- Author
-
F.F. van den Berg
- Title
- A translational approach to severe acute pancreatitis
- Supervisors
-
M.A. Boermeester
J.C. Alverdy - Co-supervisors
-
H.C. van Santvoort
Y. Issa - Award date
- 28 May 2021
- Number of pages
- 250
- ISBN
- 9789464232417
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Despite decades of research, it is still unclear why some patients with acute pancreatitis develop severe, life-threatening complications while others resolve uneventful. There are still significant knowledge barriers that prevent the successful translation of early animal studies to large-scale clinical trials. This thesis has mainly aimed to identify disease modifiers that can be targeted to prevent clinical deterioration. We hypothesized that the individual’s genetic background and the composition and function of its gut microbiota are major contributors for severe complications such as persistent (multiple) organ failure and secondary infections.
Through a comprehensive systematic review of the literature, we were able to identify credible associations between laboratory and genetic markers, and the risk and severity of acute pancreatitis. In addition, using a large cohort of patients we identified novel genetic associations in the genes ZNF106 and SLC52A1 with (early) multiple organ failure in acute pancreatitis. Finally, we were able to demonstrate that manipulation of the gut microbiota through western-type diet feeding impacted infections and mortality in animal models of necrotizing pancreatitis and postoperative abdominal sepsis. More importantly, we observed that this lethal phenotype was reversed by oral prophylactic butyrate supplementation in mice with necrotizing pancreatitis.
While these results may be used to direct future translational studies and clinical trials, we must appreciate the complexity of the interplay between host and microbial factors that underlie these severe conditions. A deep sequential analysis of these factors using advanced techniques (i.e., metagenomics, metabolomics, [epi-]genomics, transcriptomics, single-cell sequencing), clinically relevant (animal) models and large well-described patient cohorts may provide us with a more detailed understanding. - Persistent Identifier
- https://hdl.handle.net/11245.1/5f05f116-bc30-40be-847c-0c4a766051da
- Downloads
-
Thesis (complete)
Front matter
Introduction and thesis outline
Chapter 1: The management of gall stone pancreatitis
Chapter 2: Early laboratory biomarkers for severity in acute pancreatitis: A systematic review and meta-analysis
Chapter 3: Meta-analysis and field synopsis of genetic variants associated with the risk and severity of acute pancreatitis
Chapter 4: Whole-exome sequencing identifies SLC52A1 and ZNF106 variants as novel genetic risk factors for (early) multiple-organ failure in acute pancreatitis
Chapter 5: Western-type diet influences mortality from necrotizing pancreatitis and demonstrates a central role for butyrate
Chapter 6: Spatio-regional assessment of the gut microbiota in experimental necrotizing pancreatitis
Chapter 7: Prospective study for profiling of the gut microbiota in patients with severe acute pancreatitis: The POEMA study protocol
Chapter 8: Mice fed an obesogenic western diet, administered antibiotics, and subjected to a sterile surgical procedure develop lethal septicemia with multidrug-resistant pathobionts
Chapter 9: Summary
Chapter 10: Conclusions and future perspectives
Chapter 11: Nederlandse samenvatting
List of publications; List of authors; PhD portfolio; Acknowledgments/Dankwoord; About the author
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