Contribution to the field of intestinal transplantation and ischemia reperfusion injury

Patients with intestinal failure are primarily treated with parenteral nutrition. This treatment can be accompanied by severe potentially life-threatening complications like recurrent line infections, vascular access problems and liver disease. For these patients intestinal transplantation (ITx) represents the only life-saving therapy. However, experience with ITx remains limited since it is still characterized by several medical, surgical, and immunobiological challenges, resulting in limited long-term survival. One of them is the inevitable ischemia reperfusion injury (IRI) of the bowel, that necessarily accompanies ITx, harms the intestinal barrier, leading to translocation and sepsis and compromises acceptance of the intestinal graft. Outside the field of ITx, intestinal IRI is a very frequent pathology with a high mortality. The latter is due to late diagnosis by lack of biomarkers and limited treatment options.

This thesis - based on clinical studies and rodent experiments - aimed to deliver a contribution to both the field of intestinal transplantation as well as the field of intestinal ischemia reperfusion injury.

Part 1: Intestinal Transplantation – Clinical Studies

In the first part we described the current experience with ITx in Belgium and at our center. In particular, we analyzed the long-term results of the Leuven Immunomodulatory Protocol. This experimentally-proven multi-step regimen aims to promote acceptance of the intestinal graft without resorting to classical heavy immunosuppression and its associated side effects. In 13 consecutive patients, the protocol increased 5-year patient survival to 92 percent, kept the risk of rejection low and limited complications like infection, tumor development or renal failure.

Furthermore we contributed three medical aspects to the ITx field: i) enteric hyperoxaluria as novel indication for combined kidney and intestinal transplantation; ii) non-steroidal anti-inflammatory drugs provoke small bowel enteropathy and should be prohibited to ITx recipients; and iii) a systematic review on quality of life after adult intestinal transplantation revealed encouraging results of ITx as a quality of life improving therapy.

Also two innovative surgical strategies were described to facilitate ITx: i) pre-operative arterial embolization safely facilitates exenteration of abdominal organs prior to multivisceral transplantation in case of portomesenteric thrombosis; and ii) subcutaneously placed osmotic self-inflatable tissue expanders safely enlarge the abdominal wall in ITx candidates, facilitating abdominal closure after ITx.

Part 2: Intestinal Ischemia Reperfusion Injury – Experimental Studies

In the second part, we firstly summarized the most recent advances in the pathophysiological mechanisms of IRI during ITx, with special emphasis on the key factors in innate immune activation and how these factors may take part in the process of rejection or graft acceptance. However, the process of intestinal IRI is of course not limited to ITx. Every day, one in a thousand hospital admissions is due to intestinal ischemia which bears an in-hospital mortality up to 80%. To improve survival after intestinal ischemia, there is an urgent need to develop timely diagnostic techniques and effective treatment options to protect the bowel from mucosal barrier damage. In order to study the process of intestinal IRI and find new biomarkers and treatment options, we developed a reproducible and validated rat model of intestinal IRI. Firstly, in this model we revealed that villin-1 - a cytoskeletal protein in the epithelial brush border of the intestine - is a valuable serological biomarker of intestinal IRI. Secondly, we found that activation of the farnesoid X receptor - a natural bile acid receptor in the intestine - improved survival, preserved intestinal integrity, prevented bacterial translocation and limited inflammation.

These findings might not only find an application in the setting of ITx but are promising targets for various conditions associated with acute intestinal ischemia.