Department of Gastroenterology & Hepatology

Novel Therapies For Cystic Fibrosis, Diarrheal Diseases And Pancreatitis

Our lab aims to develop drug-based therapies for diseases associated with impaired gastrointestinal electrolyte transport, using epithelial organoids as a model.

Pharmacological repair of CFTR function in cystic fibrosis

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF gene, which encodes a tightly regulated epithelial chloride and bicarbonate channel, CFTR. Novel modulator drugs that improve mutant CFTR function have transformed treatment of CF, but not all people with CF have benefited. We aim to increase our knowledge of CFTR-dependent anion secretion, in the hope that a better understanding of its role in the pathophysiology of the disease may ultimately improve pharmacological treatment of people with CF. Further, we aim to correct luminal dehydration and to prevent luminal obstruction in CF through stimulation of alternative pro-secretory or anti-absorptive pathways.

CFTR dysfunction in pancreatitis

Pancreatitis is a common, progressive inflammatory disease with a high mortality rate and with no specific therapy currently available. CFTR dysfunction contributes to the pathophysiology of both genetic and acquired forms of pancreatitis. In the pancreas, CFTR is expressed exclusively in the ductal epithelial cells, and is crucial for the formation of a bicarbonate-rich secretion. Our aim is to further elucidate the molecular mechanisms involved in the disruption of CFTR function in pancreatitis and to develop new therapies based on pharmacological restoration of CFTR function.

Novel therapies for diarrheal diseases

The aim of this project is to identify novel small molecule compounds that can be developed into drugs for the treatment of infectious diarrhea, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). Exogenous, microbial products, as well as endogenous signaling molecules and inflammation mediators can severely dysregulate intestinal electrolyte and fluid homeostasis. This project investigates the disease mechanism of diarrhea, and explores new therapeutic options, including protein kinase-, guanylyl cyclase- and ion channel modulators identified in high-throughput screens.

Key publications

  1. Groeneweg TA, Baigal E, Leung A, Kremers GJ, Bijvelds MJC. Krisanaklan reduces intestinal anion and fluid secretion through inhibition of Na+/K+-ATPase and K+ channel activity. Ann N Y Acad Sci. 2026;1556:e70152.
  2. Li P, Wang X, Zhou J, Yao Y, Wang Y, …, Bijvelds MJC, Pan Q. Primary human intestinal organoids model enteric infection of monkeypox virus and enable scalable drug discovery. Sci Adv. 2026;12:eaea8280.
  3. Angyal D, Groeneweg TA, Leung A, Desain M, Dulla K, de Jonge HR, Bijvelds MJC. Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium. Cell Mol Biol Lett. 2024;29:18.
  4. Bijvelds MJC, Roos FJM, Meijsen KF, Roest HP, Verstegen MMA, et al. Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers. J Cyst Fibros. 2022;21:537-43.
  5. Ikpa PT, Meijsen KF, Nieuwenhuijze NDA, Dulla K, De Jonge HR, Bijvelds MJC. Transcriptome analysis of the distal small intestine of Cftr null mice. Genomics. 2020;112:1139-50.
  6. Ikpa PT, Doktorova M, Meijsen KF, Nieuwenhuijze NDA, Verkade HJ, Jonker JW, De Jonge HR, Bijvelds MJC. Impaired intestinal farnesoid X receptor signaling in cystic fibrosis mice. Cell Mol Gastroenterol Hepatol. 2020;9:47-60.
  7. De Jonge HR, Ardelean MC, Bijvelds MJC, Vergani P. Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas. FEBS Lett. 2020;594:4085-108.
  8. Bijvelds MJC, Tresadern G, Hellemans A, Smans K, Nieuwenhuijze NDA, et al. Selective inhibition of intestinal guanosine 3',5'-cyclic monophosphate signaling by small-molecule protein kinase inhibitors. J Biol Chem. 2018;293:8173-81.
  9. Bijvelds MJC, Loos M, Bronsveld I, Hellemans A, Bongartz JP, Ver Donck L, et al. Inhibition of heat-stable toxin-induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. J Infect Dis. 2015;212:1806-15.
  10. Dekkers JF, Wiegerinck CL, De Jonge HR, Bronsveld I, Janssens HM, De Winter-de Groot KM, Brandsma AM, De Jong NW, Bijvelds MJC. et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013;19:939-45.
  11. Bijvelds MJC, de Jonge HR, Verkade HJ. Bile acid handling in cystic fibrosis: marked phenotypic differences between mouse models. Gastroenterology. 2012;143:e19-20.
  12. Bijvelds MJC, Bot AG, Escher JC, De Jonge HR. Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology. 2009;137:976-85.

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