Intestinal Transplantation Research Articles

Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization

Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.

Historical Cohort Study of Congenital Isolated Hypoganglionosis of the Intestine: Determining the Best Surgical Interventions.

No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients were collected between 1992 and 2020, including the type of enterostomy, type of revision, and length of the intestines. Ganglion cells in the myenteric plexus were enumerated using Hu C/D staining. The ratio of the length of the small intestine to its height was defined as the intestinal ratio (IR). The outcomes were assessed using the stoma output, growth parameters including the body mass index (BMI), and parenteral nutrition (PN) dependency. All patients required a diverting enterostomy. The IR ranged from 0.51 to 1.75 after multiple non-transplant surgeries. The stoma types were tube-stoma, end-stoma, Santulli-type, and Bishop-Koop (BK)-type. Patients with Santulli- or BK-type stomas had better BMIs and less PN dependency in terms of volume than those with end-stomas or tube-stomas. Two patients with BK-type stomas were off PN, and three who underwent an intestinal transplantation (Itx) achieved enteral autonomy. The management of CIHG involves a precise diagnosis using Hu C/D staining, neonatal enterostomy, and stoma revision using the adjusted IR and Itx if other treatments do not enable enteral autonomy.

Long-term outcomes of liver transplantation for homozygous familial hypercholesterolaemia in Australia and New Zealand

Background and aimsHomozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. MethodsWe analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. ResultsNine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4–27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. ConclusionsLT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible.

Living-donor intestinal transplantation

Due to advances in surgical techniques, perioperative care, and new immunosuppressive agents, intestinal transplantation has become a valid therapeutic choice for chronic intestinal failure. Intestinal transplantation has been performed most commonly using deceased donation, while less than 2% of which have been from living donation. Living donor intestinal transplantation obtaining a segmental intestinal graft, usually from close relatives. Preliminary results show that acute/chronic rejection rates, postoperative opportunistic infections, and graft versus host disease are significantly reduced after living donor intestinal transplantation, contributing to improved graft and patient survivals. Due to a severe shortage of organ donation, especially in children, living donor intestinal transplantation has increasingly become an important treatment option for patients with chronic intestinal failure in China.

S1795 An Evaluation of Infections and Outcomes Following Intestinal Transplantation

S1795 An Evaluation of Infections and Outcomes Following Intestinal Transplantation

S1186 Intestinal Microbiota Transplant vs Standard Management in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-Analysis of Randomized Controlled Trials

S1186 Intestinal Microbiota Transplant vs Standard Management in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-Analysis of Randomized Controlled Trials

S199 Recipient Functional Status Impacts on Short and Long-Term Intestinal Transplant Outcomes in US Adults: Evidence from the United Network for Organ Sharing Database 1994-2017

S199 Recipient Functional Status Impacts on Short and Long-Term Intestinal Transplant Outcomes in US Adults: Evidence from the United Network for Organ Sharing Database 1994-2017

S1824 Changing Landscape of Intestinal Transplant With Improving Survival Outcomes in Minority Population: A US Database Study From 1990-2022

S1824 Changing Landscape of Intestinal Transplant With Improving Survival Outcomes in Minority Population: A US Database Study From 1990-2022

Present state of intestinal transplantation in Japan

IntroductionIntestinal transplantation (ITx) is the ultimate treatment for intestinal failure (IF). In Japan, most cases of IF are a result of pediatric disease, including secondary or congenital intestinal disease or allied disorders of Hirschsprung’s disease. Here, we report the results of the Japanese ITx registry.MethodsA web-based survey form was completed. We investigated the number, age, sex, indication, surgical procedure, immunosuppressants, postoperative course, and the effects of transplantation in patients who underwent cadaveric or living-donor ITx.ResultsBy the end of 2022, 42 cases of ITx have been performed in 38 patients in Japan. The donor sources included cadavers (29 cases) and living donors (13 cases). The surgical method was isolated ITx (N = 40) and combined liver and ITx (n = 2). Survival rates were 92%, 73%, and 59% at 1 year, 5 years, and 10 years, respectively. Ninety percent of patients completely discontinued parenteral nutrition. Approximately 80% of the patients had a performance status of 1 or less, indicating that the QOL of patients after ITx was extremely good.ConclusionThe results of ITx are acceptable to treat IF patients and the QOL after transplantation is also good.

