Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns.

Juanola, Oriol; Hassan, Mohsin; Kumar, Pavitra; Yilmaz, Bahtiyar; Keller, Irene; Simillion, Cedric; Engelmann, Cornelius; Tacke, Frank; Dufour, Jean-François; De Gottardi, Andrea; Moghadamrad, Sheida (2021). Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns. Gut microbes, 13(1), pp. 1-20. Taylor & Francis Group 10.1080/19490976.2021.1911534

[img]
Preview
Text
KGMI_13_1911534.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (4MB) | Preview

Intestinal microbiota regulates multiple host metabolic and immunological processes. Consequently, any difference in its qualitative and quantitative composition is susceptible to exert significant effects, in particular along the gut-liver axis. Indeed, recent findings suggest that such changes modulate the severity and the evolution of a wide spectrum of hepatobiliary disorders. However, the mechanisms linking intestinal microbiota and the pathogenesis of liver disease remain largely unknown. In this work, we investigated how a distinct composition of the intestinal microbiota, in comparison with germ-free conditions, may lead to different outcomes in an experimental model of acute cholestasis. Acute cholestasis was induced in germ-free (GF) and altered Schaedler's flora (ASF) colonized mice by common bile duct ligation (BDL). Studies were performed 5 days after BDL and hepatic histology, gene expression, inflammation, lipids metabolism, and mitochondrial functioning were evaluated in normal and cholestatic mice. Differences in plasma concentration of bile acids (BA) were evaluated by UHPLC-HRMS. The absence of intestinal microbiota was associated with significant aggravation of hepatic bile infarcts after BDL. At baseline, we found the absence of gut microbiota induced altered expression of genes involved in the metabolism of fatty and amino acids. In contrast, acute cholestasis induced altered expression of genes associated with extracellular matrix, cell cycle, autophagy, activation of MAPK, inflammation, metabolism of lipids, and mitochondrial functioning pathways. Ductular reactions, cell proliferation, deposition of collagen 1 and autophagy were increased in the presence of microbiota after BDL whereas GF mice were more susceptible to hepatic inflammation as evidenced by increased gene expression levels of osteopontin, interleukin (IL)-1β and activation of the ERK/MAPK pathway as compared to ASF colonized mice. Additonally, we found that the presence of microbiota provided partial protection to the mitochondrial functioning and impairment in the fatty acid metabolism after BDL. The concentration of the majority of BA markedly increased after BDL in both groups without remarkable differences according to the hygiene status of the mice. In conclusion, acute cholestasis induced more severe liver injury in GF mice compared to mice with limited intestinal bacterial colonization. This protective effect was associated with different hepatic gene expression profiles mostly related to tissue repair, metabolic and immune functions. Our findings suggest that microbial-induced differences may impact the course of cholestasis and modulate liver injury, offering a background for novel therapies based on the modulation of the intestinal microbiota.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Kumar, Pavitra; Yilmaz, Bahtiyar; Keller, Irene; Simillion, Cedric André Marie; Dufour, Jean-François; De Gottardi, Andrea and Moghadamrad, Sheida

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1949-0984

Publisher:

Taylor & Francis Group

Language:

English

Submitter:

Rahel Fuhrer

Date Deposited:

06 Jul 2021 14:00

Last Modified:

06 Jul 2021 14:00

Publisher DOI:

10.1080/19490976.2021.1911534

PubMed ID:

33847205

Uncontrolled Keywords:

Intestinal microbiota acute cholestasis bile acids gene expression germ-free mice metabolism

BORIS DOI:

10.48350/157371

URI:

https://boris.unibe.ch/id/eprint/157371

Actions (login required)

Edit item Edit item
Provide Feedback