eprintid: 34638 rev_number: 23 eprint_status: archive userid: 5207 dir: disk0/00/03/46/38 datestamp: 2024-03-28 08:09:44 lastmod: 2024-03-28 08:10:01 status_changed: 2024-03-28 08:09:44 type: doctoralThesis metadata_visibility: show creators_name: Schühle, Svenja title: Deciphering the role of the gut microbiota in murine MASH and MASH-to-HCC transition subjects: ddc-500 divisions: i-140001 divisions: i-850300 adv_faculty: af-14 cterms_swd: Immunologie cterms_swd: Krebs cterms_swd: Metabolismus abstract: Having reached an epidemic magnitude, obesity has experienced a drastic increase in prevalence over the past decades. Together with obesity, associated pathologies, including metabolic syndrome, became more common, which further increase the risk of long-term complications. As such, chronic manifestation of these conditions frequently leads to metabolic dysfunction-associated steatohepatitis (MASH). MASH has gained significantly in importance due to the lack of treatment options and the progression towards fibrosis and hepatocellular carcinoma (HCC), making it the fastest-growing cause of primary liver cancer. The intestinal microbiota is known to be influenced by a variety of metabolic diseases and to actively contribute to inflammatory events. Indications for a role of the microbiota in chronic liver diseases exist, but if and how intestinal bacteria drive the progression of MASH towards HCC remains uncertain. To investigate the role of the microbiota in choline-deficient high fat diet (CD-HFD)-induced MASH and HCC I depleted intestinal bacteria using a broad-spectrum antibiotics (ABx) cocktail. To decipher the effect of microbiota depletion on different stages of pathogenesis, I performed ABx treatment either prophylactically or therapeutically after disease onset. I analyzed the effect of microbiota depletion on MASH and HCC pathogenesis by characterizing immunological, transcriptional and metabolic signatures in the mice. To evaluate the effects of CD-HFD feeding and the ABx treatment on intestinal bacteria, I determined the microbiota composition by shotgun metagenomic sequencing. My data confirmed that the CD-HFD MASH model can recapitulate previously described mechanisms involving the gut-liver axis and that ABx-mediated microbiota depletion reduces MASH development. Moreover, I was able to show that ABx treatment limits MASH-to-HCC transition in CD-HFD mice by preventing fibrosis development, which resulted in a lower liver tumor incidence. In addition, prophylactic ABx treatment modified certain tumor characteristics, which were possibly linked to an increased tumor size observed in these mice. Therapeutic ABx treatment reversed this effect, indicating an ambivalent role of microbial presence at different stages of the pathogenesis. Furthermore, I found diminished IgA-dependent activation of FCGR1-expressing myeloid cells as the likely cause of ABx-mediated reduced fibrogenesis, which was presumably supported by a variety of metabolic and transcriptional changes upon ABx treatment with additional beneficial effects on MASH-to-HCC transition. Although further research is needed to understand the spectrum of underlying mechanisms, my study confirms the detrimental contributions of intestinal bacteria to the MASH-to-HCC transition and suggests an ambivalent role of bacteria depending on the disease stage. date: 2025 id_scheme: DOI id_number: 10.11588/heidok.00034638 own_urn: urn:nbn:de:bsz:16-heidok-346385 date_accepted: 2024-03-14 advisor: HASH(0x55fc36cacf30) language: eng bibsort: SCHUHLESVEDECIPHERIN20240326 full_text_status: restricted place_of_pub: Heidelberg citation: Schühle, Svenja (2025) Deciphering the role of the gut microbiota in murine MASH and MASH-to-HCC transition. [Dissertation] document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/34638/1/2024-03%20Thesis%20Svenja%20-%20FINAL.pdf