Histoire de la vaginoplastie : évolution technique et sociologique

Technical advances in gender-affirming genital surgery have allowed the modern surgeon to create a vagina, vulva and clitoris from a male sex. This surgery, commonly known as vaginoplasty, should in fact be identified as aidopoiesis, since it is not a question of improving an already existing vagina but of creating a female sex. Numerous technical advances made since 1930 throughout the world now offer a safe and proven surgical strategy for female genital gender affirmation. Most of these techniques are derived from advances in intersex genital surgery. The first vaginoplasties described in the context of gender affirmation were performed in Berlin in the 1930s. After the Second World War, the greatest advances in vaginoplasty were made in Denmark. It was not until Geroges Burou in Casablanca and Harold Gillies, aided by Ralph Millard in England, in the mid-fifties that the modern technique of invagination of the penile skin took over from neo-vaginal grafting techniques. The creation of the clitoris from the glans penis and a more aesthetic vulva were the major advances from the 1970s. Other flap or intestinal transplant techniques were also developed, often to correct the failure of penile skin invagination. Some of the patients who benefited from these early technical advances, such as Lili Elbe and Christine Jorgensen later on, helped to make this surgery, which had long remained taboo, popular with the general public. Pioneers such as the gynaecologist Georges Burou in Casablanca have contributed, with the greatest discretion, to the well-being of gender-affirmed people by improving these techniques. Today, this hard-won heritage cannot be ignored by surgeons interested in vaginoplasty.

Liver Inclusion Appears to Be Protective Against Graft Loss-Due-to Chronic But Not Acute Rejection Following Intestinal Transplantation.

In intestinal transplantation, while other centers have shown that liver-including allografts have significantly more favorable graft survival and graft loss-due-to chronic rejection (CHR) rates, our center has consistently shown that modified multivisceral (MMV) and full multivisceral (MV) allografts have significantly more favorable acute cellular rejection (ACR) and severe ACR rates compared with isolated intestine (I) and liver-intestine (LI) allografts. In the attempt to resolve this apparent discrepancy, we performed stepwise Cox multivariable analyses of the hazard rates of developing graft loss-due-to acute rejection (AR) vs. CHR among 350 consecutive intestinal transplants at our center with long-term follow-up (median: 13.5years post-transplant). Observed percentages developing graft loss-due-to AR and CHR were 14.3% (50/350) and 6.6% (23/350), respectively. Only one baseline variable was selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to AR: Transplant Type MMV or MV (p < 0.000001). Conversely, two baseline variables were selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to CHR: Received Donor Liver (LI or MV) (p = 0.002) and Received Induction (p = 0.007). In summary, while MMV/MV transplants (who receive extensive native lymphoid tissue removal) offered protection against graft loss-due-to AR, liver-containing grafts appeared to offer protection against graft loss-due-to CHR, supporting the results of other studies.

The human microbiome and modern approaches to its preservation (analytical review)

Annotation. The article is devoted to the analysis of modern data on the diversity of the microbiome of the human body and the characteristics of the latest trends for its preservation. Scientific search engines, databases of electronic resources PubMed, IRBIS, and Google Scholar were used for information analysis using bibliosemantic, system review methods. The results of research by Ukrainian and foreign scientists indicate a huge positive influence of the microbiome of the human body on physiological and biochemical processes. Specialists in biology and medicine differentiate the microbiome as an “organ”- system that participates in the processes of digestion and metabolism, provides protective functions of mucous membranes, and supports the immune system in working order. The analytical review presents modern data on the formation of the human microbiome as a result of the joint long-term evolution of the human body with microorganisms that inhabited its biotopes. References from scientific sources on the study of the localization of the microbiome and the interaction of microorganisms of different biotopes to maintain homeostasis are discussed in the work. Modern scientific data provide examples of microbiome disturbances in the etiology of human diseases. In particular, changes in the microbiome correlate with the occurrence of gastrointestinal and systemic diseases. Discussions continue among scientists about the causes of dysbiosis and ways to correct it. An analysis of the results of research on the feasibility of using certain means of improving the microbiome with the help of probiotics and intestinal microbiota transplantation was carried out. The article presents the latest classification of probiotic preparations, requirements for modern means of dysbiosis correction, and approaches to the creation of immobilized probiotics.

