Development of non-alcoholic steatohepatitis is associated with gut microbiota but not with oxysterol enzymes CH25H, EBI2, or CYP7B1 in mice

Jacqueline Wyss; Tina Raselli; Annika Wyss; Anja Telzerow; Gerhard Rogler; Niklas Krupka; Bahtiyar Yilmaz; Thomas S B Schmidt; Benjamin Misselwitz

doi:10.1186/s12866-024-03195-7

Development of non-alcoholic steatohepatitis is associated with gut microbiota but not with oxysterol enzymes CH25H, EBI2, or CYP7B1 in mice

BMC Microbiol. 2024 Feb 28;24(1):69. doi: 10.1186/s12866-024-03195-7.

Authors

Jacqueline Wyss^#¹, Tina Raselli^#², Annika Wyss², Anja Telzerow³, Gerhard Rogler², Niklas Krupka¹, Bahtiyar Yilmaz^{1

4}, Thomas S B Schmidt^#⁵, Benjamin Misselwitz^#^{1

2}

Affiliations

¹ Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
³ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
⁴ Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, 3008, Bern, Switzerland.
⁵ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany. sebastian.schmidt@embl.de.

^# Contributed equally.

Abstract

Liver steatosis is the most frequent liver disorder and its advanced stage, non-alcoholic steatohepatitis (NASH), will soon become the main reason for liver fibrosis and cirrhosis. The "multiple hits hypothesis" suggests that progression from simple steatosis to NASH is triggered by multiple factors including the gut microbiota composition. The Epstein Barr virus induced gene 2 (EBI2) is a receptor for the oxysterol 7a, 25-dihydroxycholesterol synthesized by the enzymes CH25H and CYP7B1. EBI2 and its ligand control activation of immune cells in secondary lymphoid organs and the gut. Here we show a concurrent study of the microbial dysregulation and perturbation of the EBI2 axis in a mice model of NASH.We used mice with wildtype, or littermates with CH25H^-/-, EBI2^-/-, or CYP7B1^-/- genotypes fed with a high-fat diet (HFD) containing high amounts of fat, cholesterol, and fructose for 20 weeks to induce liver steatosis and NASH. Fecal and small intestinal microbiota samples were collected, and microbiota signatures were compared according to genotype and NASH disease state.We found pronounced differences in microbiota composition of mice with HFD developing NASH compared to mice did not developing NASH. In mice with NASH, we identified significantly increased 33 taxa mainly belonging to the Clostridiales order and/ or the family, and significantly decreased 17 taxa. Using an Elastic Net algorithm, we suggest a microbiota signature that predicts NASH in animals with a HFD from the microbiota composition with moderate accuracy (area under the receiver operator characteristics curve = 0.64). In contrast, no microbiota differences regarding the studied genotypes (wildtype vs knock-out CH25H^-/-, EBI2^-/-, or CYP7B1^-/-) were observed.In conclusion, our data confirm previous studies identifying the intestinal microbiota composition as a relevant marker for NASH pathogenesis. Further, no link of the EBI2 - oxysterol axis to the intestinal microbiota was detectable in the current study.

Keywords: EBI2; Microbiota; NASH; Oxysterol; Steatosis.

MeSH terms

Animals
Diet, High-Fat / adverse effects
Disease Models, Animal
Epstein-Barr Virus Infections* / pathology
Gastrointestinal Microbiome*
Herpesvirus 4, Human
Liver / pathology
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / pathology
Oxysterols*

Substances

Oxysterols

Grants and funding

Grant 32473B_156525/SNSF_/Swiss National Science Foundation/Switzerland