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. Author manuscript; available in PMC: 2025 May 1.
Published in final edited form as: Pediatr Transplant. 2024 May;28(3):e14756. doi: 10.1111/petr.14756

From Intestinal Failure to Transplantation: review on the current need for transplant indications under multidisciplinary transplant programs worldwide

Vikram K Raghu 1, Carolina Rumbo 2, Simon P Horslen 1
PMCID: PMC11115375  NIHMSID: NIHMS1983771  PMID: 38623905

Abstract

Children with intestinal failure face many challenging decisions, such as when to move forward with intestine transplant. In the most recent era, intestine transplant frequency continues to decline. Newer treatment options including hormonal therapies that stimulate intestinal adaptation have allowed for more children to extend their rehabilitation. More children may achieve enteral autonomy, but many children still develop complications that require intestine transplant. In this review, we explore the history of intestinal rehabilitation and intestine transplant, summarize the current state of intestinal rehabilitation, describe the role of intestine transplant within the framework of intestinal rehabilitation, and hypothesize the future directions of the field.

Introduction

Intestinal failure results from loss of intestinal mass or function to the point where adequate nutrition cannot be maintained.1 Most commonly, this occurs from short bowel syndrome due to a variety of causes necessitating surgical removal of a portion of intestine.2 Alternatively, functional deficits of the intestine such as abnormal motility or absorption may result in intestinal failure. By definition, children with intestinal failure require parenteral nutrition to support their growth and development.1

The natural history of intestinal failure largely depends on etiology (Figure 1). Those with short bowel syndrome may experience adaptation of the remaining bowel over time and eventual resolution of their intestinal failure. For a portion of children with short bowel syndrome, the adaptation of the remaining bowel is insufficient to reach enteral autonomy, the state of no longer requiring parenteral support. For those with abnormal motility or intrinsic malabsorptive processes, there may not be a path to enteral autonomy through medical means.

Figure 1.

Figure 1.

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Etiologies of intestinal failure

Intestine transplants interrupt the natural history of intestinal failure and allow children to achieve enteral autonomy. In this review, we will explore the history of intestinal failure and transplant, delineate the indications for intestine transplant, and analyze how advances in the field have reframed the approach to intestine transplant decisions.

History of parenteral nutrition

Interest in providing alternative means of nutrition dates back centuries. In the late 1800s, the first such non-enteral support was provided to a man with Pott’s disease using subcutaneous fat injections.3 Over the following centuries, the technique of providing such nutrition evolved from subcutaneous means to intravenous routes. In the 1950s, the first intravenous fat emulsions received approval for use but were quickly removed from the market.4,5 It was in 1967 that Stanely Dudrick first successfully provided total parental nutrition to an infant who could not receive any enteral support. That child survived for 22 months and became the first example of the potential for providing long-term alternative nutrition.6

As the technique of providing complete parenteral nutrition evolved, the major limitation became the necessity to keep these patients in the hospital to provide such support. Almost as soon as parenteral nutrition long-term efficacy became established, efforts began to provide parenteral nutrition at home. In the early 1970s, an artificial gut apparatus allowed patients to be discharged from the hospital.7,8 The first long-term home parenteral nutrition patient was discharged from the University of Toronto using this artificial gut system with a compressed air delivery mechanism that allowed for overnight infusion of complete parenteral nutrition.9 She ultimately survived at home for over 20 years with careful monitoring of electrolytes and nutrients.10

Through the work of these early pioneers, it became clear that home parenteral nutrition required careful coordination from an expert team. Multidisciplinary home parenteral nutrition teams formed to manage this care both in the United States and Europe.10 Home parenteral nutrition provided a means to allow patients with intestinal failure to leave the hospital, but it was not a cure.

History of intestine transplant

Even before the advent of parenteral nutrition, intestine transplant began to receive consideration as a potential definitive cure for intestinal failure. In the late 1950s, the first intestine transplant was performed in dogs.11 However, it took nearly 30 years until the first successful human intestine transplant were performed.12–15 Much of the progress of intestine transplant, like other solid organ transplants, hinged on the development of appropriate immunosuppression. For the early years of intestine transplant, success was predicated on the appropriate use of cyclosporine.16 Then, in the early 1990s, tacrolimus became the mainstay of maintenance immunosuppression across forms of solid organ transplant.17–19 By the early 2000s, intestine transplant established itself as the treatment for complicated intestinal failure. Figure 2 details the timeline of events in the development of parenteral nutrition, intestinal rehabilitation, and intestine transplant.

