hepatocarcinogenesis Hepatocellular carcinoma Inflammatory response Intrahepatic inflammation Lipopolysaccharide Mdr2 Microbiome Microbiota

Journal

BMC microbiology
ISSN: 1471-2180
Titre abrégé: BMC Microbiol
Pays: England
ID NLM: 100966981

Informations de publication

Date de publication:
15 04 2021
Historique:
received: 09 12 2020
accepted: 31 03 2021
entrez: 16 4 2021
pubmed: 17 4 2021
medline: 17 11 2021
Statut: epublish

Résumé

Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Sections du résumé

BACKGROUND
Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development.
RESULTS
Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred.
CONCLUSION
In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Identifiants

DOI: 10.1186/s12866-021-02171-9 PMID: 33858327 PMC: PMC8048083
pubmed: 33858327
doi: 10.1186/s12866-021-02171-9
pii: 10.1186/s12866-021-02171-9
pmc: PMC8048083
doi:

Substances chimiques

ATP Binding Cassette Transporter, Subfamily B 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

113

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Auteurs

J Behary (J)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia.

A E Raposo (AE)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

N M L Amorim (NML)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

H Zheng (H)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

L Gong (L)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

E McGovern (E)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

J Chen (J)

Liver Injury and Cancer, Centenary Institute, University of Sydney, Sydney, Australia.

K Liu (K)

Liver Injury and Cancer, Centenary Institute, University of Sydney, Sydney, Australia.
AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.

J Beretov (J)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Department of Anatomical Pathology, St George Hospital, Sydney, Australia.

C Theocharous (C)

Department of Anatomical Pathology, St George Hospital, Sydney, Australia.

M T Jackson (MT)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

J Seet-Lee (J)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.

G W McCaughan (GW)

Liver Injury and Cancer, Centenary Institute, University of Sydney, Sydney, Australia.
AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.

E M El-Omar (EM)

St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia.
Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia.

A Zekry (A)

St George and Sutherland Clinical School, UNSW, Sydney, Australia. a.zekry@unsw.edu.au.
Microbiome Research Centre, St George and Sutherland Clinical School, UNSW, Sydney, Australia. a.zekry@unsw.edu.au.
Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia. a.zekry@unsw.edu.au.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Sous-famille B de transporteurs à cassette liant l'ATP › Defining the temporal evolution of gut...
questionsmedicales.fr › Eucaryotes › Animaux › Defining the temporal evolution of gut...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Defining the temporal evolution of gut...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Defining the temporal evolution of gut...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Dysbiose › Defining the temporal evolution of gut...
questionsmedicales.fr › Environnement et santé publique › Environnement › Écosystème › Biodiversité › Biote › Microbiote › Microbiome gastro-intestinal › Defining the temporal evolution of gut...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Defining the temporal evolution of gut...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Defining the temporal evolution of gut...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Defining the temporal evolution of gut...
questionsmedicales.fr › Phénomènes physiques › Temps › Defining the temporal evolution of gut...