- Dr Kaatje Lenaerts, Principal Investigator
- Prof. Jacques Pirenne, Co-Investigator
- Dr Steven Olde Damink, Co-Investigator
- Prof. Cornelis Dejong, Co-Investigator
- Dr Darius Mirza, Collaborator
- Dr Francisca Joly, Collaborator
- Dr Joep Grootjans, Collaborator
- Maastricht University Medical Centre, Maastricht, The Netherlands
- Impact of Small Bowel Transplantation on the Intestinal Immunological Barrier
Preparation of a donor small bowel for transplantation entails a temporarily interruption of the blood flow to this organ. The intestine is very sensitive to this shortage of blood supply and, in particular, to restoration of the blood flow after transplantation. This so-called ischemia-reperfusion damage makes the donor intestine more vulnerable for rejection by the recipient. Rejection is the most common and life-threatening complication after intestinal transplantation (ITx), and has a high incidence.
Efforts to understand the underlying mechanisms of intestinal ischemia-reperfusion-induced damage in humans revealed that Paneth cells, important gatekeepers of the intestinal barrier, are lost during this event, and endoplasmic reticulum stress was identified as a key pathophysiologic mechanism. Furthermore, preliminary data of a pilot study in intestinal biopsies from ITx patients show diminished presence of an antimicrobial protein produced by these Paneth cells in the first days after transplantation and during rejection, indicating impaired Paneth cell function. Paneth cells play a crucial role in preventing bacterial translocation and are essential regulators of the intestinal microbiota composition, both determinants of intestinal homeostasis.
We will first study Paneth cell loss and endoplasmic reticulum stress in intestinal biopsies obtained from patients at regular intervals after ITx in a multicenter cohort study. Furthermore, we will study fecal and ileal microbiota composition in samples collected at the same time points. We hope to establish a relationshipbetween Paneth cell loss/antimicrobial impairment and the diversity of the bacterial communities before and after ITx, and link this to the occurrence of acute rejection. Furthermore, we will invest in searching and validating new markers for acute rejection.
In conclusion, we expect that the results of this translational research project will increase insight into the role of the Paneth cells in the pathology of ITx-related complications, and its relation to microbiota alterations, which will offer potential targets for therapy. In addition, new biomarkers for acute rejection during ITx will help diagnosis and guidance of treatment success.