Preserving the Gut: Give It What It Wants

Intestinal transplantation is gradually becoming a valid treatment modality for those suffering from intestinal failure. Numerous centers across the globe are developing Intestinal Transplant Programs, and the improvements in surgeon expertise and immune suppression are culminating in improvements in clinical outcomes. The lack of an effective intestinal-specific preservation solution is one key aspect that needs to be addressed to improve the quality of transplanted organs. Historically, the development of preservation solutions for other commonly transplanted organs has focused on an intravascular flush solution that removes blood and cools the tissue to reduce the rate of degenerative processes with little attention to tissue-specific requirements. The most important advance in organ preservation technology has been the advent of the University of Wisconsin (UW, Dupont, WI) solution. Despite the benefit of UW solution for the preservation of other organs (liver and pancreas), maximum storage time for small bowel remains relatively short (6–10 hr); furthermore, graft quality is often compromised. Because of the confines of clinical practice, it is by default that the clinical standard for intestine consists of a vascular flush with UW solution as a part of multivisceral organ procurement. Fortunately, the intestine has an alternate route of access, the lumen. The concept of flushing the intestinal lumen with preservation solution is relatively new (as is the field of intestinal transplantation), likely stemming from potential issues of sepsis and a reluctance to physically manipulate the intestine. Interestingly, when keywords such as intestinal, preservation, transplantation, and luminal were entered into PubMed, there were only 19 “hits,” indicating a remarkable lack of research on this topic. A number of existing preservation solutions have been tested experimentally as an intraluminal flush; these include saline, Ringer's, Eurocollins, UW, Custodiol (Dr. Franz Köhler Chemie GmbH), Celsior (Genzyme), and Polysol (Doorzand Medical Innovations). Some of the components of these solutions include buffers, antioxidants, osmotic agents, glucose, amino acids, and other protective compounds in an attempt to control energetic, osmotic, and oxidative stresses. Of particular relevance to the current study by Mihai et al. entitled “Intestinal Intraluminal Preservation Using Macromolecular Solutions,” sodium concentrations ranged between 10 mM for Custodiol and 135 mM for Polysol (27 mM for UW solution). Comparisons of various combinations of these solutions seem to indicate that order of efficacy is Polysol– Celsior–Custodiol–UW–Ringer's or saline; however, this conclusion is clearly open to interpretation. Although the number of studies in total is small, results from most of these studies (but not all) seem to indicate that a higher sodium concentrations (100 and 135 mM in Celsior and Polysol) result in better preservation. However, other components vary considerably between solutions. The study by Mihai et al. addresses the impact of high (125 mM) versus low (65 mM) sodium in an intraluminal preservation solution (while maintaining approximate Na/K ratios) in a more controlled manner. Although additional components (primarily sulfate and chloride) varied to some degree between the solutions selected, the authors conclude that “low” sodium may reduce preservation injury while ‘high’ sodium may have some detrimental effects. These results at first glance seem to contradict previous studies; however, additional mechanisms are likely at work in the established preservation solutions; it would be interesting to modify Celsior and Polysol to reduce the sodium concentration to 65 mM to determine whether any improvement in outcomes is possible. As the development of an intestinal-specific intraluminal preservation solution progresses, it is likely that provision of greater amounts of amino acids (much greater than provided in the Polysol solution, total amino acid content=11 mM) will play a role in facilitating mucosal protection. With this in mind, the provision of sodium in an intraluminal solution would be a key element, because substrate uptake (glucose and amino acids) across the mucosa is sodium dependent. Whether 65 mM is limiting with respect to substrate transport remains to be determined, but this issue may need to be balanced with the potential negative effects of high sodium presented in the current article by Mihai et al. It is becoming increasingly clear that a strategy of luminal administration of an effective preservation solution has the potential to take advantage of the intestine's well-known ability for preferential substrate uptake through the mucosa and delivery of protective agents directly to the site of injury. The intraluminal provision of protective or trophic agents during storage may be key in “priming” the tissue, so that the return to a healthy, proliferative state is possible after ischemia-reperfusion. The study by Mihai et al. is relevant to our own research interests. Specifically, our laboratory has been focusing on the subject of designing an intraluminal preservation solution (1). Research has lead us to the development of a nutrient-rich preservation solution that is specifically tailored to the physiologic requirements of the intestine. The solution we have developed has evolved from a rudimentary combination of amino acids to a more complex version that includes osmotic agents, buffer, enzyme inhibitors, and antioxidants that facilitate energy production and control of oxidative stress while, at the same time, limiting edema (Table 1). Accumulating evidence suggests that a nutrient-rich luminal flush (delivered immediately after the standard intravascular flush with UW solution) not only reduces toxic elements (enzymes, secretions, and bacteria) but also, more importantly, delivers a trophic stimulus to the mucosal surface.TABLE 1: An intestinal-specific intraluminal preservation solutionTo date, evidence has demonstrated significant protective effects of an intraluminal preservation solution in experimental models of organ preservation (2) (Fig. 1a), ischemia-reperfusion (1, 3, 4), and transplantation (5) (Fig. 1b). Although the improvements in tissue ATP and total adenylates, and a reduction in oxidation end-products can be achieved with this novel strategy, (2, 3, 5) the requirements for intestinal preservation extend beyond that of direct energetic and oxidative concerns (1, 4). Energetic, oxidative, and osmotic stresses have direct consequences on the regulation of fundamental stress or prosurvival-kinase mechanisms that have a major impact on survival, cell recovery, and growth. Of particular relevance is the positive correlation between overall graft quality and a reduction in proinflammatory or proapoptotic mediators afforded by a intraluminal preservation solution. Specifically, the involvement of an upregulation of proliferative mitogen-activated protein kinase (MAPK) signals (extracellular signal-regulated kinase [ERK]) and a concomitant suppression of proapoptotic or proinflammatory signals (JNK/P38/caspase 3) are instrumental in facilitating mucosal protection and the maintenance of graft viability (1, 4). The preservation solution we have been focusing on contains approximately 68 mM Na; the findings of Mihai et al. support the use of this “low” concentration. However, it remains to be seen whether any potential benefits of increasing sodium to facilitate substrate uptake may outweigh the detrimental effects demonstrated by Mihai et al.FIGURE 1.: (a) Graft quality after 12 hr cold storage. (b) Transplantation of rodent grafts after 6 hr storage. Reprinted with permission from Transplantation. Copyright 2003, Lippincott, Williams & Wilkins.In summary, we anticipate that an intestinal-specific intraluminal preservation solution will become the cornerstone for maintaining viability of this unique organ during storage and would encourage other laboratories to contribute their perspective to this understudied field.

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