Seminars in Pediatric Surgery 23 (2014) 291–297

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Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg

Short bowel syndrome in children: Surgical and medical perspectives Riccardo Coletta, MDa,b, Basem A. Khalil, FRCS (Paed Surg)a,b, Antonino Morabito, MDa,b,n a b

Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit, Royal Manchester Children's Hospital, Oxford Rd, Manchester M13 9WL, UK School of Medicine, University of Manchester, Manchester, UK

a r t i c l e in fo

Keywords: Short bowel syndrome Intestinal failure Autologous gastrointestinal reconstructive surgery Children LILT STEP

a b s t r a c t The main cause of intestinal failure in children is due to short bowel syndrome (SBS) resulting from congenital or acquired intestinal lesions. From the first lengthening procedure introduced by Bianchi, the last three decades have seen lengthening procedures established as fundamental components of multidisciplinary intestinal rehabilitation programs. Debate on indications and timing of the procedures is still open leaving SBS surgical treatment a great challenge. However, enteral autonomy is possible only with an individualized approach remembering that each SBS patient is unique. Current literature on autologous gastrointestinal reconstruction technique was reviewed aiming to assess a comprehensive pathway in SBS non-transplant management. & 2014 Elsevier Inc. All rights reserved.

Introduction The purpose of this review is to provide current state-of-the-art review of the non-transplant management of short bowel syndrome (SBS). Although optimal therapy for SBS remains unknown, a variety of innovative surgical procedures have been developed in the last few decades in addition to medical therapy. Multidisciplinary management has been recognized as the only effective paradigm leading to successful enteral autonomy. In this review, we will focus on the autologous gastrointestinal reconstructive (AGIR) procedures and on the current pharmacological approaches as integral components of SBS multidisciplinary treatment. We will also provide an update on the protocol-driven strategies to promote intestinal rehabilitation. Recent research into regenerative medicine as applied to SBS will also be discussed.

Short bowel syndrome Short bowel syndrome is defined as a multisystemic condition caused by suboptimal absorption of nutrients due to inadequate small intestinal length.1 Data from a large tertiary center in Canada shown that the overall incidence of SBS was 22.1 per 1000 neonatal intensive care unit (NICU) admissions and 24.5 per 100,000 live births. The mortality rate of the condition is high n Corresponding author at: Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit, Royal Manchester Children's Hospital, Oxford Rd, Manchester M13 9WL, UK. E-mail address: [email protected] (A. Morabito).

http://dx.doi.org/10.1053/j.sempedsurg.2014.09.010 1055-8586/& 2014 Elsevier Inc. All rights reserved.

with reported survival rates in pediatric SBS ranging from 73% to 89%.2 The actual length of small intestine required for optimal absorption is still controversial; however, bowel length o 100 cm in the first year of life is regarded as abnormal. Less than 40 cm traditionally requires therapy according to the practice of most centers.3 In addition, the gestational age of the child and the timing of the actual incident that caused short bowel will need to be taken into consideration when defining short bowel syndrome.1 The majority of underlying conditions that lead to major loss of intestine in neonates and infants have their origins in intrauterine life. Moreover, massive intestinal resection continues to be associated with significant morbidity and mortality rates. In children, the conditions most commonly leading to extensive small bowel resections are necrotizing enterocolitis (NEC), intestinal atresia, gastroschisis, and extensive aganglionosis in Hirschsprung disease.4,5 The consequences of short bowel syndrome are huge. Intestinal failure occurs when intestinal function is insufficient to meet the body's nutrition and hydration needs, and supplementary parenteral nutrition and/or intravenous fluid (PN/IV) support is required.6 In a study from seven tertiary neonatal units in Italy, intestinal failure was seen in 0.1% (26/30,353) of all live births and 0.5% (26/5088) among those admitted to the NICU.7 With most children dependent on total parenteral nutrition (TPN) for long periods of time, damage to the liver is common. Several medical therapies have been used to enhance bowel adaptation. TPN is used to enhance growth and nutrition of the child until adaptation occurs. In the event of failed adaptation and in the face of liver failure and reduced venous access, transplantation becomes the