Figure 2.

Figure 2.

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Timeline of milestones in the advancement of intestinal rehabilitation and transplantation.

Indications for intestine transplant

By 2001, the role of intestine transplant to treat intestinal failure had been well-established. However, clear guidelines were lacking regarding the appropriate indications for intestine transplant. The American Society for Transplantation established guidelines regarding appropriate indications in adults and pediatrics.20 They named three categories of patients that should be considered for intestine transplant: those with complications of intestinal failure, those with low likelihood of survival, and those with substantially reduced quality of life. Complications of intestinal failure included severe liver disease, recurring sepsis, and impending loss of vascular access. Those with low likelihood of survival included those with extremely short bowel syndrome, which was described as <10 cm of small bowel distal to the ligament of Treitz with no ileocecal valve, as well as enterocyte defects such as microvillus inclusion disease and tufting enteropathy. The final category of quality of life was described as those with such high output that fluid needs were challenging to manage as well as those with pseudo-obstruction who had recurrent dilation and pain.

In April 2001, the Center for Medicare and Medicaid Services (CMS) approved their first document outlining indications for intestine transplant, which was subsequently revised in 2006.21 In this document, intestine transplant is indicated for those who “failed total parenteral nutrition.” They specifically define failure as biochemical, clinical, histologic evidence of liver failure; thrombosis of at least two or more great vessels; two sepsis episodes requiring hospitalization or a single episode of fungemia, septic shock, or acute respiratory distress syndrome; or frequent episodes of severe dehydration. By providing the indications that would be covered by public health insurance, CMS essentially established US criteria for determining intestine transplant eligibility.

Through advances in parenteral nutrition management and mitigation of complications, the landscape of intestine transplant has changed. Thus, in 2019, a new consensus panel revisited the existing intestine transplant indications.22 In the document generated by the working group of transplant experts, the original indications underwent considerable scrutiny to determine whether adjustments were appropriate. In particular, the group called into question whether loss of 2 access sites as well as recurrent sepsis without life-threatening episodes were sufficient to justify intestine transplant. They further evaluated the data supporting the use of intestine transplant to improve quality of life and removed recurrent episodes of dehydration from their proposed revised listing criteria. Finally, alternative indications for intestine transplant including intra-abdominal desmoids and mesenteric ischemia without a necessity for pre-existing parenteral nutrition failure were suggested as additional relevant criteria to be considered.

These indications for intestine transplant have been summarized as a failure of home parenteral nutrition management, which operates under the assumption of having a home parenteral nutrition program. While this is typically the case in much of North America and Europe, there are many countries in which home parenteral nutrition remains unavailable.23 In these cases, children with intestinal failure may only receive such life-sustaining therapy in the hospital. In these situations, intestine transplant has been proposed as a suitable alternative to hospital-based parenteral nutrition.

Intestinal failure-associated liver disease

Nearly simultaneously with parenteral nutrition use, reports began of liver injury in those receiving it.24 Even these early reports correlated this liver injury with lipid emulsions, but it was not until the 1990s in which phytosterols and pro-inflammatory omega-6 fatty acids were directly implicated in the pathogenesis of parenteral nutrition-associated liver disease.25,26 Soy-based lipid emulsions, the predominant emulsion used at the time, contained high levels of both phytosterols and omega-6 fatty acids. From this connection, fish-oil based lipid emulsions, which were both devoid of phytosterols and low in omega-6 fatty acids, came to be identified as a potential treatment for cholestatic liver disease.27–29 While studies have shown their efficacy in treating cholestasis, it remains unclear whether this is due to the lack of phytosterols, the deficiency of omega-6 fatty acids, or simply the restriction of their dosing to 1 g/kg/day.

