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The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro 1 , but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging 2 . Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment.

GVHD as a complication of SOT presents both a diagnostic and therapeutic challenge. Typically affecting the skin, gastrointestinal tract, and liver, GVHD occurs when donor lymphocytes engrafted in recipient tissues are activated by host antigen-presenting cells resulting in cytokine release and donor cell-mediated cytotoxicity to host tissue. Here, we describe a 5-year-old girl who developed fatal, refractory GVHD after isolated intestinal transplantation when recipient immune cells failed to repopulate the allograft in the setting of CMV viremia. Persistence of the donor immune cells in the allograft mucosa, rather than engraftment in the recipient bone marrow, likely perpetuated this refractory GVHD. Early diagnosis and intervention are critical to reduce morbidity and mortality. Thus, periodic monitoring of peripheral blood and allograft mucosal chimerism with sensitive detection methods may allow early detection and potentially curative enterectomy in similar cases of refractory GVHD., (© 2019 Wiley Periodicals, Inc.)

Background: Although serial transverse enteroplasty (STEP) improves function of dilated short bowel, a significant proportion of patients require repeat surgery. To address underlying reasons for unsuccessful STEP, we compared small intestinal mucosal characteristics between initial and repeat STEP procedures in children with short bowel syndrome (SBS)., Methods: Fifteen SBS children, who underwent 13 first and 7 repeat STEP procedures with full thickness small bowel samples at median age 1.5 years (IQR 0.7-3.7) were included. The specimens were analyzed histologically for mucosal morphology, inflammation and muscular thickness. Mucosal proliferation and apoptosis was analyzed with MIB1 and Tunel immunohistochemistry., Results: Median small bowel length increased 42% by initial STEP and 13% by repeat STEP (p=0.05), while enteral caloric intake increased from 6% to 36% (p=0.07) during 14 (12-42) months between the procedures. Abnormal mucosal inflammation was frequently observed both at initial (69%) and additional STEP (86%, p=0.52) surgery. Villus height, crypt depth, enterocyte proliferation and apoptosis as well as muscular thickness were comparable at first and repeat STEP (p>0.05 for all). Patients, who required repeat STEP tended to be younger (p=0.057) with less apoptotic crypt cells (p=0.031) at first STEP. Absence of ileocecal valve associated with increased intraepithelial leukocyte count and reduced crypt cell proliferation index (p<0.05 for both)., Conclusions: No adaptive mucosal hyperplasia or muscular alterations occurred between first and repeat STEP. Persistent inflammation and lacking mucosal growth may contribute to continuing bowel dysfunction in SBS children, who require repeat STEP procedure, especially after removal of the ileocecal valve., Level of Evidence: Level IV, retrospective study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: The aim of this study is to examine the feasibility of the small intestinal submucosa (SIS) when the longitudinal staples during Bianchi's procedure are replaced with SIS graft., Methods: The mesentery of the bowel was separated based on the bifurcated vessels in five beagles. A 2×7-cm longitudinal half of the bowel was excised and the defect was repaired using SIS with similar blood supply in Bianchi's operation. Six months later, intestinal motility in the SIS-grafted area was recorded. Tissue preparations were obtained from the reorganized area. An organ bath technique with electrical field stimulation was applied. Both the native small intestine and grafted area were morphologically investigated using immunohistochemistry., Main Results: All dogs survived and thrived with no anastomotic leakage. Isoperistaltic migrating contractility during fasting was observed through the grafted segment including the reorganized area. The SIS-reorganized tissue contracted in response to an acetylcholine agonist and electrical field stimulation. The mucosa was covered with normal epithelium. Reorganization of neural and smooth muscle cells was observed., Conclusions: SIS has the potential for use as a scaffold that promotes the formation of a physical and physiological neointestine. Our present proposal approaches a novel surgical treatment in patients with short bowel syndrome., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Short bowel syndrome-associated intestinal failure (SBS-IF) as a consequence of extensive surgical resection of the gastrointestinal (GI) tract results in a chronic reduction in intestinal absorption. The ensuing malabsorption of a conventional diet with associated diarrhea and weight loss results in a dependency on parenteral nutrition and/or intravenous fluids (PN/IV). A natural compensatory process of intestinal adaptation occurs in the years after bowel resection as the body responds to a lack of sufficient functional nutrient-processing intestinal surface area. The adaptive process improves bowel function but is a highly variable process, yielding different levels of symptom control and PN/IV independence among patients. Intestinal rehabilitation is the strategy of maximizing the absorptive capacity of the remnant GI tract. The approaches for achieving this goal have been limited to dietary intervention, antidiarrheal and antisecretory medications, and surgical bowel reconstruction. A targeted pharmacotherapy has now been developed that improves intestinal absorption. Teduglutide is a human recombinant analogue of glucagon-like peptide 2 that promotes the expansion of the intestinal surface area and increases the intestinal absorptive capacity. Enhanced absorption has been shown in clinical trials by a reduction in PN/IV requirements in patients with SBS-IF. This article details the clinical considerations and best-practice recommendations for intestinal rehabilitation, including optimization of fluids, electrolytes, and nutrients; the integration of teduglutide therapy; and approaches to PN/IV weaning.

