The Role of Antimicrobial Peptides in Primary Sclerosing Cholangitis

• Applicant: Dr. Igor Spivak
• Subject Area: Gastroenterology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445667004

• Final Report Year: 2023

Final Report Abstract

Portal Hypertension (PHT) arises from increased pressure in venous vessels connecting the gastro-intestinal tract with the liver. Most implicated in advanced liver disease and cirrhosis, it can also develop in non-cirrhotic patients, such as in non-alcoholic steatohepatitis (NASH), where the development of PHT could precede fibrosis/cirrhosis. Although evidence exists for an impact of the microbiome on PHT from studies in humans and animals, it remains unclear whether the microbiome has a direct influence on PHT, or the alterations embody epiphenomena of advanced liver disease. Moreover, specific microbes affecting PHT development and severity, and the underlying mechanisms remain unknown. In a model of non-cirrhotic PHT, which allows to minimize side-effects of advanced liver disease and triggering noxious substances, we were able to show that the microbiome is crucial for an increase of pressure upon partial portal venous ligation (PPVL). A restitution of the microbiome upon PPVL through fecal transfer could trigger a surge in portal pressure in animals compared to those protected through the depletion of the microbiome. Subsequently, we analyzed factors through which the microbiome could exert an influence on the host organ systems within the course of PHT. A metabolomic analysis of portal blood identified products that were enriched in a microbiomedependent matter upon the induction of PHT. Discovering cells within the mesentery and their transcriptomic landscape through single cell RNA sequencing (scRNA-seq), we could shed light on populations in which the impact of the microbiome within the course of PHT triggers patterns of gene expression associated with angiogenesis and collagen-production. This insight and a deeper understanding of underlying mechanisms of PHT dependent on the microbiome from our ongoing investigations will be used to define novel potential therapeutic targets.

Publications

• Local and systemic effects of microbiome‐derived metabolites. EMBO reports, 23(10).
  Spivak, Igor; Fluhr, Leviel & Elinav, Eran
  
• Risk factors for non-alcoholic fatty liver disease delineate the battlegrounds in optimizing disease prevention. Hepatobiliary Surgery and Nutrition, 11(3), 492-494.
  Spivak, Igor & Elinav, Eran
  
• Gastrointestinal microbiome: Evaluation of testing technologies. Esophageal Disease and the Role of the Microbiome, 147-161. Elsevier.
  Spivak, Igor & Elinav, Eran
  
• Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes. Nature, 624(7992), 645-652.
  Nobs, Samuel Philip; Kolodziejczyk, Aleksandra A.; Adler, Lital; Horesh, Nir; Botscharnikow, Christine; Herzog, Ella; Mohapatra, Gayatree; Hejndorf, Sophia; Hodgetts, Ryan-James; Spivak, Igor; Schorr, Lena; Fluhr, Leviel; Kviatcovsky, Denise; Zacharia, Anish; Njuki, Suzanne; Barasch, Dinorah; Stettner, Noa; Dori-Bachash, Mally; Harmelin, Alon ... & Elinav, Eran