Pure fish-oil based lipid emulsions have only been used to treat cholestasis and their indication specifically advises that data do not support their use in prevention of cholestasis.27–29 Combination lipid emulsions containing components of fish oil, soybean oil, coconut oil high in medium chain triglycerides, and olive oil were created to balance the benefits of exclusive fish-oil based emulsions in a complete fat source that contains both omega-3 and omega-6 fatty acids.30 Their use has been adopted widely as a measure to prevent cholestasis,31 with mixed reports about their utility in preventing liver disease and some concerns about their use as a primary lipid source in a developing infant in need of a rich source of docosahexaenoic acid and arachidonic acid for growth and neurodevelopment.32

As the term suggests, intestinal failure-associated liver disease extends beyond lipid emulsions with several other factors contributing to the liver disease progression. Key contributing factors likely include some intrinsic factors to specific children, such as degree of prematurity, underlying diagnosis, and residual intestinal anatomy. With regards to the latter, there is a hypothesized role of gut dysbiosis affecting the gut-liver axis and resulting in worsening liver injury.33 More directly, septic events have been shown to significantly increase the progression of liver disease and, thus, reducing central-line associated bloodstream infections can have a significant impact on reducing liver injury.34

Over the last 15 years, the advance in intestinal rehabilitation including the shift in lipid emulsion management has been accompanied by a dramatic decline in the number of intestine transplants performed, especially in the number of liver-bowel transplant performed in the youngest age group.35 However, the portion of transplants performed containing liver grafts has remained constant, suggesting that there is a continued need for these transplants. While some of these occur for anatomical reasons, studies continue to show a high incidence of liver disease in those with intestinal failure.36 This includes the historically frequent cholestasis as well as fatty liver, cirrhosis, and portal hypertension.

Sepsis

Despite the advances in multidisciplinary intestinal rehabilitation, sepsis remains a leading cause of morbidity and mortality.2,36 This primarily stems from central line associated bloodstream infection (CLABSI) but intra-abdominal infection and urinary tract infection must be considered in those with complex abdominal anatomy. CLABSI may set the stage for endovascular infection, especially in those with thrombosis.

Prevention of CLABSI starts with effective care of the central venous catheter. Recent guidelines from the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition support the use of specialized care bundles to protect the central venous catheter.37,38 Careful attention to the catheter has proven to have a significant impact on CLABSI rate.38,39 Beyond care technique, antimicrobial lock therapy used prophylactically can prevent CLABSI.40–42 In the United States, ethanol had been the antimicrobial lock of choice for years until recent orphan drug designation for the injectable form of ethanol as an ablative agent to treat symptomatic hypertrophic cardiomyopathy has resulted in a near 100-fold increase in cost.43,44 Globally, alternatives have largely replaced ethanol use, such as taurolidine and sodium ethylenediaminetetraacetic acid (EDTA). These locks have shown effectiveness at preventing CLABSI without additional complications related to line integrity.41,42

When CLABSI does occur, management centers around typical sepsis management, including aggressive fluid resuscitation in a patient population highly susceptible to dehydration.37 Multiple studies have demonstrated the high rate of CLABSI in febrile presentations.45,46 Thus, these children often require inpatient admission for empiric antimicrobial therapy while awaiting confirmation through blood culture. Given their dependency on long-term central venous access, line removal at presentation is the exception rather the rule. In other words, these patients should be treated through their central line as a means of catheter salvage. Central line removal should only occur when deemed necessary due to treatment failure or clinical instability.37

Severe sepsis may have a role in the decision to move forward with intestine transplant. Indications for intestine transplant include statements about recurrent sepsis involving intensive care or fungemia.20,22 However, the role that recurrent CLABSI has as a determining factor to move towards intestine transplant is poorly defined. Each CLABSI results in another hospital stay for a child, increases complication risks such as liver disease, and carries the potential to lead to significant morbidity or mortality.47,48

Venous thromboembolism

As significant strides have been made in preventing liver disease and delaying the need for transplant, children now live much longer with parenteral nutrition dependence. However, with prolonged parenteral nutrition use comes the need for long-term central access. Maintaining access can be a challenge. Central venous catheters require placement into one of the internal jugular, subclavian, or femoral veins. With the potential for fecal contamination in the groin, femoral access can be high-risk in young children with excessive stooling from short bowel syndrome. Coupled with the necessity of upper extremity access for transplant, the upper extremity access points become critical to maintain.