Background: In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients., Methods: In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105 min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800 μg native GLP-2., Results: The GLP-2 injection increased jejunal mucosal blood flow by 79±37% compared to conditions, where no treatment was given (p<0.001). The significant effect was present at least 105 min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation., Conclusions: GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: The aim of the present study was to investigate the segment- and time-related changes in rat short bowel syndrome and construct a 4-dimensional (4D) geometrical model of intestinal adaptation., Methods: Sprague-Dawley rats were divided into 3 groups: 2-day, 7-day, and 15-day postresection groups in which 75% of the jejunoileum was removed. Histological and morphometrical parameters in the remaining proximal to distal intestinal segments, from the jejunum to the distal colon, were comparatively evaluated in the groups. The data were used to construct a 4D geometric model in which villi were considered as cylinders, and their surface area was expressed as cylinder lateral area., Results: Major adaptive changes were observed in the ileum consisting of an increase in both the diameter of base and the height of villi. A parallel reduction in their number/mm was observed. The resulting ileal architecture was characterized by a limited number of large villi. An opposite pattern was observed in the jejunum whose postresection structure consisted of an increased number of villi. No changes were observed in the colon. Postresection restructuring was early and faster in the ileum than in the jejunum resulting in an increase in absorptive area of 81.5% and 22.5% in the ileum and jejunum, respectively., Conclusions: Postresection adaptation is intestinal segment-specific because all of the major changes occur in the ileum rather than in the jejunum. Sparing ileal segments during resection may improve the outcome of patients undergoing extensive intestinal resection. Our 4D model can be used to test interventions aimed at optimizing postresection intestinal adaptation.

Purpose of Review: Intestinal transplantation (ITx) and multivisceral transplantation (MVTx) has evolved into a viable treatment option for short bowel syndrome and intestinal failure due to a variety of factors including improved immunosuppressive regimens, superior surgical and medical management, and enhanced posttransplant monitoring., Recent Findings: The transplant pathologist is a central member of the transplant team in all phases of solid organ transplantation and as such, plays an important role in the evaluation of early and late complications after ITx and MVTx. Central among the tools for the pathologist is the mucosal biopsy, used for discerning histopathological changes in the allograft. The principal complications seen in the late posttransplant phase are acute rejection, chronic rejection, infections, and a variety of other inflammatory conditions. In order to more precisely characterize these conditions, the transplant pathologist must also be able to utilize numerous other laboratory tests and panels of molecular biomarkers that serve as ancillary information to complement the biopsy impression., Summary: Using this array of tools, the transplant pathologist is now able to provide rapid and precise information regarding the gastrointestinal (GI) transplant complications, a function that allows the clinical team to appropriately and successfully intervene and that helps contribute to the observed improvement in patient and graft survival.

Background: Successful small intestinal (SI) adaptation following surgical resection is essential for optimizing newborn growth and development, but the potential for adaptation is unknown. The authors developed an SI resection model in neonatal piglets supported by intravenous and enteral nutrition., Methods: Piglets (n = 33, 12-13 days old) were randomized to 80% SI resection with parenteral nutrition feeding (R-PN), 80% SI resection with PN + enteral feeding (R-EN), or sham SI transection with PN + enteral feeding (sham-EN). In resected pigs, the distal 100 cm of ileum (residual SI) and 30 cm of proximal SI were left intact. All pigs received parenteral nutrition postsurgery. Enteral nutrition piglets received continuous gastric infusion of elemental diet from day 3 (40:60 parenteral nutrition:enteral nutrition). Piglets were killed 4, 6, or 10 days postsurgery., Results: By 10 days, R-EN piglets had longer residual SI than R-PN and sham-EN pigs (P < .05). At days 6 and 10, R-EN piglets had greater weight per length of intact SI (P < .05) and isolated mucosa (P < .05) compared to other groups. Greater gut weight in R-EN piglets was facilitated by a greater cellular proliferation index (P < .01) by 4 days compared to other groups and greater overall ornithine decarboxylase activity vs R-PN piglets (P < .05)., Conclusions: This new model demonstrated profound SI adaptation, initiated early postsurgery by polyamine synthesis and crypt cell proliferation and only in response to enteral feeding. These changes translated to greater gut mass and length within days, likely improving functional capacity long term.

Background: Significant bowel lengthening can occur in an isolated intestinal segment with the use of linearly directed distractive forces, resulting in increased surface area and epithelial cell proliferation. We hypothesized that reimplantation of this lengthened intestine into normal jejunum would preserve this gain in intestinal length and function similar to normal jejunum., Methods: An intestinal lengthening device was inserted into isolated jejunal segments in pigs, and fully expanded over 8 days. Lengthened segments were then reimplanted into normal intestinal continuity. Pigs were studied after another 28 days. Function was assessed by motility, mucosal enzyme activity, barrier function, and intestinal ion transport., Results: Lengthened segments were significantly longer than control segments and had nearly 2-fold greater surface area. Bowel lengthening was maintained 4 weeks after reimplantation. Motility after reimplantation was similar to nonoperated pigs. Barrier function, mucosal disaccharidase levels, and electrophysiologic measures declined immediately after lengthening but returned to nearly normal levels 28 days after reimplantation., Conclusion: Bowel lengthening results in a transient decline in mucosal absorptive function and smooth muscle contractility. However, function approaches that of normal bowel after reimplantation into enteric flow. These data may support the use of this technique as a potential new option for the treatment of patients with short bowel syndrome.