Application of Intestinal Barrier Molecules in the Diagnosis of Acute Cellular Rejection After Intestinal Transplantation.

Diagnosing acute rejection after intestinal transplantation currently heavily relies on histopathological analysis of graft biopsies. However, the invasive risks associated with ileoscopic examination and the inaccessibility for biopsy after ileostomy closure hinder real-time detection of rejection responses. Molecules comprising the intestinal barrier have been identified as physiological and molecular biomarkers for various bowel conditions and systemic diseases. To investigate the potential of barrier function-related molecules in diagnosing rejection after intestinal transplantation, plasma samples were collected longitudinally from transplant recipients. The samples were categorized into "indeterminate for rejection (IND)" and "acute rejection (AR)" groups based on clinical diagnoses at each time point. The longitudinal association between plasma levels of these barrier function-related molecules and acute rejection was analyzed using the generalized estimating equations (GEE) method. Logistic GEE models revealed that plasma levels of claudin-3, occludin, sIgA, and zonulin were independent variables correlated with the clinical diagnosis of acute rejection. The subsequent prediction model demonstrated moderate ability in discriminating between IND and AR samples, with a sensitivity of 76.0%, specificity of 89.2%, and accuracy of 84.6%. In conclusion, monitoring plasma levels of claudin-3, occludin, sIgA, and zonulin shows great potential in aiding the diagnosis of acute rejection after intestinal transplantation.

Preclinical Study of DCD and Normothermic Perfusion for Visceral Transplantation.

Considering recent clinical and experimental evidence, expectations for using DCD-derived intestines have increased considerably. However, more knowledge about DCD procedure and long-term results after intestinal transplantation (ITx) is needed. We aimed to describe in detail a DCD procedure for ITx using normothermic regional perfusion (NRP) in a preclinical model. Small bowel was obtained from pigs donors after 1h of NRP and transplanted to the recipients. Graft Intestinal samples were obtained during the procedure and after transplantation. Ischemia-reperfusion injury (Park-Chiu score), graft rejection and transplanted intestines absorptive function were evaluated. Seven of 8 DCD procedures with NRP and ITx were successful (87.5%), with a good graft reperfusion and an excellent recovery of the recipient. The architecture of grafts was well conserved during NRP. After an initial damage of Park-chiu score of 4, all grafts recovered from ischemia-reperfusion, with no or very subtle alterations 2days after ITx. Most recipients (71.5%) did not show signs of rejection. Only two cases demonstrated histologic signs of mild rejection 7days after ITx. Interestingly intestinal grafts showed good absorptive capacity. The study's results support the viability of intestinal grafts from DCD using NRP, contributing more evidence for the use of DCD for ITx.

Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.

Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.

The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers.

Unlike other solid organs, no standardized treatment algorithms exist for intestinal transplantation (ITx). We established a consortium of American ITx centers to evaluate current practices. All American centers performing ITx during the past 3 y were invited to participate. As a consortium, we generated questions to evaluate and collect data from each institution. The data were compiled and analyzed. Ten centers participated, performing 211 ITx during the past 3 y (range, 3-46; mean 21.1). Induction regimens varied widely. Thymoglobulin was the most common, used in the plurality of patients (85/211; 40.3%), but there was no consensus regimen. Similarly, regimens for the treatment of acute cellular rejection, antibody-mediated rejection, and graft-versus-host disease varied significantly between centers. We also evaluated differences in maintenance immunosuppression protocols, desensitization regimens, mammalian target of rapamycin use, antimetabolite use, and posttransplantation surveillance practices. Maintenance tacrolimus levels, stoma presence, and scoping frequency were not associated with differences in rejection events. Definitive association between treatments and outcomes, including graft and patient survival, was not the intention of this initial collaboration and is prevented by the lack of patient-level data and the presence of confounders. However, we identified trends regarding rejection episodes after various induction strategies that require further investigation in our subsequent collaborations. This initial collaboration reveals the extreme heterogeneity of practices among American ITx centers. Future collaboration will explore patient-level data, stratified by age and transplant type (isolated intestine versus multivisceral), to explore the association between treatment regimens and outcomes.

Intestinal Donation and Utilization: Single-Center Analysis Within Eurotransplant.

