Protective effect of bone marrow mesenchymal stem cells in intestinal barrier permeability after heterotopic intestinal transplantation

AIM: To explore the protective effect of bone marrow mesenchymal stem cells (BM MSCs) in the small intestinal mucosal barrier following heterotopic intestinal transplantation (HIT) in a rat model.

Attenuation of graft ischemia-reperfusion injury by urinary trypsin inhibitor in mouse intestinal transplantation

AIM: Ischemia/reperfusion (I/R) injury is one of the major obstacles for intestinal transplantation (ITx). Urinary trypsin inhibitor (Ulinastatin, UTI) suppresses proteases and stabilizes lysosomal membranes. We supposed that Ulinastatin would diminish I/R injury of intestinal graft.METHODS: UTI- treated group and untreated control group were investigated by histological assessment at 1.5, 4, 24, and 72 h after ITx. Myeloperoxidase (MPO)activity was used as the activity of neutrophils, and malondialdehyde (MDA) was used as an index of lipid peroxidation. TNFα and i-NOS mRNA expression in graft tissue were measured by semi-quantitative RT-PCR.CD11b+ Gr1+ cells in graft lamina propria were analyzed by flow cytometry.RESULTS: Histological scores of the graft showed that the tissue injury was markedly attenuated by UTI treatment at different time points after ITx, with reduced MPO and MDA value in the grafts. The expression of TNFα and i-NOS mRNA was profoundly inhibited, while the infiltration of CD11b+ Gr1+ cells into the intestinal graft was decreased in UTI group.CONCLUSION: Urinary trypsin inhibitor attenuates I/R injury in mouse intestinal transplantation by reducing monocytes infiltration and down-regulation of TNFα and i-NOS mRNA expression.

Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report

BACKGROUND Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab,such as induction therapy,salvage treatment for acute cellular rejection,and treatment for chronic ulcerative inflammation,in intestinal transplant recipients.However,the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data.We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation(ITx).CASE SUMMARY The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis.The patient underwent living-donor related intestinal transplant.His immunosuppression regimen consisted of daclizumab,tacrolimus,and steroids.Although he did not show rejection while on tacrolimus monotherapy,routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant.Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft.Since the endoscopic findings suggested ulcerative lesions in Crohn’s disease,infliximab treatment was considered.Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab.CONCLUSION Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.

Management of intestinal failure in inflammatory bowel disease:Small intestinal transplantation or home parenteral nutrition?

Inflammatory bowel disease and Crohn’s disease in particular, is a common cause of intestinal failure. Current therapeutic options include home parenteral nutrition and intestinal transplantation. For most patients, home intravenous therapy including parenteral nutrition, with a good probability of long-term survival, is the favoured choice. However, in selected patients, with specific features that may shorten survival or complicate home parenteral nutrition, intestinal transplantation presents a viable alternative. We present survival, complications, quality of life and economic considerations that currently influence individualised decision-making between home parenteral nutrition and intestinal transplantation.

Follow-up and surveillance of immunosuppressive treatment in intestinal transplantation

Objective To evaluate the efficiency of monitoring parameters and methods of immunosuppresive treatment in intestinal transplantation and to provide scientific evidence for establishment of Intestinal Transplant Registry.

Non-composite combined liver and intestinal allotransplantation

BACKGROUND: Patients with short bowel syndrome may require combined liver and intestinal transplantation due to total parenteral nutrition(TPN)-related liver damage. We report combined liver and intestinal allotransplantation as a non-composite technique in a patient in China. METHODS: During the operation, a 380 cm long intestine was transplanted with systemic drainage and aortic inflow, while the liver graft was placed in a piggyback fashion. Warm ischemic time of the donor graft was 2 minutes and 30 seconds, and cold ischemic time for intestinal and the liver graft was 6 hours and 40 minutes and 8 hours and 7 minutes, respectively. Immunosuppressants used after operation included tacrolimus, methylprednisolone, mycophenolate mofetil and Zenapax. RESULTS: The recipient recovered with no evidence of rejection and was kept well on tube feeding. Eventually, he died of massive hemorrhage of the thoracic cavity on day 210 after transplantation. CONCLUSION: The non-composite combined liver and intestinal allotransplantation is superior to composite technique in adult patients, particularly those who have had abdominal infection or repeated abdominal operations.