If full-thickness mucosa, including the mucosal crypt, has been almost denuded, mucosa cannot regenerate as has been shown by animal models. The authors experienced an unusual mucosal regeneration exceed denuded bowel that occur in midgut volvulus of duration 2 days in a 6-day-old infant. Santulli's jejunostomy was performed using seriously denuded small bowel to prevent short bowel syndrome, despite the risks of leakage or stricture. Subsequently, stomal mucosa was fully regenerated when grossly identified 19 days after the second operation without any surgical complications.

Background: Small intestinal submucosa (SIS) is a porcine-derived, acellular, collagen-based matrix that has been tested without seeded smooth muscle cells (SMCs) for intestinal tissue engineering. We examined the expression patterns of contractile proteins of SIS with SMCs implanted in an in vivo rodent model., Materials and Methods: Intestinal SMCs were isolated from Lewis rat pups. Four-ply tubular SMCs-seeded SIS or blank SIS scaffolds were implanted in an adult rat jejunal interposition model. Recipients were sacrificed at 2, 4, and 8 wk following the implantation. The retrieved specimens were examined using antibodies against contractile proteins of SMCs., Results: Cultured intestinal SMCs expressed α-smooth muscle actin (α-SMA), calponin, and less smooth muscle myosin heavy chain (SM-MHC) in vitro. Cell-seeded SIS scaffolds contracted significantly over 8 wk of implantation but were comparable to SIS scaffolds without cell seeding. Implanted cell-seeded SIS scaffolds at 2 wk expressed extensive α-SMA, some calponin, and minimal SM-MHC. At 4 wk, α-SMA-expressing cells decreased significantly, whereas calponin or SM-MHC expressing cells were rarely detected. A small number of α-SMA-expressing cells were present at 8 wk, whereas more calponin or SM-MHC expressing cells emerged in proximity with the anastomotic interface., Conclusions: Cell-seeded SIS contracted significantly after implantation, but the expressions of contractile proteins were present at the site of SIS interposition. No organized smooth muscle was formed at the site of implantation. A better scaffold design is needed to produce structured smooth muscle., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Ischemia and reperfusion (IR) injury of the intestine is a major cause of morbidity and mortality following small bowel transplantation. The current study evaluates the effect of ischemic preconditioning (IPC) on the intestinal microcirculation in the late phase of IR injury of the intestine., Methods: Sixty rats were randomly allocated to 5 study groups (n = 12 per group): (1) sham, (2) IR (3) IPC, (4) pyrrolidine dithiocarbamate (PDTC) (HO-1 inducer), and (5) zinc protoporhyrin (ZnPP) (HO-1 inhibitor). Mucosal perfusion and leukocyte-endothelial interactions were measured with the aid of an intravital microscope. At the end of the experiments, blood samples for lactate dehydrogenase (LDH) levels and biopsies of ileum for histologic evaluation were obtained., Results: IPC significantly improved the mucosal perfusion and decreased the leukocyte-endothelial interactions. Histologic examination showed that ileal mucosa was significantly less injured in the IPC and PDTC groups as compared with the IR group., Conclusions: IPC protects the intestine from late reperfusion injury. HO-1 is involved in this protection. These findings may be of significant importance in clinical small bowel transplantation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: Few infant animal models have been used to study infantile short bowel syndrome (SBS). Most SBS models involve removal of the proximal small bowel followed by jejunoileal anastomosis, which has unclear clinical relevance to human infantile SBS that often results from surgical treatment for necrotizing enterocolitis and involves removal of the ileum, ileocecal valve, and part of or the entire colon. Our objective was to develop a more appropriate SBS model in developing rats., Materials and Methods: Twenty-day-old weanling rats were divided into 2 surgery groups, ileocecal resection (ICR) and sham groups, and a control group that did not undergo surgery. All were fed a liquid diet ad libitum for 7 days after surgery or for 7 days in the controls, and body weight, food intake, and stool changes were recorded daily. The rats were then euthanized and intestinal lengths and weights were recorded. Samples of intestine from the distal jejunum and proximal colon were collected for histology. Mucosal samples from the middle, distal jejunum, and colon were collected for measurements of mucosal weights, DNA, RNA, and protein levels. Maltase activity was determined in the small intestine., Results: Eighty-five percent of rats survived the ICR with subsequent development of diarrhea, hyperphagia, and poor growth. Adaptive responses to ICR, as compared with sham, were evidenced by increased intestinal and mucosal weights, DNA, RNA, and protein levels, increased maltase activity and villous thickness in distal jejunum, and increased mucosal thickness in the colon., Conclusions: This ICR model in weanling rats is appropriate for studying human infantile SBS.

Recent evidence suggests that bombesin (BBS) is involved in modulation of growth and differentiation of normal small intestine. The purpose of the present study was to evaluate the effects of BBS on enterocyte turnover after massive small bowel resection in a rat. Male Sprague-Dawley rats were divided into three experimental groups: Sham rats underwent bowel transection and re-anastomosis, short bowel syndrome (SBS) rats underwent a 75% small bowel resection, and SBS-BBS rats underwent bowel resection and were treated with BBS given subcutaneously at a dose of 20 mug/kg, once daily, from postoperative day 3 through 14. Parameters of intestinal adaptation (bowel and mucosal weights, mucosal DNA and protein, villus height and crypt depth), enterocyte proliferation and enterocyte apoptosis were determined in jejunum and ileum on day 15 following operation. RT-PCR technique was used to determine Bax and Bcl-2 gene expression in ileal mucosa. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with P less than 0.05 considered statistically significant. Treatment with BBS resulted in a significant increase in ileal bowel and mucosal weight, ileal mucosal DNA and protein, jejunal and ileal villus height, jejunal crypt depth, and jejunal and ileal proliferation index compared to SBS-animals. SBS rats showed a significant increase in Bax and Bcl-2 expression in ileum that was accompanied by a significant increase in cell apoptosis compared to sham animals. SBS-BBS rats demonstrated a significant decrease in Bax and Bcl-2 expression in ileum and a decrease in apoptotic index compared to SBS-animals. In conclusion, in a rat model of SBS, BBS enhances enterocyte turnover and stimulates structural intestinal adaptation. Decreased Bax expression may be responsible for the inhibitory effect of BBS on enterocyte apoptosis.

