Research program / group uitklapper, klik om te openen
The van Mil Group studies the role of bile acids in diseases of the liver and gut. For decades, liver-derived bile acids were believed to solely function as strong detergents essential for the solubilization and absorption of dietary lipids and fat-soluble vitamins. Bile acid accumulation in the liver is detrimental, since in high concentrations bile acids are toxic and lead to end stage liver disease, prominent in patients with mutations in bile acid and phospholipid transporters. We now know that bile acid concentrations are tightly regulated by the farnesoid X receptor (FXR), a nuclear receptor activated by endogenous bile acids. In addition, FXR regulates glucose and fat metabolism, making it an attractive drug target for diabetes, obesity and associated liver disease. Our group has previously shown that FXR activation ameliorates intestinal inflammation (Gadaleta et al, 2011), and therefore, targeting FXR may be beneficial for patients with chronic intestinal inflammation.
Currently, our research builds on these findings. Our main research questions currently are:
- What are the mechanisms by which bile acids and FXR regulates intestinal integrity?
- What are the molecular mechanism by which FXR activates transcription?
- Can we design bile acid derivatives that specifically target the anti-inflammatory function of FXR?
- Bile acids and the microbiome are crucial for intestinal health, how are they related?
We make use of both cellular, organoid and in vivo models to investigate the effects of bile homeostasis and FXR function on gastrointestinal disease. With our clinical and industrial collaborators, we aim to translate these research findings to improve patient care.
- Suzanne van der Veen - technician
- Kristel van Rooijen - technician
- Judith de Jong - PhD student
- Joanna Wolthuis - PhD student (shared with PI Jeroen de Ridder)
- Noortje IJssennagger - post doc
- Stefania Magnusdottir - post doc
Areas of expertise uitklapper, klik om te openen
Saskia is associate professor and received her PhD from the University of Utrecht in 2004, on the topic of genetic disorders of pediatric cholestasis (bile acid homeostasis impairment). She received a Marie Curie fellowship to do a postdoc at Imperial College London with Professors Catherine Williamson and Malcolm Parker to study the role of the bile salt sensor farnesoid X receptor in intrahepatic cholestasis of pregnancy. In 2007, she was awarded a competitive NWO-VENI grant and she started as a junior group leader at UMC Utrecht to follow up on her previous research on the roles of bile acids in liver and intestinal disease. Her group uncovered that activation of the bile acid sensor FXR leads to inhibition of intestinal inflammation in different mouse models. With the NWO-VIDI grant, she now studies the molecular mechanisms by which FXR regulates transcription of metabolic and anti-inflammatory genes. Following up from these findings, she is now the project coordinator of the EU FP7-funded FXR-IBD consortium, in which her group, together with the group of Dr Bas Oldenburg (UMCU), TES Pharma (Perugia, Italy) and Enterome Bioscience (Paris, France), aims to develop novel diagnostic and therapeutic approaches for IBD patients (www.fxr-ibd.eu).
More contact information uitklapper, klik om te openen
3584 CG Utrecht
Detailed CV uitklapper, klik om te openen
Key publications uitklapper, klik om te openen
- Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice.
Massafra V, Milona A, Vos HR, Ramos RJJ, Gerrits J, Willemsen ECL, Ramos Pittol JM, Ijssennagger N, Houweling M, Prinsen HCMT, Verhoeven-Duif NM, Burgering BMT, van Mil SWC. Gastroenterology. 2017 May;152(6):1462-1476.e10. doi: 10.1053/j.gastro.2017.01.014.
- Ijssennagger, N, Belzer, C, Hooiveld, GJ, Dekker, J, van Mil, SWC, Müller, M, Kleerebezem, M, van der Meer, R & van Mil, SWC 2015, 'Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon' Proceedings of the National Academy of Sciences of the United States of America, vol 112, no. 32, pp. 10038-43.
- Ijssennagger N, Janssen AW, Milona A, Ramos Pittol JM, Hollman DA, Mokry M, Betzel B, Berends FJ, Janssen IM, van Mil SW, Kersten S. J Hepatol. 2016 May;64(5):1158-66. doi: 10.1016/j.jhep.2016.01.016.
- Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
- Bijsmans, ITGW, Guercini, C, Ramos Pittol, JM, Omta, W, Milona, A, Lelieveld, D, Egan, DA, Pellicciari, R, Gioiello, A, van Mil, SWC & van Mil, SWC 2015, 'The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression' Scientific Reports, vol 5, pp.14086., 10.1038/srep14086
- Gadaleta, RM, van Erpecum, KJ, Oldenburg, B, Willemsen, ECL, Renooij, W, Murzilli, S, Klomp, LWJ, Siersema, PD, Schipper, MEI, Danese, S, Penna, G, Laverny, G, Adorini, L, Moschetta, A & van Mil, SWC 2011, 'Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease.' Gut, vol 60, no. 4, pp. 463-472.
- Milona, A, Owen, BM, Cobbold, JF, Willemsen, ECL, Cox, IJ, Boudjelal, M, Cairns, W, Schoonjans, K, Taylor-Robinson, SD, Klomp, LWJ, Parker, MG, White, R, van Mil, SWC & Williamson, C 2010, 'Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function' Hepatology, vol 52, no. 4, pp. 1341-1349.
- van Mil, SWC, Milona, A, Dixon, PH, Mullenbach, R, Geenes, VL, Chambers, J, Shevchuk, V, Moore, GE, Lammert, F, Glantz, AG, Mattsson, LA, Whittaker, J, Parker, MG, White, R & Williamson, C 2007, 'Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology, vol 133, no. 2, pp. 507-516. (IF=16.7, 116 citations)