Venous thromboembolism occurs frequently in this population, especially at the sites of central venous catheter placement.49 The high risk of thrombosis may be in part to the high glucose infusion rates necessary to sustain growth in addition to the simple presence of a foreign body in the vein. Recurrent sepsis events, disruptions to catheter integrity, and even the small caliber of the central veins in young children all likely play a role.50 Preventing catheter-related thrombosis has become one of the critical missions of intestinal rehabilitation. Prevention begins with reducing the incidence of events that may contribute to thrombosis, e.g., sepsis. Certain antimicrobial lock solutions, especially sodium EDTA, have been shown to reduce the incidence of line-related occlusions in addition to limiting CLABSIs.42 This dual effect is critical for this population.

Identification of thrombus can present its own challenges. Examination of a child may show dilated veins on the skin or edema of the face and extremities. Ultrasonography has been used most frequently both in diagnosis and in screening but largely depends on an experienced operator.37 Direct venography serves as the gold standard to assess vasculature but is invasive.51 Venography can often accompany interventional procedures for catheter placement or exchange; it is typically not performed in isolation without cause. Indirect imaging through magnetic resonance venography (MRV) can produce a more complete picture than ultrasound with better visualization of the entire vascular tree, eliminating some of the risk of confusing a large collateral with a central vessel. Guidelines have not yet supported routine MRV to screen for thrombosis but rather support its use as a secondary image to confirm ultrasound findings.37

After identification, the appropriate use of anticoagulation may reduce progression. Recent work suggests that continuing prophylactic anticoagulation indefinitely may lead to better outcomes in this population than limited use over six months.52 Once the loss of 2 out of 4 upper extremity central veins has occurred, evaluation for intestine transplant is indicated.20,22 It is imperative to remember that access can be crucial after the transplant, especially in the early recovery phase. Thus, access limitation can actually preclude successful transplant and must be considered even if the child seems well at the time of evaluation. This decision to move forward with a transplant in a growing child without other complications can be quite difficult. The complexity behind these decisions establishes the important role the interventional radiologist or interventional cardiologist can play in transplant decision making when nonstandard access is being considered.

Other indications

Renal insufficiency can be a significant complicating issue in those with intestinal failure due to recurring episodes of subclinical or clinically apparent dehydration. Over time, repeated insults to the kidneys result in suboptimal filtration and poor function.20,22 The issue of the optimal timing to consider intestine transplant in the face of recurrent dehydration remains challenging, especially as pre-emptive transplant may obviate the need for future kidney transplant, which is associated with poor outcomes in adults.53 However, as immunosuppression after transplant continues to rely heavily on tacrolimus, renal injury may continue after transplant even in the absence of parenteral support needs.

While failure of parenteral nutrition remains the most common indication for intestine transplant, certain anatomic considerations may require multivisceral transplant. Intraabdominal tumors can have extensive involvement that includes the liver, mesentery, intestine, and the major vessels supplying these areas. Invasive desmoid tumors in those with Gardner syndrome have been listed in reports for indications of multivisceral transplant.22 In addition, neuroendocrine tumors with liver metastases or primary hepatic tumors invading the mesenteric vessels have been described with good results after multivisceral transplant.54,55 Thus, consideration should be given to any tumor where complete resection must be performed and such resection would involve the liver and abdominal viscera.

Similar consideration has been given to extensive portomesenteric thrombosis. When a surgical shunt or isolated liver transplant is precluded by extension of the thrombus or when such a thrombus causes intestinal ischemia and infarction, multivisceral transplant may be considered.56,57

Finally, a growing number of patients now a decade or more after their initial transplant have entered a phase of chronic rejection without a clear treatment. Similar to deceased donor kidney transplant, intestine transplant has yet to successfully overcome the issue of late graft loss from chronic rejection.35 As such, a growing portion of individuals require retransplant. This population represents a unique challenge with an often-sensitized immune system. As such, many centers employ specific immunosuppression protocols to try to limit the effects of sensitization on the transplant.58 This may be true even in those who are sensitized through other means (e.g., frequent blood transfusion) and not just those seeking retransplant.