Intestinal donor criteria are classically kept strict, thereby limiting donor supply. Indications for intestinal transplantation (ITx) are rare, but improved outcome and new emerging indications lead to increased demand and relaxing donor criteria should be considered. We sought to compare the donor criteria of intestines transplanted at our center with predefined (per protocol) criteria, and to determine how relaxing donor criteria could impact the potential donor pool. Donor criteria used in 22 consecutive ITx at our center between 2000 and 2020 were compared with predefined criteria. Next, multiorgan donors effectively offered by our Donor Network to Eurotransplant between 2014 and 2020 were retrospectively screened, according to predefined and effectively used intestinal donation criteria. Finally, utilization rate of offered intestines was calculated. In our ITx series, the effectively used donor criteria were less strict than those initially predefined. With these relaxed criteria, a favorable 5-year graft/patient survival of 75% and 95%, respectively was reached. Applying these relaxed criteria would lead to a 127% increase in intestinal offers. Paradoxically, 70% of offered intestines were not used. In conclusion, a significant increase in intestinal donation could be obtained by relaxing donor criteria, while still achieving excellent outcome. Offered intestines are underutilized.

Heterotopic intestine and abdominal wall transplantation in a miniature swine: A model for graft immunology.

In order to accurately monitor graft immunology, we have developed a method for performing intestine and abdominal wall transplantation heterotopically in miniature swine. The procedure consisted of simultaneous segmental terminal ileum and full-thickness abdominal wall transplantation in Lanyu miniature swine, with the intestinal and the abdominal wall grafts being placed on the recipient's bilateral rear flank. Five transplantations were technically successful. One animal died on the first post-transplant day due to anesthesia-related issues, three abdominal wall and four intestinal grafts survived, while one abdominal wall graft failed due to vascular thrombosis. Acute cellular rejection (ACR) of the intestinal graft could occur preceding, simultaneously with or following ACR of the abdominal wall graft. Our experimental model demonstrates the technical feasibility of heterotopic intestine and abdominal wall transplantation in miniature swine without grafting in gastrointestinal continuity. This model could be suitable for further studies of graft immunology.

Stem cell Derived Extracellular Vesicles to Alleviate ischemia-reperfusion Injury of Transplantable Organs. A Systematic Review.

The possible beneficial effects of stem cell-derived EV on ischemia-reperfusion injury (IRI) in organ transplantation have been frequently investigated; however, the source of EV, as well as the methods of isolation and administration vary widely. We conducted a systematic review to summarize current pre-clinical evidence on stem cell-derived EV therapy for IRI of transplantable organs. PubMed, Embase and Web of Science were searched from inception until August 19th, 2022, for studies on stem cell-derived EV therapy for IRI after heart, kidney, liver, pancreas, lung and intestine transplantation. The Systematic Review Center for Laboratory animal Experiments (SYRCLE) guidelines were followed to assess potential risk of bias. The search yielded 4153 unique articles, of which 96 were retained. We identified 32 studies on cardiac IRI, 38 studies on renal IRI, 21 studies on liver IRI, four studies on lung IRI and one study on intestinal IRI. Most studies used rodent models of transient ischemic injury followed by in situ reperfusion. In all studies, EV therapy was associated with improved outcome albeit to a variable degree. EV-therapy reduced organ injury and improved function while displaying anti-inflammatory-, immunomodulatory- and pro-regenerative properties. A multitude of animal studies support the potential of stem cell-derived EV-therapy to alleviate IRI after solid organ transplantation but suffer from low reporting quality and wide methodological variability. Future studies should focus on determining optimal stem cell source, dosage, and timing of treatment, as well as long-term efficacy in transplant models.

Central venous catheter safety in pediatric patients with intestinal failure.

Children with intestinal failure (IF) require long-term central venous access to provide life-sustaining parenteral nutrition. Mechanical, thrombotic, and infectious complications are potentially life-threatening and may necessitate central venous catheter (CVC) replacement. Repeated central line replacements may lead to a loss of vascular access sites and increases risk for intestinal transplantation. Children with IF face unique challenges for CVC safety given their young age, altered anatomy, and increased risk of thrombosis and infection. The following review addresses preventative, diagnostic, and treatment strategies for central line safety concerns specific to children with IF as well as recommendations for promoting catheter safety during activities, travel, and emergencies.