Semi-mature MyD88-silenced bone marrow dendritic cells prolong the allograft survival in a rat model of intestinal transplantation

Background Semi-mature dendritic cells （DCs） may induce tolerance rather than immunity.However,little is known about the regulatory mechanism by which these DCs induce transplant tolerance.Myeloid differentiation factor 88 （MyD88） is a key adaptor of Toil-like receptor signaling,which plays a critical role in DC maturation.Activation of MyD88-silenced immature DCs results in the generation of semi-mature DCs.We explored the possibility of using these DCs to induce intestinal transplant tolerance in rats.Methods MyD88 expression was silenced in bone marrow DCs （F344 rats） using small interfering RNAs for 24 hours,at which point,lipopolysaccharide （LPS） was added to the culture for another 48 hours.These cells were analyzed for their in vitro and in vivo tolerizing capacities.Results Semi-mature DCs expressing moderate levels of MHC class Ⅱ and low levels of co-stimulatory molecules were found to produce interleukin （IL）-10,while IL-12 production was decreased.In vitro co-culture with completely allogeneic T cells from Wistar rats led to a significant decrease in alloreactive T-cell responses.In vivo,the transfer of semi-mature DCs （1×106 ceils） followed by the transplantation of fully mismatched intestinal grafts （F344 rats） led to significantly prolonged survival compared to rats receiving immature and mature DCs.Serum from semi-mature DC-treated rats contained lower concentrations of the pro-inflammatory cytokines IL-2 and interferon-Y 5 days after transplantation.Conclusion Semi-mature DCs may promote inducible allograft tolerance and this study suggests a new strategy by which to facilitate the induction of transplant tolerance.

Recipient functional status impacts on short and long-term intestinal transplant outcomes in United States adults

BACKGROUND Recipient functional status prior to transplantation has been found to impact post-transplant outcomes in heart,liver and kidney transplants.However,information on how functional status,before and after transplant impacts post-transplant survival outcomes is lacking.AIM To investigate the impact of recipient functional status on short and long term intestinal transplant outcomes in United States adults.METHODS We conducted a retrospective cohort study on 1254 adults who underwent first-time intestinal transplantation from 2005 to 2022.The primary outcome was mortality.Using the Karnofsky Performance Status,functional impairment was categorized as severe,moderate and normal.Analyses were conducted using Kaplan-Meier curves and multivariable Cox regression.RESULTS The median age was 41 years,majority(53.4%)were women.Severe impairment was present in 28.3%of recipients.The median survival time was 906.6 days.The median survival time was 1331 and 560 days for patients with normal and severe functional impairment respectively.Recipients with severe impairment had a 56%higher risk of mortality at one year[Hazard ratio(HR)=1.56;95%CI:1.23–1.98;P<0.001]and 58%at five years(HR=1.58;95%CI:1.24–2.00;P<0.001)compared to patients with no functional impairment.Recipients with worse functional status after transplant also had poor survival outcomes.CONCLUSION Pre-and post-transplant recipient functional status is an important prognostic indicator for short-and long-term intestinal transplant outcomes.