Intestinal rehabilitation programs in the management of intestinal failure

One of the greatest advances in the care of children with intestinal failure has been the development of the multidisciplinary team. At a minimum, the team includes the pediatric gastroenterologist, surgeon, dietitian, and a nurse specialist.59 However, many teams involve neonatologists; social workers; psychologists; rehabilitation services such as occupational therapy, speech therapy, and physical therapy; and interventional radiologists. Consensus definitions have not specifically included the transplant surgeon distinctly from the pediatric surgeon largely since individual intestinal rehabilitation programs may not always provide intestine transplant services. Despite this, the transplant surgeon and entire intestine transplant team can have a critical role in intestinal rehabilitation and should be involved early in the management before an urgent need for transplant arises. This may be implemented at an individual patient level with referrals for transplant evaluation or at a center level with direct communication between the intestinal rehabilitation provider and the transplant team with official evaluation of individual patients only occurring when a definitive indication for transplant arises.

Surgical management of intestinal failure

As noted previously, the pediatric surgeon plays a critical role in intestinal rehabilitation. For many patients, this begins with the initial operation leading to short bowel syndrome. There is a balance that must be considered at that time weighing the risks of excess bowel loss with the risks of complications arising from not removing marginal quality bowel. As the care of children with shorter and shorter small bowel lengths continues to advance, many surgeons now have begun to err on the side of removing marginal bowel earlier in the process. During this initial operation, a precise description of bowel anatomy including length and type of remaining segments (e.g., ileum vs jejunum) can be very beneficial. As many infants have this initial surgery early in life, the exact measure of bowel length should be accompanied by an estimate of fractional bowel length remaining relative to the expected bowel length for size or age.60

The presence of an ostomy has correlated with delayed weaning from parenteral nutrition.61 Thus, reversal of an ostomy and placement of the bowel in continuity must be advocated. The timing of ostomy reversal varies but, in the absence of concerns regarding distal motility, should be performed at the earliest safe time. Until that time, data suggest that refeeding the ostomy with either proximal effluent or directly with formula may limit complications of disuse and aid in adaptation through direct stimulation of enterohormones.

In the child with short bowel syndrome whose weaning from parenteral nutrition stalls, the surgeon can be of critical importance in reestablishing progression. This is especially true in the case where bowel dilation occurs, often proximal to anastomosis or functional obstruction. In those with normal motility, these segments may be addressed using longitudinal intestinal lengthening and tailoring or serial transverse enteroplasty (STEP).62,63 Both operations aim to utilize the dilated segment to create a longer length of narrowing bowel with better absorption and function in the process. In recent years, the STEP has become the preferred procedure due to its relative ease although both procedures should be performed by expert surgeons familiar with the considerations of the appropriate segment of bowel to involve and the optimal orientation.64

Addressing bowel dilation in those with adequate bowel length often involves similar principles of trying to limit the intestinal diameter and thereby improving function. Tapering without lengthening can often be performed in these situations.64 In those with abnormal motility, the decision may be more challenging as intestinal lengthening procedures may not address the issue. Some still advocate for tapering procedures in these patients when significant dilation occurs to help with symptomatic relief. Certainly, the more common procedures performed in these children involve methods of decompression such as placement of a gastrostomy tube and decompressing ileostomy.65,66 However, the heterogeneity of clinical phenotypes among those with motility disorders makes prescriptive surgical planning a challenge and should instead be individualized based on known anatomy and bowel function.

Just as the transplant surgeon serves as a consultant to the intestinal rehabilitation team, the pediatric surgeon can provide important input into the transplant decision making process. Often times, reconstructive surgeries may obviate the need for transplant. In others, surgery may be required to temporize a situation and allow for a more favorable transplant surgery in time. At some centers, unique expertise in both pediatric surgery and transplant surgery allows providers to make thoughtful surgical care plans.

Role of transplant in the era of GLP-2 analogues

The role of glucagon-like peptide 2 (GLP-2) in intestinal growth had been described decades before its pharmacologic use for augmenting intestinal adaptation.67,68 Teduglutide, a GLP-2 analogue with a key substitution of glycine in place of alanine that lengthens half-life, has allowed for manipulation of the GLP-2 axis to stimulate adaptation in those with short bowel syndrome for whom natural adaptation has ceased.69,70 In the clinical trials, significantly more patients reduced their parenteral support requirements than those using placebo while a fraction of patients successfully achieved enteral autonomy during the study period.71–74