Intestinal failure is a condition characterized by malnutrition and/or dehydration as a result of the inadequate digestion and absorption of nutrients. The most common cause of intestinal failure is short bowel syndrome, which occurs when the functional gut mass is reduced below the level necessary for adequate nutrient and water absorption. This condition may be congenital, or may be acquired as a result of a massive resection of the small bowel. Following resection, the intestine is capable of adaptation in response to enteral nutrients as well as other trophic stimuli. Identifying factors that may enhance the process of intestinal adaptation is an exciting area of research with important potential clinical applications.

Ischemic injury of the small bowel may recover after revascularization, provided that full-thickness infarction did not occur. Animal studies showed that if the mucosal crypts remain viable, rapid mucosal restitution occurs hours after injury. The treatment of transmucosal infarction that does not extend to full wall thickness, however, was not investigated thoroughly. The patient presented had a mesenteric event leading to resection of about half of his small bowel. The unresected segment had severe ischemic injury, which seemed to cause transmucosal, but not transmural, infarction. Imaging of the remaining small bowel revealed a seromuscular layer denuded of mucosa. The ischemic damage was too deep to allow rapid regeneration, and the patient had short-bowel syndrome. A year later, during operation for stricture complications, new mucosa covered parts of the small-bowel surface, encouraging the surgeon to elect a conservative approach. Sixteen months after the injury, normal mucosa covered the entire small bowel, and enteral feeding resumed successfully. This report shows that infarcted small-bowel mucosa may regenerate even months after injury.

Although total parenteral nutrition prevents patients with short bowel syndrome from dying of starvation, having short bowel remains a severely debilitating condition. The best current treatment for inadequate absorptive surface area is through intestinal transplantation. However, this therapy is associated with significant morbidity and patients suffer from consequences of long-term immunosuppression. Additionally, the numbers of organs are limited. A new frontier in medicine is the field of tissue engineering. We will review the progress of intestinal bioengineering with a focus on the use of animal models. Investigators initially used autologous tissue as a patch to study intestinal regeneration. Subsequent studies focused on the use of absorbable biomaterials as a patch for tissue ingrowth. The most novel methodology consists of seeding a resorbable scaffold and implanting this construct to observe the regeneration of neointestine. Successful creation of esophagus, stomach, small bowel and colon has been demonstrated. Although these studies are preliminary, the results suggest that tissue-engineered intestine will become a real therapeutic option in the not too distant future for patients with inadequate intestinal tissue.

Introduction: After establishing a new method of autologic-allotopic ileum mucosa transplantation as a therapy for short-bowel syndrome, the effects of glutamine and human epithelial growth factor (human EGF) on the transplanted ileum mucosa were evaluated., Methods: Ileum mucosa was transplanted in 28 young beagle dogs in a demucosed vascularised transverse colon segment. The ileum mucosa was kept in place with silicone stents in all animals. Eight animals of the control group were irrigated with saline solution. In the second group with 10 animals, 100 mg/kg glutamine were administered daily in the lumen. The 10 animals of the third group were treated with 25 microg/kg human EGF per day subcutaneously and irrigated with saline solution. 4 weeks later, histological specimens were harvested from the colon coat-ileum mucosa complex, the normal ileum and normal colon. Lumen diameter, percentage ileum mucosa uptake as well as mucosa and colon muscle coat thickness were evaluated., Results: In all groups, the diameter of the lumen was larger than 10 mm after fixation, due to the silicone stent. The group with glutamine irrigation showed the largest lumen diameter. A complete mucosa lining of the inner surface of the colon muscle coat was achieved in none of the animals. The highest percentage of ileum mucosa uptake was found in the group with glutamine irrigation. In most animals, the transplanted ileum mucosa was markedly thinner than normal ileum mucosa. Only in the group with glutamine irrigation did we find two animals with nearly normal mucosa thickness. The longitudinal muscle of the transplanted colon coat was thicker in all three groups compared to normal colon. There were no differences in thickness of the circular muscle in all animals compared to normal colon., Conclusions: Silicone stents maintain a lumen after autologic-allotopic ileum mucosa transplantation. However, additional irrigation with glutamine, as well as treatment with human EGF subcutaneously could not provide a complete lining of the colon muscle coat with transplanted ileum mucosa. A modification of the operative procedure is necessary to achieve a colon muscle coat that is completely lined with ileum mucosa before the absorptive capacity of the transplanted colon coat-ileum mucosa complex can be evaluated.