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only hope for these children.8 The current estimated survival on parenteral nutrition for short bowel syndrome at 5 years ranges from 52% to 73%.9 The concept of establishing intestinal failure centers involving the total care of the patient including optimal enteral nutritional management, parenteral nutrition, and central line care, non-transplant surgery and intestinal transplantation has been accepted widely as of ultimate benefit to the child, but is often difficult to put into practice.1–10

Autologous gastrointestinal reconstructive procedures In all SBS patients, the goal of treatment is to promote and enhance the adaptation process over time to possibly gain enteral autonomy, minimize complications, and offer an acceptable quality of life to both children and carers. Intestinal adaptation has been defined as the small intestine's ability to increase its absorptive capacity to compensate for the reduction of absorptive surface area caused by intestinal resection.11 Timing of intestinal adaptation is variable,12 unique to each individual and usually occurs during the first 2 years following massive intestinal resection in adults; longer and perhaps more vigorously in children.13 Intestinal adaptation in children is influenced by growth and development and thus occurs over a longer period in younger children.5 Massive resection stimulates modification in thickness and length of the muscle layers and structural modification of crypts to villi. Distention of remain bowel is the most common consequence after massive resection.14

The adaptive intestinal process prompted the possibility to design autologous gastrointestinal reconstructive procedures. Indeed, pre-requisite condition for successful non-transplant surgery is evidence of a segment or segments of dilated bowel with a lumen diameter more than twice the normal for age and weight. Surgical attempts at improving mucosal absorption have been varied and imaginative. In 1980, Bianchi15 proposed a bowellengthening technique called Longitudinal Intestinal Lengthening and Tailoring (LILT). Boeckman and Traylor16 performed the first clinical application of this procedure in 1981 to a 4-year-old PNdependent child with a 50-cm jejunum, who was also at risk from precarious venous access. Within 10 weeks, the patient was able to wean off PN and has continued to thrive on enteral nutrition. The pathophysiology behind the LILT is based on the anatomical evidence of mesenteric blood vessels that enter the small bowel loop along its lateral aspects. Accordingly, it is possible to divide the dilated bowel longitudinally in the midline along the mesenteric and antemesenteric borders and to create two fully vascularized isopropulsive hemiloops, which are anastomosed isoperistaltically with the distal loop anastomosed to the remnant colon. The tailored bowel is half the diameter and up to double the length of the original loop without significant loss of absorptive mucosa. Propulsion, although not uniform, is effectively isoperistaltic with a reduction in stasis and sepsis (Figure 1). The benefits of LILT are the combined possibility to double the length in addition to better propulsion—a significant problem in dilated dysmotile bowel. This procedure has been demonstrated clinically to improve fat and carbohydrate absorption and slow transit

Fig. 1. The LILT procedure. (A) Blunt dissection between the peritoneal leaves of the mesentery, with development of a midline intravascular plane (bowel division depicted by dotted line). (B and C) Formation of hemiloops by manual suturing inverts the bowel edges and preserves all mucosa. (D–E) Isoperistaltic anastomosis between hemiloops in S shape or spiral shape. (Adapted with permission from Bianchi, 1984.)

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Fig. 2. (A) Schematic of proximal and distal tube stomas. (B) The end is then sutured to the inside of the anterior abdominal wall, as in a tube jejunostomy.

time.17 Bowel lengthening is usually followed by an increase in absorption, with reports of 28–100% of survivors weaned off PN and others significantly reducing their PN dependence.10 Furthermore, in 2012, Khalil et al.1 described the 10-year experience in LILT treatment reporting 91% of SBS out of TPN and highlighting the advantages of the Bianchi procedure. LILT is better performed if intestinal dilatation has occurred. In the event of absent bowel dilatation, a pre-lengthening bowel expansion could be performed. Since Georgeson et al.18 described the concept of “controllable expansion-recycle,” Bianchi19 adopted this concept to create a better and feasible model to autologous bowel expansion. A catheter is placed in the distal end of the proximal small bowel and secured using a purse-string suture. The end is then sutured to the inside of the anterior abdominal wall, as in a tube jejunostomy. The catheter is then brought out of the abdominal wall as a proximal tube stoma. The colon or its remnant is treated the same way. The level of stomas depends on the remnant bowel (Figure 2). The child is fed post-operatively, and the proximal tube stoma is clamped for progressively longer periods after feeds. The aim is to achieve circumferential expansion of the bowel to about twice its original size.20 In 2003, Kim et al.21 described a different lengthening procedure called serial transverse enteroplasty (STEP), which reduces bowel diameter, increases bowel length, and establishes isopropulsive bowel continuity without loss of mucosa. A GIA stapler is applied sequentially, from alternating and opposite directions, in transverse, partially overlapping fashion creating a zigzag–like channel of approximately 2–2.5 cm in diameter (Figure 3). The STEP can be performed as a primary bowel-lengthening procedure. However, maximal bowel lengthening can probably be achieved

