Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Safari, Z.
Role of the relationships between genetic background, diet and microbiome in susceptibility to liver steatosis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 141
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Moissl-Eichinger Christine
- Zatloukal Kurt
- Altmetrics:
- Abstract:
- Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to more progressive steatosis. Gut microbiota is normally involved in the intestinal energy harvest and its role has been increasingly established in the pathogenesis of obesity and NAFLD. Therefore, the intestinal microbiota populations are potential therapeutic targets in the management of NAFLD. NAFLD results from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, firstly, we utilized two commonly used inbred strains of mice, NAFLD-prone C57Bl/6J and NAFLD-resistant A/J mice as well as four derivative lines generated by crossing. These strains harbour one specific chromosome from A/J in a C57Bl/6J genetic background and are termed as Chromosome Substituted Strains (CSSs). In the first part of this project, analysis of metabolic parameters and gut microbiota in the founder strains, as well as the selected CSS strains, revealed some interactions between diet, liver phenotype and metabolic parameters. The microbiome composition was different between CSSs and the founder strains, although the CSSs had all C57Bl/6J genetic background. We also observed Verrucomicrobiaceae (a bacterium associated with metabolic health) in A/J and all the CSSs harbouring one chromosome from A/J regardless of their liver phenotype. We did not observe a strong link between the microbiome and metabolic parameters concerning the severity of steatosis in these CSSs. Based on these findings we conclude that the genetic effect is stronger than the effect of diet or microbiome in controlling the disease phenotype. In the second part, we found that 8 weeks of High Fat Diet (HFD) treatment induced marked liver steatosis in mice together with a perturbed microbiome. Interestingly, only 7 days of chow diet was enough to recover the liver to a normal status while the microbiome was accordingly reshaped to a close to initial pattern. The abundance of some of the bacteria including Prevotella, Parabacteroides, Lactobacillus, Allobaculum was reversible upon diet change from HFD to CD. The HFD caused fat deposition (steatosis) in the liver which correlated with the gut microbiome changes. This correlation suggests that microbiome modifications contribute to the metabolic effects of HFD feeding and that restoration of a normal microbiota may lead to improvement of the liver phenotype. In the third part, we observed that A/J and C57Bl/6J mice have different microbiome structure and composition. We further demonstrated that for some metabolic parameters as well as some bacterial species A/J and C57Bl/6J respond differently to HFD and antibiotic treatments. We also performed microbiota exchange between A/J and C57Bl/6J mice strains. The donor gut microbiota from one strain was introduced, established, and changed the gut microbiota of the recipients from the other strain. The differences in the microbiome of A/J and C57Bl/6J under different treatments did not correlated with their different phenotypes as microbiome exchange by faecal microbiome transplantation did not lead to clear phenotypical changes in these two strains. This suggests that the effect of genetics on liver phenotype is stronger than the one from the gut microbiome. Conclusion: We found different microbiome composition in genetically different mice with different susceptibilities to steatosis including CSSs as well as in their founder strains i.e. C57Bl/6J and A/J. We also found that HFD changes microbiota and trigger steatosis and diet switching from HFD to chow in only 7 days can reverse both hepatosteatosis and gut microbiota composition. We conclude that microbiota changes can contribute to diet effects as its changes correlated with phenotype. Altogether, these findings show that microbiome, genetics and diet interact with each other in different levels and influence NAFLD development or aggravation.