Introduction: Since a standard therapy for short bowel syndrome does not yet exist, every search for new surgical methods would be worthwhile. In previous studies we could show that autologous-allotopic ileum mucosa transplantation is feasible. After a modification of our technique a vascularized colon muscle coat lined completely with transplanted ileum mucosa could be engendered., Method: In 12 young beagles autologous ileum mucosa was transplanted in a demucosed vascularized transverse colon segment. The colon coat-ileum mucosa complex was anastomosed with the small bowel immediately after transplantation, 4 weeks later the animals were sacrificed and histology specimens were harvested from the colon coat-ileum mucosa complex, normal ileum and normal colon. After fixation in 2.5% glutaraldehyde the samples were frozen (-40 degrees C) and 14 micro m sections were stained with hemalaun and eosin. The lumen diameter, the mucosa, submucosa and colon muscle coat thickness, as well as the mucosal crypt depth were evaluated., Results: The diameter of the colon coat-ileum mucosa-complex was smaller than the diameter of normal ileum and colon with no significant stenosis. There were no marked differences in thickness of mucosa and depth of the mucosal crypts compared to the controls, but the transplanted mucosa showed a slightly higher rate of shortened villi. The submucosal layer was thicker following transplantation and showed good neovascularization. The circular muscle layer of the transplanted colon coat was up to 178% thicker and the thickness of the transplanted longitudinal muscle layer differed between 58% and 143% in comparison to normal colon., Conclusions: Only a few histologic differences between transplanted and normal ileum mucosa could be observed after autologous-allotopic ileum mucosa transplantation. Therefore a nearly normal function of the colon coat-ileum mucosa complex has to be expected. Long term experiments of the histologic changes as well as further functional studies are on-going in order to finally apply autologous-allotopic ileum mucosa transplantation clinically.

The surgical treatment of short-bowel syndrome has been traditionally based on the correction of mechanical obstruction, which is responsible for bacterial overgrowth syndrome, or on intestinal expansion procedures. Since the introduction of clinical intestinal transplantation by Lillehei in 1964, there have been remarkable advances in the immunosuppressive regimens to control rejection and in preservation techniques, monitoring and critical care. Newer and more powerful immunosuppressants have helped to transform intestinal transplantation into a clinical reality-transplantation can now be a life-saving procedure for patients with intestinal failure. It is currently indicated in the event of life-threatening complications of an underlying disease or from total parenteral nutrition (TPN). Rehabilitation in successful cases is excellent.

Purpose: The aim of this study was to investigate the early adaptive responses in metabolism and gut function after massive small bowel resection., Methods: Male Wistar rats underwent an 80% small bowel resection (Ent group, n = 9) or a transection and reanastomozing (Sham group, n = 7). After 24 hours, substrate fluxes across the gut were determined together with intestinal protein synthesis, polyamine concentrations in gut tissue, and gut function by testing intestinal permeability using the urinary recovery of lactulose and rhamnose. To test for the effect of starvation, healthy starved rats were studied., Results: In the Ent group, intestinal uptake of glucose, lactate, glutamine, phenylalanine, branched chain amino acids, and total amino acids were equal to or higher than that in Sham rats. Intestinal protein synthesis increased, accompanied by an increase in spermidine to spermine polyamine ratios in the ileum and in the jejunal muscular layer. The urinary lactulose to rhamnose ratio also increased, suggesting increased intestinal permeability., Conclusions: 24 hours after massive small bowel resection, adaptive responses in metabolism and gut function already can be observed, as indicated by increased intestinal uptake of substrates and increased protein synthesis. This, however, is accompanied by an increase in intestinal permeability, which may indicate impaired intestinal barrier function. J Pediatr Surg 36:1746-1751., (Copyright 2001 by W.B. Saunders Company.)

Background: Small intestinal submucosa (SIS) is an extracellular matrix used in tissue engineering studies to create de novo abdominal wall, urinary bladder, tendons, blood vessels, and dura mater. The purpose of this study is to evaluate the feasibility of using SIS as a scaffold for small bowel regeneration in an in situ xenograft model., Materials and Methods: Twenty-three dogs had a partial defect created on the small bowel wall which was repaired with a SIS patch. Four dogs underwent small bowel resection with placement of an interposed tube of SIS. The animals were followed 2 weeks to 1 year., Results: Three of the 23 dogs with SIS placed as a patch died shortly after surgery due to leakage from the site. The other 20 dogs survived up to time of elective necropsy with no evidence of intestinal dysfunction. At necropsy, the bowel circumference in the patched area had no stenosis. Histological evaluation showed the presence of a mucosal epithelial layer, varying amount of smooth muscle, sheets of collagen, and a serosal covering. Architecturally, the layers were not well organized in the submucosal region. An abundance of inflammatory cells was present in the early postoperative period but receded with time. All 4 dogs with a tubular segment of SIS interposed had significant problems. One had partial obstruction at 1 month, and 3 died in the early postoperative period due to leakage., Conclusions: This preliminary study suggests that SIS patches can be used for small bowel regeneration. Tubular segmental replacement is not feasible at this time., (Copyright 2001 Academic Press.)

The aim of surgical treatment of short bowel syndrome is to increase the intestinal absorptive capacity by increasing the area of absorption or by slowing intestinal transit. The use of serosal patching to grow new intestinal mucosa is a technique for enlarging the intestinal surface. The regenerated intestine develops by lateral ingrowth from the neighbouring mucosa and is functionally similar to normal intestinal mucosa. The present review summarizes the main contributions of the rabbit, the rat and the canine models used to date for growing neomucosa using the serosal patch technique, as well as examining the influence of some growth factors on the development of neomucosa.