when it is performed sequentially after a Bianchi procedure.22 Although referred to in general terms as a “lengthening procedure,” the clear effect is to alter the volume to surface area of the intestine to improve absorption and propulsive contraction, as demonstrated by improved maintenance of nutrition in an animal model employing the STEP procedure.21 Both techniques essentially improve nutrient absorption by reducing stasis, bacterial overgrowth, and facilitating food contact with bowel mucosa through returning the bowel lumen diameter closer to normal without loss of adapted bowel mucosa along with restoration of propulsive movements of intestinal contents. The procedures have limitations. The LILT can be technically difficult. Leak and stricture formation, and risk of injury to intestinal blood supply have been reported.23,24 With the STEP, anastomotic leak with intestinal perforation typically at the apex of the staple lines has been reported, and it is wise to place a reinforcing suture here to avoid this complication.25 A retrospective review of a large single-center experience comparing the outcome of Bianchi and STEP in terms of survival, PN weaning, and complications was unable to detect significant differences. Although the series reported a trend toward an increased rate of weaning in STEP patients (60%) compared with the LILT procedure (55%) and a shorter time needed to wean off PN with STEP (4.8 months) compared with the Bianchi procedure (8.4 months), no differences in patient survival were noted.26 Recently (2013), King et al. reviewed SBS outcomes based on the two most commonly used lengthening procedures, the LILT procedure and the serial transverse enteroplasty procedure (STEP). This study found no significant difference in survival between LILT procedures carried out in the last 15 years and the STEP in the last 10 years. The data

Fig. 3. Schematic drawing of STEP procedure. (A) The small arrows show the direction of insertion of the GIA stapler and the sites of the mesenteric defects. (B) The staplers are placed in the 901 and 2701 orientations using the mesentery as the 01 reference point.

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Fig. 4. (A) Bowel simulator cut at 601 and tabularized. (B) Spiral lengthening and tailoring result. (Adapted with permission from Cserni etal.28)

gathered suggested that the percentage of patients weaned was significantly higher in the LILT group than in the STEP group.27 The most recent lengthening and tailoring technique described is called Spiral Intestinal Lengthening and Tailoring (SILT).28 Briefly spiral incision lines are drawn with a sterile marking pen at 451–601 to the longitudinal axis of a dilated small bowel segment. Marking sutures were placed where the spiral incision lines meet on the antemesenteric and mesenteric borders and held with small artery forceps. The bowel is incised on one side along the marker lines with diathermy and with scissors. The bowel loop is flipped over, and the spiral incision is completed according to the marking. The bowel is then stretched longitudinally over an intraluminal catheter to a uniformly longer tube of narrower diameter (Figure 4). SILT may offer a new opportunity for the surgical treatment of short bowel syndrome because it seems to require less manipulation on the mesentery than the Bianchi procedure and does not alter the orientation of the muscle fibers like STEP.29 In addition, the bowel does not have to be as dilated as in the LILT or the STEP. Historically, a number of other procedures have been attempted, and some successes have been reported.18 Reversed antiperistaltic segment(s) have been suggested when sufficient bowel mucosa is available, but transit time is rapid. The antiperistaltic segment functions by inducing retrograde peristalsis distally and disrupting the motility of the proximal intestine. In addition, the disruption of the intrinsic nerve plexus slows myoelectrical activity in the distal remnant. Single or multiple reversed segments suffer from a critical length–effect ratio, and there is incomplete knowledge of their most effective site or sites. They remain a serious consideration either in isolation or as part of a combination of techniques.30 Experimental studies on antiperistaltic segments demonstrate slowed intestinal transit, improved absorption, reduced weight loss, and prolonged survival after intestinal resection, but some reports do not show a beneficial effect.31 The optimal length of the reversed segment would appear to be approximately 10 cm in adults and 3 cm in children. The reversed segment should be created as distal in the small intestinal remnant as feasible to receive the benefit of proximal absorptive surface. Care must be taken to identify a satisfactory vascular arcade to the segment and to avoid complete rotation of the mesentery during reversal to prevent intestinal ischemia. Hutcher et al.32 introduced colon interposition because of the colon's slower motility and its ability to absorb fluid and electrolytes.32 The antiperistaltic colon interposition is placed distally, similar to the reversed small intestinal segment. Interposed colonic segments absorb water, electrolytes, and nutrients in addition to their effect on intestinal transit.33 In experimental studies, isoperistaltic colon interposition generally resulted in slower transit time, less weight loss, and improved survival after resection. Results with antiperistaltic colon interposition, however, have been less consistent. The length of colon interposed seems to be less critical than with reversed segments of small intestine. According to the Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit experience in Manchester, simultaneous or