Liver-inclusive intestinal transplantation results in decreased alloimmune-mediated rejection but increased infection

Background and aims:A co-transplanted liver allograft has been thought to protect other organs from rejection-mediated injury;however,detailed analyses of co-transplanted liver on intestinal allograft outcomes have not been conducted to date.The aimof the study was to compare immune-mediated injury,causes of graft failure and clinical outcomes between recipients who underwent either a liver-inclusive intestinal transplant(LITx)or liver-exclusive intestinal transplant(LETx).Methods:Between May 2000 and May 2010,212 adult patients undergoing LITx(n¼76)and LETx(n¼136)were included.LITx underwent either liver combined intestinal or full multivisceral transplantation.LETx underwent either isolated intestinal or modified multivisceral transplantation.Results:During 44.9631.4 months of follow-up,death-censored intestinal graft survival was significantly higher for LITx than LETx(96.9%,93.2%and 89.9%vs 91.4%,69.3%and 60.0%at 1,3 and 5 years;p¼0.0001).Incidence of graft loss due to rejection was higher in LETx than in LITx(30.9%vs 6.6%;p<0.0001),while infection was the leading cause of graft loss due to patient death in LITx(25.0%vs 5.1%;p<0.0001).Despite similar immunosuppression,the average number(0.87 vs 1.42,p¼0.02)and severity of acute cellular rejection episode(severe grade:7.9%vs 21.3%;p¼0.01)were lower in LITx than in LETx.Incidence of acute antibody-mediated rejection was also significantly lower in LITx than in LETx(3.6%vs 15.2%;p¼0.03).Incidence of chronic rejection was reduced in LITx(3.9%vs 24.3%;p¼0.0002).Conclusions:Intestinal allografts with a liver component appear to decrease risk of rejection but increase risk of infection.Our findings emphasize that LITx has characteristic immunologic and clinical features.Lower immunosuppression may need to be considered for patients who undergo LITx to attenuate increased risk of infection.

Chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction (CIPO) is a se- vere digestive syndrome characterized by derangement of gut propulsive motility which resembles mechanical obstruction, in the absence of any obstructive process. Although uncommon in clinical practice, this syndrome represents one of the main causes of intestinal failure and is characterized by high morbidity and mortality. It may be idiopathic or secondary to a variety of diseases. Most cases are sporadic, even though familial forms with either dominant or recessive autosomal inheritance have been described. Based on histological features in- testinal pseudo-obstruction can be classified into three main categories:neuropathies, mesenchymopathies, and myopathies, according on the predominant involvement of enteric neurones, interstitial cells of Cajal or smooth muscle cells, respectively. Treatment of intestinal pseu- do-obstruction involves nutritional, pharmacological and surgical therapies, but it is often unsatisfactory and the long-term outcome is generally poor in the majority of cases.

Latest developments in chronic intestinal pseudo-obstruction

Chronic intestinal pseudo-obstruction(CIPO)is a type of intestinal dysfunction presenting as symptoms of intestinal obstruction but without actual mechanical obstruction.An extremely low incidence,non-specific clinical symptoms,strong heterogeneity,and no definitive cause in some patients make CIPO very difficult to diagnose correctly.Imaging and gastrointestinal manometry are commonly used.Most patients have progressive worsening of their symptoms and require intervention,and nutritional assessment and treatment are very important to determine the prognosis.With improvements in surgical techniques,small bowel transplantation is a feasible treatment option for patients with advanced CIPO;however,the long-term prognosis for CIPO patients remains unsatisfactory.Generally,the disease is rare and difficult to diagnose,which leads to clinicians’lack of understanding of the disease and results in a high rate of misdiagnosis.This review describes the characteristics of CIPO and the latest developments in diagnosis and treatment,in detail.The goal of our review is to improve clinicians'understanding of CIPO so that the disease is identified quickly and accurately,and treated as early as possible to improve patients’quality of life.