Background: Control of allograft rejection remains the most difficult dilemma in intestinal transplantation. Standard endoscopic surveillance to date has not been always accurate in the diagnosis of rejection. We describe the first application of a zoom video endoscope in monitoring graft mucosa in humans after intestinal transplantation., Method: A zoom video endoscope, which can magnify the image up to 100-fold, was used in this study. The patient was a 31-year-old man who received an isolated intestinal transplant. Surveillance endoscopy with the zoom video endoscope was performed through the ileostomy. Endoscopic biopsies were done at the same time., Results: The zoom video endoscope showed the microscopic architecture of the graft mucosa such as villi and crypts with outstanding quality. We found that an enlargement of the crypt areas appeared to correlate with morphologic changes of early rejection. This finding was reversed with the treatment of rejection., Conclusions: The zoom video endoscope successfully showed the detailed information of intestinal mucosa. The ability to visualize a more representative view of the graft mucosa could lead to better detection of early rejection. A greater experience with this unique method will provide more accurate assessment of the intestinal allograft.

There is no standard treatment for the short-bowel syndrome. The aims of surgical therapy are based on: slowing the intestinal transit, increasing the absorbing intestinal area and small-bowel transplantation. Searching for a new surgical treatment we developed an alternative for increasing the absorbing small-bowel area by means of autogenic allotopic small-bowel mucosa transplantation in beagle dogs. In young animals we isolated the transverse colon leaving the blood supply intact. Colonic continuity was reestablished and two abdominal stomata were performed at the ends of the isolated transverse colon. A week thereafter the colonic mucosa of the isolated transverse colon was surgically removed and autologous small-bowel mucosa was transplanted in the demucosed colon. The animals were then sacrificed 2, 4 and 6 weeks after transplantation and the colon-coat-ileal-mucosa complex (CIC) was histologically examined. The ileal mucosa could be transplanted in the demucosed colon showing histological characteristics of ileal mucosa. The circular muscle of the colon coat developed a hypertrophy which was present even 6 weeks after transplantation. In this study we could show that autogenic allotopic small-bowel mucosa transplantation is feasible in beagle dogs and may prove a novel method of small bowel expansion in cases of small-bowel syndrome.

Background/purpose: Previous studies have shown that intestinal crypt cell transplantation using biodegradable scaffolds can generate stratified epithelium reminiscent of embryonic gut. The authors propose to tissue engineer small intestine on biodegradable scaffolds by transplanting intestinal epithelial organoid units, which maintain the epithelial mesenchymal cell-cell interaction necessary for epithelial survival, proliferation, and differentiation., Methods: Intestinal epithelial organoid units were isolated from neonatal Lewis rats by enzyme digestion and differential sedimentation. Organoid units were seeded on to tubular scaffolds made of nonwoven polyglycolic acid (PGA) sprayed with 5% polylactic acid (PLA). Polymers either were coated (28 constructs) or noncoated (33 constructs) with collagen type I. A total of 61 organoid unit polymer constructs were implanted into 61 animals. Animals were killed and constructs harvested at 2, 6, 7, 8, 9, 10, 12, and 14 weeks., Results: Histological analysis showed formation of neomucosa characterized by columnar epithelium with goblet, and paneth cells were evident in 47 of the 61 constructs. The outer walls were composed of fibrovascular tissue, degradable polymer, extracellular matrix, and smooth muscle-like cells. Immunofluorescent microscopy showed apical staining of brush border enzymes, sucrase and lactase, and basolateral staining for laminin, indicating the establishment of cell polarity. Electrophysiology of Ussing-chambered neomucosa and adult ileal mucosa exhibited similar transepithelial resistance., Conclusion: These results suggest that intestinal crypt cells heterotopically transplanted as epithelial organoid units on PGA-PLA tubular scaffolds can survive, reorganize, and regenerate complex composite tissue resembling small intestine demonstrating organ morphogenesis, cytodifferentiation, and phenotypic maturation.

Parenteral nutrition and improving supportive treatment have resulted in prolonged survival for patients with short bowel syndrome. However, definitive therapy for patients with short bowel syndrome must focus on increasing small intestinal mucosal mass. Intestinal lengthening procedures rely on intestinal dilation to accomplish this. The authors hypothesized that partial intestinal obstruction would result in consistent dilation of the intestine and would provide increased intestinal mass for use in intestinal lengthening. The authors developed a partially obstructing prosthetic valve to dilate the intestine before intestinal lengthening. This report describes the changes elicited by the valve. Twelve weanling pigs were divided randomly into two groups of six. One group had valve placement 240 cm distal to the ligament of Treitz; the other had sham surgery. The survival rate was 100% for both groups, and the mean weight gain was similar. Both groups were fed pig chow mush and were killed 5 weeks after surgery. Intestinal diameter was measured, and the small intestine was harvested, preserved, and sectioned for microscopic examination. The mean bowel diameter 15 cm proximal to the valve was 4.7 cm in the valved group and 3.3 cm in the sham group (42% increase). Total mucosal thickness, villus height, crypt depth, and villus density were significantly greater for the valved pigs in all sections (proximal and distal to the valve). Surface index and intestinal circumference were significantly greater in the valved pigs in all sections proximal to the valve, but there was no significant difference in these values for sections distal to the valve. There was no significant difference in villus cell density between the two groups at any location. Chronic partial obstruction of the small intestine results in consistent dilation of the intestine, with growth of all layers of the bowel, including the mucosa. This dilation and mucosal growth results in a true increase in surface area and is an ideal first step toward sequential lengthening.