sequential combinations of newer and older techniques, like bowel expansion-recycle followed by LILT and/or other bowellengthening procedures in addition to reversed segments or colon interposition especially in the ultrashort bowel state, may prove more beneficial. This combined approach, which the authors term the Manchester model, has been used in their Unit (Figure 5).

Medical approach to short bowel syndrome Medical management of SBS focuses on bowel adaptation, replacement of fluid and nutrient losses, achieving or maintaining adequate weight, and controlling diarrhea.34 In the early phase of intestinal adaptation (1–3 months), stabilization of large fluid and electrolyte losses, maintaining fluid balance, and controlling acid/ base balance are mandatory.35 As a consequence of intestinal adaptation, accelerated intestinal transit, gastric acid hypersecretion, intestinal bacterial overgrowth, and malabsorption of fats and bile salts could lead to severe diarrhea, affecting outcomes. The common pharmacological therapies to avoid the SBS consequences include antimotility agents, antisecretory agents, and parenteral infusion therapy. Antimotility medications are used to slow peristalsis and improve absorption of fluid, electrolytes, and nutrients.36 Loperamide and diphenoxylate-atropine are typically the first-line choices for antimotility agents.37 Moreover, loperamide is effective, as shown in patients with ileostomy in which loperamide treatment resulted in a 27% decrease in the wet weight of ostomy effluent (P o 0.02).38 In small clinical studies, diphenoxylate and loperamide had similar efficacy for the treatment of chronic diarrhea, although some trials have shown a modest advantage for loperamide over diphenoxylate.39 Second-line agent includes clonidine, an α2-adrenergic agonist, which has been shown to increase intestinal transit time and decrease fecal weight in patients with SBS. However, clonidine is commonly used to treat hypertension, so blood pressure should be monitored closely when starting this medication. Patients with severe coronary heart disease, chronic renal insufficiency, and hemodynamic instability may not be good candidates for clonidine therapy.40 Dosage of the selected first-line antimotility agent should be escalated in a stepwise manner at intervals of 3–5 days, until benefit is observed or the recommended maximum dosage is reached. Hypersecretion of gastrin and gastric acid occurs in patients after extensive small bowel resection and often resolves within a few weeks or months following resection.41 Prime candidates for the intestinal inhibitor include cholecystokinin, secretin, and neurotensin. Proton pump inhibitors (PPIs), including lansoprazole, pantoprazole, omeprazole, and esomeprazole, are typical first-line agents of choice.42 Typical second-line agents used to combat gastric hypersecretion include histamine type 2 receptor (H2) antagonists. H2 antagonists block the function of histamine, a local mediator of acid secretion released from the gastric mucosa in response to the hormone gastrin. Somatostatin analogs inhibit the release of gastrointestinal hormones and reduce secretion of intestinal and pancreatic fluids, which reduces diarrhea in patients

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Fig. 5. Combined simultaneous procedures: (A) STEP and LILT; (B) LILT and STEP; (C) LILT and reverse colonic interposition; and (D) STEP and reverse colonic interposition.