Transplantation of an eight-organ multivisceraI graft in a patient with frozen abdomen after complicated Crohn's disease

To report an extended multivisceral transplantation （MVTx） including right kidney and ascending colon in a patient with complicated Crohn＇s disease （CD）. A 36-year old female suffering from short bowel syndrome and frozen abdomen due to fistulizing CD after multiple abdominal operations underwent MVTx of eight organs including stomach, pancreatoduodenal complex, liver, intestine, ascending colon, right kidney, right adrenal gland, and greater omentum in November 2003. Immunosuppression consisted of alemtuzumab, tacrolimus and steroids. The patient was off parenteral nutrition by postoperative wk 3. She experienced one episode of pneumonia. The patient recovered completely and discharged 2.5 mo and was doing well 30 mo after MVTx. This is one of the very rare cases in which a complete mulitivisceral graft of eight abdominal organs was transplanted orthotopically.

Potential importance of early treatment of SARS-CoV-2 infection in intestinal transplant patient: A case report

BACKGROUND Predispositions for severe coronavirus disease 2019(COVID-19)are age,immunosuppression,and co-morbidity.High levels of maintenance immunosuppression render intestinal transplant(ITx)patients vulnerable for severe COVID-19.COVID-19 also provokes several gastroenterological pathologies which have not been discussed in ITx,so far.CASE SUMMARY During the second European COVID-19 wave in November 2020,an ITx recipient was admitted to the hospital because of electrolyte disturbances due to dehydration.Immunosuppression consisted of tacrolimus,azathioprine,and low-dose corticosteroids.During hospitalization,she tested positive on screening COVID-19 nasopharyngeal polymerase chain reaction swab,while her initial test was negative.She was initially asymptomatic and had normal inflammatory markers.Tacrolimus levels were slightly raised,as Azathioprine was temporarily halted.Due to elevated Ddimers at that time,prophylactic low-molecular weight heparin was started.Seven days after the positive test,dyspnea,anosmia,and C-reactive protein increase(25 mg/L)were noted.Remdesivir was administered during 5 d in total.High stomal output was noted in two consecutive days and several days thereafter.To exclude infection or rejection,an ileoscopy and biopsy were performed and excluded these.Four weeks later,she was discharged from the hospital and remains in good health since then.CONCLUSION Early eradication of severe acute respiratory syndrome coronavirus 2 in ITx recipients may be warranted to prevent acute rejection provocation by it.

Effects of L-arginine on serum nitric oxide, nitric oxide synthase and mucosal Na^+-K^+-ATPase and nitric oxide synthase activity in segmental small-bowel autotransplantation model