Teduglutide has shifted transplant decision-making in several ways. When weaning from parenteral nutrition halts, providers now have teduglutide as a means to prolong the adaptation phase of rehabilitation. This can allow some patients to successfully wean from parenteral nutrition who in the past may have been unable to do so. Patient selection for teduglutide remains a significant challenge. Those with high parenteral support needs and lacking endogenous GLP-2 production from ileum and proximal colon may be theorized to have the greatest reductions in support. However, attempts to correlate anatomy with achievement of enteral autonomy in adults have been unsuccessful.75,76 Alternatively, clinical features may better predict enteral autonomy, including the amount of oral intake at the onset of therapy.76 Health economic studies have shown that uniformly using teduglutide in all patients is not cost-effective, further underscoring the need for appropriate patient selection.77,78

Pre-emptive use of teduglutide during adaptation to produce a hyperadaptive state has not been studied. It is unclear if early teduglutide use in those with intestinal failure due to short bowel syndrome would truly produce improved adaptation or if it would simply allow patients to reach the same adaptive potential faster. Similarly, the role of teduglutide in those suffering from complications of parenteral nutrition remains uncertain. While successful weaning from parenteral nutrition may save a transplant in some, others may simply risk developing additional complications. As a general rule of thumb, any patient considering teduglutide with any parenteral nutrition complication should likely be evaluated for transplant.

Should we transplant for quality of life?

As the mortality on parenteral nutrition decreases with more effective intestinal rehabilitation, fewer children will die on long-term home parenteral nutrition. For these children on parenteral nutrition without complications, the question of transplant does arise. Some argue that transplanting healthier patients may lead to fewer complications post-transplant. Others suggest that the outcomes of intestine transplant are not equivalent to chronic home parenteral nutrition.79 While it is certainly difficult to justify pre-emptive intestine transplant as a means of prolonging life, quality of life should be considered in making this type of decision.

Studies on quality of life in children on parenteral nutrition have been mixed in terms of comparing long-term parenteral nutrition to post-transplant care. In adults receiving parenteral nutrition, weekly days of support correlates with quality of life.80 However, in children who have experienced parenteral nutrition since infancy, the effect may be slightly different. Some studies actually suggest higher or at least similar self-reported quality of life scores in children receiving long-term parenteral nutrition compared with those who have achieved enteral autonomy.81 In qualitative work, families have suggested that the stress of weaning from parenteral nutrition and the hypervigilance around enteral intake during weaning may contribute to this finding.82,83 Ultimately, intestine transplant for quality of life must be a shared decision between the patient and provider.

Outcomes of intestine transplant

Pre-emptive transplant may be more broadly applied if transplant outcomes improve. In the most recent pediatric analysis of the Intestine Transplant Registry, five-year outcomes after intestine transplant have reached just over 70% graft and patient survival.35 Over 60% of all intestine transplant recipients wean completely from parenteral nutrition, and over 75% of those who receive a colon-inclusive graft successfully do so. Taken together, these data suggest that a truly successful intestine transplant does successfully cure intestinal failure but that not every intestine transplant reaches that level of success. One of the great challenges in the interpretation of these outcomes is the heterogeneity of the patients combined in these data. For example, intestine transplant can refer to an isolated intestine in a relatively healthy patient with intestinal failure who has lost two access sites. On the other hand, intestine transplant can describe a patient who receives a full multivisceral transplant for decompensated cirrhosis complicated by extensive portomesenteric thrombosis. These patients have very different pre-transplant clinical profiles and naturally different expectations after transplant. Thus, to truly understand the potential of an intestine transplant for an individual patient, consultation with an expert team can provide a more accurate depiction of the likelihood of success. Furthermore, the majority of intestine transplant outcomes are reported at 5- or 10-year intervals. However, when transplanting a young pediatric patient, the goal is to thrive well into adulthood. Such long-term data are not available for intestine transplant, which further complicates decision-making.

The future of intestinal rehabilitation and transplant

Intestinal rehabilitation continues to evolve as novel therapies emerge to support the adaptation process. Newer GLP-2 analogues in longer-acting forms will allow for more sporadic dosing.84,85 Interestingly, these longer acting analogues have shown a different pharmacodynamic profile in animal studies, producing similar results in terms of villous height and crypt depth but also causing intestinal lengthening.86 It has been hypothesized that producing additional length may be a more durable effect and allow for discontinuation of the medication once enteral autonomy has been achieved. This is contrary to teduglutide, which has traditionally been considered lifelong therapy in those who respond.87 Intestinal lengthening has also been achieved in animal models by stimulating GLP-1 in addition to GLP-2.88 The potential for combination GLP-1 and GLP-2 treatments may augment the results achieved by GLP-2 alone.