with SBS.43,44 Octreotide may be effective for patients who fail to respond sufficiently to other antidiarrheal therapies. Octreotide, a long-acting analog of the peptide hormone somatostatin, inhibits diarrhea through multiple mechanisms, including inhibition of gastrin and other GI hormones. In addition, octreotide prolongs intestinal transit time in patients with SBS.45 Small bowel bacterial overgrowth can occur in conjunction with SBS and is related to alterations of intestinal anatomy, motility, and gastric acid suppression.46 The anatomy of the GI remnant can be a primary driver of bacterial overgrowth because blind loops or small bowel dilation reduces intestinal motility resulting in stagnation of intestinal contents and promotion of local bacterial fermentation.47 Intestinal bacterial overgrowth is treated with antibiotic therapy. However, when treating symptomatic intestinal bacterial overgrowth with antibiotics, drug rotation and inclusion of antibiotic-free intervals may decrease the potential for the development of resistant strains. If symptoms persist despite antibiotic and probiotic therapy, reducing dosages of motility and acid-suppressing drugs or switching to antidiarrheal agents may be helpful.48 The main therapeutic objective in the management of SBS is to maintain the patient's nutritional status and normalize macronutrient and micronutrient status. However, the nutritional care of children with chronic intestinal disease remains a challenge for many pediatric specialists. The nutritional support of patients with SBS is complex and must be individualized based on the acute and chronic medical issues and conditions of each patient. The “hepatosparing” TPN regimen proposed by Khalil et al.1 consists of fat-free/fat-reduced (nil to 0.5 g/kg/day), 3.75 g/kg/day of protein and 14 g/kg/day of glucose during the first 4 weeks of life and during episodes of sepsis and a low-fat regimen (1–1.5 g/kg/day) with the same amount of protein and glucose in the typical situation. All the patients enrolled on this TPN regimen are fed orally and feeding adds more energy to their daily intake. This supplemental TPN regime provides approximately 81.8 kcal/kg/day. The “hepatosparing” TPN regimen has been proposed as a way to rescue liver function in patients referred with TPN-associated liver disease. The lipid emulsions used in the United States are soybeanand/or sunflower oil-based which are rich in omega-6 fatty acids, including arachidonic acid, which lead to the production of pro-inflammatory cytokines. In order to prevent or delay the

development of intestinal failure-associated liver disease, many groups are now limiting lipid administration to 1 g/kg/day or lower.49,50 However, lipid limitation should be used cautiously in neonates as extended periods of limitation may lead to growth retardation. Another area of investigation to prevent IFALD involves using fish oil-based lipid emulsions that are rich in omega-3 fatty acids, which have anti-inflammatory properties. The recent literature reported omegaven as an effective way to reverse cholestasis injuries compared to patients who received soybean oil-based lipid emulsions.51 Furthermore, other groups have reported chemical reversal of IFALD with the use of lipid emulsions rich in omega-3 fatty acids.52 Growth hormone was the first medication approved by the US Food and Drug Administration (in 2003) specifically for use in patients with SBS receiving specialized nutritional support in conjunction with optimal management.53 The use of this growth factor has been limited, largely owing to concerns with regard to efficacy and the fact that only short-term use was approved. Recently, a new glucagon-like peptide 2 analog, called Teduglutide, has been proposed as hormone with the ability to restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion.54 The advent of teduglutide, like most other new therapies, represents an incremental improvement in the care of patients with SBS/IF and likely will allow the clinician an additional option for patient management.

Future autologous treatment of short bowel syndrome The future of SBS therapies may lie in a truly artificial or artificially grown and harvested intestine. The development of bioengineering techniques and molecular medicine has focused researchers' attention on the possibility of using tissue-engineered small intestine (TESI). In 1988, the pioneering study of Vacanti et al.55 described a method to attach cell preparations to biodegradable artificial polymers in organ culture and implanting this polymer–cell scaffold into animals. In 1997, Choi and Vacanti tissue engineered small intestine on biodegradable scaffolds by transplanting intestinal epithelial organoid units in the rat model. Rodent organoid units, seeded on a