Young female beagles underwent either 85% resection of the small intestine; simultaneous 85% resection and patching of incised ideal remnant with colon serosa or with muscularis propria from transposed colon; or muscularis propria patching of ileum without resection of the small intestine. Patch areas were created in antiperistaltic position of participating bowel loops. After 20 weeks 50% of serosal patch and 34% of muscularis propria patch were overgrown by neomucosa. After 40 weeks 75% of the serosal patch was covered by neomucosa. Serosal patch area at necropsy 20 weeks after 85% resection of small intestine was 60% of the initial size; muscularis propria patch showed 44% of its primary area, but was only 12% of the initial surface area without bowel resection. Increases in resorptive surface consisted of neomucosa and an impressive adaptive elongation of short bowel, that was intensified by the simultaneous growth of the neomucosa.

An isolated bowel segment (IBS) was created in dogs by omentoenteropexy, using staged procedures. (1) Omentoenteropexy was performed at the antimesenteric border of a 15-cm jejunal segment, which was exteriorized at both ends (IBSB). (2) After 6 weeks, once dual vascularization to the IBS had been established, its mesentery was divided (IBSA) or longitudinally split, thus achieving its elongation (IBSE). A control dog underwent a Thiry-Vella (T-V) loop procedure of an identical jejunal segment. Viability of the IBSB and IBSA was previously proven by the authors, through angiographic studies. In the present study, the absorption capability of IBS variants was assessed using in situ luminal perfusion, with a bicarbonate buffer containing glucose and labeled glycine. Jejunal transport rates of these solutes were calculated from the differences in their concentrations in the perfusion solution and in the effluent. Comparisons were made among the IBS variants and between them and the T-V loop. No significant difference in the absorption capability of glucose and glycine was noted between the various IBS variants. There was a marked reduction of glucose absorption and a moderate reduction of glycine absorption in all IBS variants. when compared with the fresh T-V loop, most probably because of disuse atrophy of the mucosa. In conclusion, absorption of glucose and glycine is preserved in the IBS, created by omentoenteropexy, both after its mesenteric division and following the IBS elongating procedure.

The creation of intestinal neomucosa on grafts or materials implanted in the intestinal wall is one of the therapeutic procedures that has been tested in the short bowel syndrome. This paper presents the results obtained after intestinal implanting lyophilised dural patches in an experimental model of massive intestinal resection in rats. Data were contrasted with those of a control group subjected to massive resection without patches. The findings reveal: 1) high mortality related to the surgical technique; 2) slight improvement in the ponderal curve; 3) slowing down of intestinal transit; 4) neomucosa on the patch, with histological characteristic similar to normal. We conclude that although the creation of neomucosa on dural patches is feasible and conditions a slight improvement in the animal's nutritive status, application of the procedure is not practical in treatment for the short bowel syndrome due to the high mortality rate.

An isolated bowel segment (IBS) is a loop of intestine that has been freed from its mesenteric attachment after the development of vascular collaterals between the antimesenteric surface of the gut and the host organ. Surgical creation of such artificially vascularized isolated bowel segments is of interest to researchers for a variety of studies, and may be useful in the treatment of short bowel syndrome, allowing longitudinal division of the remaining small bowel to double its length. We created four surgical variants to study the ability of the collateral blood supply to maintain mucosal integrity in the presence or absence of normal luminal contents. In all groups, a collateral blood supply was created in a 5- to 7-cm segment of adult rat jejunum by hepatoenteropexy (Iowa model II). In Thiry-Vella (T-V) and isolated bowel segment (IBS) rats, this segment was exteriorized at both ends to exclude luminal contents. Control and IBS in continuity (IBS-C) loops were left in continuity. The mesentery of IBS and IBS-C rats was divided 5 weeks later, leaving the experimental segment entirely dependent on the collateral circulation. All animals were harvested at 7 weeks after the initial surgery. Tissues were analyzed for mucosal weight, protein content per centimeter of bowel, length of villi, depth of crypts, DNA content, and sucrase activity. We found that segments retaining luminal continuity had significantly higher mucosal weight and DNA content per centimeter of bowel compared with exteriorized loops.

Only scarce knowledge exists of morphologic changes after antiperistaltic reversal of the small intestine. Previous animal models using a reversed segment of the small intestine after massive intestinal resection have been mostly concerned with assessing absorption. A rat model was therefore developed for the purpose of studying mucosal surface area in the small intestine after reversal of an intestinal segment. A reversal of 10 cm, representing a length of about 10%, was found suitable for the investigation. Marked dilatation of the reversed segment occurred. A pronounced increase in mucosal surface area caused by mucosal hyperplasia was observed. The mucosal surface area in an anastomosed, but not reversed, segment also increased markedly compared with a group undergoing no operation, although less than in the reversed segment. We conclude that a reversed intestinal segment will increase mucosal surface area in an optimal length used for this purpose. This increase is possibly caused by prolonged exposure to intestinal chyme.

A method of small bowel mucosal augmentation called ileal mucosal fenestration and colonic autotransplantation (IMFCA) was devised and tested in pigs. In this technique, a vascularized mucosal graft was harvested from a 12-cm ileal loop, fenestrated by serial incision and then expanded to 20 cm. A 20-cm colonic loop was isolated and surgical mucosectomy was carried out. The fenestrated ileal mucosal graft was then autotransplanted into the prepared colon and the resulting composite structure was exteriorized as a Thiry-Vella loop. With this technique, ileal mucosal fenestrations healed by lateral epithelial in-growth, giving a new mucosal continuum within the recipient colon. At 60 days after surgery, the surface area of transplanted mucosa exceeded that within the original ileal loop by approximately 85 per cent. At this time, the transplanted mucosa had morphology and capacity for Na(+)-dependent glucose transport which were indistinguishable from those of control ileal mucosa.