AIM:To explore a simple method to create intestinal autotransplantation in rats and growing pigs and to investigate the effect of L-arginine supplementation on serum nitric oxide (NO), nitric oxide synthase (NOS) and intestinal mucosal NOS and Na+-K+-ATPase activity during cold ischemia-reperfusion (IR) in growing pigs. METHODS: In adult Wistar rat models of small bowel autotransplantation, a fine tube was inserted into mesenteric artery via the abdominal aorta. The superior mesenteric artery and vein were occluded. Isolated terminal ileum segment was irrigated with Ringer's solution at 4℃ and preserved in the same solution at 0-4℃ for 60 min. Then, the tube was removed and reperfusion was established. In growing pig models, a terminal ileum segment, 50 cm in length, was isolated and its mesenteric artery was irrigated via a needle with lactated Ringer's solution at 4℃. The method and period of cold preservation and reperfusion were described above. Ten white outbred pigs were randomly divided into control group and experimental group. L-arginine (150 mg/kg) was continuously infused for 15 min before reperfusion and for 30 min after reperfusion in the experimental group. One, 24, 48, and 72 h after reperfusion, peripheral vein blood was respectively collected for NO and NOS determination. At the same time point, intestinal mucosae were also obtained for NOS and Na+-K+-ATPase activity measurement. RESULTS: In adult rat models, 16 of 20 rats sustained the procedure, three died of hemorrhage shock and one of deep anesthesia. In growing pig models, the viability of small bowel graft remained for 72 h after cold IR in eight of 10 pigs. In experimental group, serum NO level at 1 and 24 h after reperfusion increased significantly when compared with control group at the same time point (152.2±61.4μmol/L /s60.8±31.6μmol/L, t=2.802, P=0.02<0.05; 82.2±24.0μmol/L vs 54.0±24.3μmol/L, t=2.490, P=0.04<0.05). Serum NO level increased significantly at 1 h post-reperfusion when compared with the same group before cold IR, 24 and 48 h post-reperfusion (152.2±61.4μmol/L vs 75.6±16.2μmol/L,t=2.820, P=0.02<0.05,82.2±24.0μmol/L,t=2.760, P= 0.03<0.05, 74.2±21.9μmol/L, t=2.822, P= 0.02<0.05). Serum NOS activity at each time point had no significant difference between two groups. In experimental group, intestinal mucosal NOS activity at 1 h post-reperfusion reduced significantly when compared with pre-cold IR (0.79±0.04 U/mg vs 0.46±0.12 U/mg, t = 3.460, P= 0.009<0.01). Mucosal NOS activity at 24, 48, and 72 h post-reperfusion also reduced significantly when compared with pre-cold IR (0.79±0.04 U/mg vs 0.57±0.14 U/mg, t= 2.380, P=0.04 <0.05, 0.61±0.11 U/mg, t= 2.309, P = 0.04<0.05, 0.63±0.12U/mg, t = 2.307, P= 0.04<0.05). In control group, mucosal NOS activity at 1 and 24 h post-reperfusion was significantly lower than that in pre-cold IR (0.72±0.12 U/mg vs 0.60±0.07 U/mg, t= 2.320, P= 0.04<0.05, 0.58±0.18 U/mg, t=2.310, P= 0.04<0.05). When compared to the normal value, Na+-K+-ATPase activity increased significantly at 48 and 72 h post-reperfusion in experimental group (2.48±0.59μmol/mg vs 3.89±1.43μmol/mg, t=3.202, P= 0.04<0.05, 3.96±0.86μmol/mg, t=3.401, P= 0.009 <0.01) and control group (2.48±0.59μmol/mg vs 3.58±0.76 μmol/mg, t=2.489, P= 0.04<0.05, 3.67±0.81μmol/mg, t= 2.542, P= 0.03<0.05). CONCLUSION: This novel technique for intestinal autotransplantation provides a potentially consistent and practical model for experimental studies of graft cold preservation. L-arginine supplementation during cold IR may act as a useful adjunct to preserve the grafted intestine.

Endoscopic monitoring in small bowel transplantation

AIM To investigate the role of endoscopic monitoring in small bowel transplantation. METHODS This study consisted of two parts: the experimental study and clinical study. In the experimental study, white outbred pigs underwent segmental small bowel allotransplantation. The proximal and distal intestine were brought out as stomas (Thiry Vella loop). The grafts, treated with or without immunosuppression, were monitored by endoscopy via stomas. In the clinical study, a female patient with short bowel syndrome received whole small bowel allotransplantation. The graft was monitored by endoscopy via distal stoma. RESULTS The most common endoscopic findings of graft rejection following small bowel allotransplantation were mucosal erythema, erosion and ulceration. Diffuse ulceration with bleeding was seen in late phase of rejection. CONCLUSION Endoscopic monitoring is essential to small bowel transplantation.

From portal to splanchnic venous thrombosis:What surgeons should bear in mind

The present study aims to review the evolution of surgical management of portal(PVT) and splanch-nic venous thrombosis(SVT) in the context of liver transplantation over the last 5 decades. PVT is more commonly managed by endovenous thrombectomy, while SVT requires more complex technical expedients. Several surgical techniques have been proposed, such as extensive eversion thrombectomy, anastomosis to collateral veins, reno-portal anastomosis, cavo-portal hemi-transposition, portal arterialization and combined liver-intestinal transplantation. In order to achieve satisfactory outcomes, careful planning of the surgical strategy is mandatory. The excellent results that are ob-tained nowadays confirm that, even extended, splanch-nic thrombosis is no longer an absolute contraindication for liver transplantation. Patients with advanced portal thrombosis may preferentially be referred to specialized centres, in which complex vascular approaches and even multivisceral transplantation are performed.