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nonwoven polyglycolic acid (PGA) fiber and implanted in rats having undergone the resection of 85% of their native intestine, were able to partially replace gut function.56 Histological analysis of the neointestine showed formation of neomucosa characterized by columnar epithelium with goblet and Paneth cells.57 Subsequently, Kim et al.58 and the Vacanti group investigated the effects of anastomosis of tissue-engineered intestine to native small bowel alone or combined with small bowel resection on neointestinal regeneration. When TESI was anastomosed to the side of the proximal small intestine of the rodents, these animals improved weight gain, suggesting a role for TESI in the management of SBS.59 In analyzing these models of treatment, there are two essential features. Firstly, all the intestinal units were derived from newborn rodents. In the clinical setting it would be difficult, and sometimes impossible, to obtain human neonatal intestinal organoids, especially for autologous stem cell transplantation. Secondly, TESI is implanted in the omentum where it will form a cyst with all the intestinal layers. The omentum provides the vascular supply to the organoids and enables integration of the absorbed nutrients with the host portal circulation. The omentum, however, is often removed or scarred in patients with SBS because of prior surgeries. Even when present, the surface area of the omentum is not large enough to generate the area of intestinal tissue needed for clinically significant results. The final point of controversy is the lack of peristalsis in the tissue-engineered bowel. Although tissues generated from intestinal organoids resemble the mucosa, functional smooth muscle layers and the neural plexus are absent. In 2012, researchers directed by Bitar demonstrated the possibility of creating a bioengineered muscle by growing rabbit colonic circular smooth muscle cells (RCSMCs) on chitosan-coated plates. Interestingly, they have created a 3D circular muscular model that contracted in response to acetylcholine (Ach) and potassium chloride (KCl) and which relaxed in response to vasoactive intestinal peptide (VIP).60 Reproduction of the three-dimensional structure of the single intestinal functional unit (the crypt with the respective villus) still represents one of the major challenges for the development of functional intestine. To solve this issue, De Coppi's group postulated a new bioengineering protocol to create an intestinal tissueengineering model by using detergent-enzymatic treatment to make a natural intestinal scaffold, as a base for developing functional intestinal tissue.61 After the enzymatic treatment, the acellular matrix showed its cylindrical structure with mesentery on the side. In addition, they postulated that the preserved crypt/ villus structure after one treatment might facilitate the establishment of the regenerating unit. Unfortunately, no in vivo experiment has been yet conducted to consolidate these results. Tissueengineered treatments would avoid problems associated with intestinal transplantation, including donor availability and complications from immunosuppressive therapy but the transition to human therapy requires a reliable technique.62 The second field of modern research drew attention to the concept of stem cells. The bowel has been used as a milestone for understanding cellular mechanisms, but it is still an open question regarding its stem cell function. More has been discovered on intestinal development today, but a regenerative solution to elongate the bowel has not been determined. Ex vivo or in vivo research based on mice model has been used because over 95% of the mouse coding genome is similar to human. In mouse development as in human, the upper gastrointestinal tract and the basic structure of the tract are conserved.63 Pioneering studies on the intestinal stem cell in the mouse small intestine dates back to 1974,64 and the first technique to demonstrate the cell pathways used transgenic knockout mice. Through these studies, several signaling pathways such as the wingless-type

MMTV integration site family (WNT), bone morphogenetic proteins (BMP), phosphatidylinositide 3-kinases (PI3K) and Notch cascade have been revealed to play a critical role in regulating proliferation and controlling stem cell regeneration.65 Modern research demonstrated that it is possible to create mini-guts in vitro from a single Lgr5 stem.66. The mini-guts recapitulate the central features of normal gut epithelium. They consist of crypts (with resident Lgr5 cells and Paneth cells) that feed into a central lumen lined by mature epithelial cells of all villus lineages. Clonal organoids expanded from a single adult colonic Lgr5þ cell have been transplanted into multiple recipient mice in which epithelial damage had been induced by chemical treatment. Although advances have been made, the practical aspects of a truly functional artificial gut or even one constructed from a patient's own stem cells remains far from a clinical reality.

Conclusion The management of the child with short bowel is a complex multidisciplinary process over a prolonged period of several years. Recent advances in the care of patients with SBS include centralized multidisciplinary intestinal failure care teams. The potential benefits of AGIR are clear and should not be denied to the short gut child with potentially adaptable functional autologous bowel. AGIR requires commitment from dedicated bowel reconstructive surgeons and adequate resources for research and development. With a multidisciplinary approach, combining both medical and surgical expertise, patients with short bowel syndrome can achieve enteral autonomy. In future, tissue and organ regeneration will change the treatment of SBS, but in the meantime, evolution of surgical and medical approaches will be mandatory to provide the best life to these patients.

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