Surgical techniques in the field have shown similar promise at promoting enteral autonomy without a transplant. Distraction enterogenesis involves the use of various techniques to stretch the existing intestine using tension.89 Recently, animal models have shown surgically inserted springs may support intestinal lengthening.90,91 Others have attempted to grow artificial intestines using intestinal stem cells onto a biological scaffold.92,93 These can then be implanted into the patient with short bowel syndrome to provide additional absorptive capacity. Studies in this space thus far have been limited mostly to proofs of concept without evidence of much clinical benefit.92 Still, the potential to transplant an artificially grown and thus immunologically autologous intestine has tremendous appeal.

The number of intestine transplants has decreased over time, especially in pediatrics.35 As discussed, this is largely due to the improvements in intestinal rehabilitation allowing for children to live longer on home parenteral nutrition. However, there is growing evidence that children on long-term parenteral nutrition are not necessarily achieving enteral autonomy at any significantly higher rate than previous eras.36 As such, many have considered that rather than eliminating a need for intestine transplant, we have simply delayed the necessity to transplant to an older age. Many transplant centers receive fewer referrals for infants with liver disease and many more referrals for older children and young adults lacking adequate central venous access. This may speak to a future increase in the number of intestine transplants performed nationally once this population reaches a point deemed failure of home parenteral nutrition.

Equity

Access to intestine transplants presents one of the major barriers for children with intestinal failure. In the United States, only nine centers performed at least one pediatric intestine transplant in the last year with centers sparsely spread across the US. Those seeking a transplant must travel to such a center to even go through the evaluation process and then often must relocate for at least a period after transplant. Moreover, local expertise may not be as familiar with the current state of intestine transplant, often affecting the counseling patients receive about its viability in the current era. Even after listing, transplant recipients seem to live closer to their transplant center than those who are listed but not recipients, which may underscore the disparities in care based on distance from a transplant center.94

Internationally, there remains significant equity concerns in access to both intestinal rehabilitation and transplant. Emerging economic countries have limited access to specialized intestinal rehabilitation programs.95 In several countries, home parenteral nutrition is not an option.96 Medications such as teduglutide may not be supported by various health systems due to the high cost. Much like the limited access to transplant, the access to surgical rehabilitation options such as intestinal lengthening procedures may be limited.

Thus, those with short bowel syndrome face the decision of living in the hospital or relocating for transplant if it is accessible. In some cases, it is not feasible due to the high costs of both the procedure and the logistics of relocation. Some countries have established partnerships, such as those in South America and Oceania, to allow for access to intestine transplants at expert centers.97,98 Much work remains to address these gaps in care.

Conclusions

Intestine transplant remains a treatment of exclusion when facing with life-threatening complications rather than a treatment of choice during the rehabilitation process. In the current era of newer treatments for short bowel syndrome such as GLP-2 analogues, the question may be asked as to whether there remains any role for intestine transplant. However, it may be that the children who once needed to be transplanted in infancy due to cholestatic liver disease are now successfully reaching late childhood and adolescence but often still with a dependency on parenteral nutrition. Some of these children will continue to require intestine transplant as a life-saving therapy. In others, intestine transplants offer freedom from parenteral nutrition when the burden of parenteral nutrition becomes too great, especially in countries where parenteral nutrition can only be given in the hospital. Thus, intestine transplant remains an important treatment modality combined with both medical and surgical intestine rehabilitation in the management of children with intestinal failure. As children with intestinal failure progress on their journeys, multidisciplinary care involving input from all those involved can help to ensure that each child receives the treatment that best suits their individual needs.

Acknowledgements/Funding

Dr. Raghu is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001856. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abbreviations:

CLABSI

central line-associated bloodstream infection

CMS

Center for Medicare and Medicaid Services

EDTA

ethylenediaminetetraacetic acid

GLP-2

glucagon-like peptide 2

MRV

magnetic resonance venography

STEP

serial transverse enteroplasty

Footnotes

Disclosure

Dr. Raghu previously served on an advisory board for Takeda Pharmaceuticals.

Data statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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