The technics of growing of small bowel neomucosa is one of the possible surgical therapies for the treatment of the short bowel syndrome. We carried out an experimental study in rats implanting patches and tubes of dura mater in the antimesenteric border of intestine. The growth of normal neomucosa is demonstrated. The animal tolerance to the dura mater patch is established in 3-4 cms. We also have proved that dura mater tubes are inefficacious. The dura mater is a good support for the growth of the small bowel neomucosa; however, it's necessary to prove their utility in the surgical treatment of short bowel syndrome.

The behavior of jejunal to colonic mucosal autografts was studied in an experimental animal model of short bowel syndrome (SBS). Histological appearances, enterocyte enzyme activities, and in vitro glucose transport were studied at the donor and recipient graft sites in control, short-bowel syndrome, and gastrocolic fistula 5-week-old Sprague-Dawley rats. Small intestinal function was maintained in the jejunocolonic graft after 80% small bowel resection; animals in which small bowel was not resected showed loss of graft function and enzyme activity. This effect is dependent on the presence of jejunal chyme: after gastrocolic fistulae, the jejunum to colon grafts lost jejunal functional activities. Total parenteral nutrition did not alter graft behavior but improved the postoperative mortality of the procedures. The results provide additional information on intestinal adaptation in SBS.

Growing intestinal neomucosa in patched intestinal defects has been investigated as a means of permanently increasing the absorptive capacity in the short bowel syndrome. Several factors, including luminal contents, appear to affect the growth and function of the neomucosa. The purpose of this study was to compare function and rate of growth of neomucosa in patched defects of the jejunum and ileum. In both the jejunum and ileum of 11 New Zealand white male rabbits 2 X 5-cm patched intestinal defects were created using the serosal surface of adjacent colon. The animals were sacrificed at 4 weeks (n = 6) and 8 weeks (n = 5) after operation. Grossly there was more complete coverage of the defect by neomucosa in the ileum at both 4 and 8 weeks (99.1 +/- 1.1% vs 92.6 +/- 6.3% overall P less than 0.005). Villous height of the ileal neomucosa was similar to normal mucosa at 8 weeks (209 +/- 21 vs 244 +/- 18 m) but was significantly less in the jejunum (209 +/- 16 vs 273 +/- 16 m, P less than 0.005). Glucose uptake by neomucosa was greater in the ileum than the jejunum (3.34 +/- .84 vs 2.39 +/- .46 nmole/min/mg, P less than 0.05) but was similar to normal mucosa at both sites. Disaccharidase activity (lactase, sucrase, and maltase) was similar in both jejunum and ileum but was significantly less in ileal neomucosa than in normal mucosa (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Exogenous 16,16-di-methyl-prostaglandin (PG) E2 administration augments mucosal hyperplasia after massive small bowel resection in the rat. We, therefore, evaluated the ability of aspirin to inhibit mucosal PG synthesis in the small intestine and further evaluated the effects of reduced PG synthesis on mucosal adaptation after a 70% jejunoileal resection in male Sprague-Dawley rats. Sixteen of 27 resected and 8 of 16 sham-operated rats were given aspirin 20 mg/kg body wt subcutaneously every 8 h for 12 days; the remainder were given vehicle only. Although mucosal PGE2, PGF2 alpha, and thromboxane B2 synthesis were all reduced by aspirin administration to 20-40% of the control values, mucosal adaptation in resected animals as measured by mucosal weight, DNA, protein, and maltase levels was only inhibited in the distal ileum. Aspirin did not affect these values in the duodenum, the upper jejunum, and the midileum. This study provides evidence for some involvement of endogenous PGs in regulation of the mucosal adaptation process in the distal ileum after massive small bowel resection in the rat. However, lack of inhibition more proximally suggests that factors other than PGs are more important.

The problems pertaining to the surgical therapy of the short bowel syndrome have not yet been solved despite numerous methods for the retardation of stool passage and the enlargement of the absorbent small intestinal surface. We therefore developed a model for the cultivation of neomucosa of endogenous origin on the perietal peritoneum of Wistar rats. In 191 young Wistar rats of each sex with a body weight of 200 to 500 grams, a loop of the small intestine was largely blocked off from the intestine with the help of Braun's anastomosis, opened up and thus sewed onto the parietal peritoneum of the laboratory animal. This led to the formation of a tube with two-thirds of the circumference consisting of small intestine and one-third of peritoneum. After the peritoneal part had been over-grown by neomucosa, the original jejunal part was removed and a tube consisting of perietal peritoneum with a muscular portion was formed around the neomucosal island. After another 4-5 months, a mucosal tube with complete neomucosal lining had formed. It was demonstrated by histological, enzyme histochemical and electron microscopy methods that the neomucosa is indeed a functioning small intestinal mucosa. Intragastric administration of a prostaglandin E2 analogue resulted in accelerated neomucosal growth as well as an increase in the height of the villi and the depth of the cryptae and a decrease in the thickness of the granular tissue. Measurements of the accumulation of 14C glucose and its inhibition by ouabain confirmed the active transport of the 14C glucose in the cell of the small intestinal neomucosa. The cultivation of functioning small intestinal mucosa on the perietal peritoneum of rats was thus accomplished.