Concise review on short bowel syndrome: Etiology, pathophysiology, and management

Adults have approximately 20 feet of small intestine,which is the primary site for absorbing essential nutrients and water.Resection of the intestine for any medical reason may result in short bowel syndrome(SBS),leading to loss of major absorptive surface area and resulting in various malabsorption and motility disorders.The mainstay of treatment is personalized close dietary management.Here we present SBS with its pathophysiology and different nutritional management options available.The central perspective of this paper is to provide a concise review of SBS and the treatment options available,along with how proper nutrition can solve major dietary issues in SBS and help patients recover faster.

Sirolimus-related pulmonary toxicity mimicking 'asthma like' symptoms

Sirolimus is an immunosuppressant with expanding use in pediatric organ transplantation, dermatology and rheumatology. We report two cases of children who developed asthma like symptoms and were diagnosed with interstitial lung disease, which responded to discontinuation of sirolimus. Pediatricians should be aware about the pulmonary side effects of sirolimus.

Current status of intestinal and multivisceral transplantation

Clinical-nutritional autonomy is the ultimate goal of patients with intestinal failure(IF).Traditionally,patients with IF have been relegated to lifelong parenteral nutrition(PN)once surgical and medical rehabilitation attempts at intestinal adaptation have failed.Over the past two decades,however,outcome improvements in intestinal transplantation have added another dimension to the therapeutic armamentarium in the field of gut rehabilitation.This has become possible through relentless efforts in the standardization of surgical techniques,advancements in immunosuppressive therapies and induction protocols and improvement in postoperative patient care.Four types of intestinal transplants include isolated small bowel transplant,liver-small bowel transplant,multivisceral transplant and modified multivisceral transplant.Current guidelines restrict intestinal transplantation to patients who have had significant complications from PN including liver failure and repeated infections.From an experimental stage to the currently established therapeutic modality for patients with advanced IF,outcome improvements have also been possible due to the introduction of tacrolimus in the early 1990s.Studies have shown that intestinal transplant is cost-effective within 1–3 years of graft survival compared with PN.Improved survival and quality of life as well as resumption of an oral diet should enable intestinal transplantation to be an important option for patients with IF in addition to continued rehabilitation.Future research should focus on detecting biomarkers of early rejection,enhanced immunosuppression protocols,improved postoperative care and early referral to transplant centers.

Vascular reconstruction of segmental intestinal grafts using autologous internal iliac vessels

Background The aim of this study was to assess whether the autologous internal iliac artery and vein could be used as an interpositional graft for vascular reconstruction in segmental intestinal allografts and autografts.Methods Thirty-four intestinal transplants(19 living-related allografts and 15 autografts)were conducted in our programs between January 2011 and January 2019.Patient characteristics,type of vascular reconstruction,and post-operative complications were reviewed.Results There were 20 males and 14 females with a median age of 35 years.Of 34 grafts,22(64.7%)(11 allografts and 11 autografts)were revascularized using the autologous internal iliac artery and vein for reconstruction.Vascular reconstruction on the back table took 2166min to complete.Both total operative time and cold ischemia time tended to be longer in the vascular-reconstruction group than in the direct-anastomosis group(5306226 vs 4406116 and 159649 vs 125666 min,respectively),but these differences were not significant.The incidence of vascular thrombosis tended to be higher in the direct-anastomosis group than in the vascular-reconstruction group(16.7%vs 0%,P=0.118).At a median follow-up of 36.9 months,no stenosis or pseudoaneurysms developed.In 19 allografts,acute rejection occurred in 4(21.1%)and chronic rejection occurred in 1(5.2%).Conclusions Our results indicate that the use of an autologous internal iliac interposition graft greatly facilitates intestinal graft implantation and minimizes the risk of vascular complications.